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Two national analyses confirm safety of 9vHPV vaccine
most of which cannot be definitively tied to the vaccine, according to two large studies published simultaneously in Pediatrics.
“The body of evidence on the safety of 9vHPV now includes prelicensure clinical trial data on 15,000 study subjects, reassuring results from postlicensure near real-time sequential monitoring by the Centers for Disease Control and Prevention’s Vaccine Safety Datalink, on approximately 839 000 doses administered, and our review of VAERS [Vaccine Adverse Event Reporting System] reports over a 3-year period, during which time approximately 28 million doses were distributed in the United States,” Tom T. Shimabukuro, MD, and colleagues reported in Pediatrics.
James G. Donahue, PhD, and colleagues, authors of the Vaccine Safety Datalink study published in the same issue, concluded much the same thing.
The new numbers bolster extant safety data on the vaccine, which was approved in 2015, wrote Dr. Donahue, an epidemiologist at the Marshfield (Wis.) Clinic Research Institute, and coauthors. “With this large observational study, we contribute reassuring postlicensure data that will help bolster the safety profile of 9vHPV. Although we detected several unexpected potential safety signals, none were confirmed after further evaluation.”
The Vaccine Safety Datalink study of 838,991 doses looked for safety signals in a prespecified group of potential events, including anaphylaxis, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, pancreatitis, seizures, stroke, and venous thromboembolism.
Dr. Donahue and coauthors used real-time vaccination data and time-matched historical controls to evaluate any changes in expected disease rates, compared with those occurring in vaccine recipients.
Most doses in the study (76%) were given to children aged 9-17 years, with 48% going to girls. The remaining 24% of doses were given to persons aged 18-26 years, with 64% going to women.
The analysis found potential safety signals in allergic reactions (43 cases), appendicitis (30 cases), pancreatitis (8 cases), and syncope (67). None of these were confirmed after further investigation.
“The safety profile of 9vHPV is favorable and comparable to that of its predecessor, 4vHPV,” Dr. Donahue and associates concluded.
The VAERS analysis was similarly reassuring. It examined all reported adverse events, not predetermined events.
Among 28 million doses, there were 7,244 adverse event reports – a rate of about 1 event per 7 million doses. Of these, 97% were nonserious, wrote Dr. Shimabukuro, deputy director of the CDC’s Immunization Safety Office, and colleagues.
The vaccine manufacturer submitted 64% of these to VAERS; health care providers submitted 27%. Adverse events were reported from postvaccine day 0 to 2 years afterward. 9vHPV was the only vaccine given in 75% of reports. Coadministered vaccines included meningococcal conjugate (1,028); tetanus and diphtheria (Td) or Tdap (673); and hepatitis A (434).
There were nine reports of anaphylaxis (five males, four females); 9vHPV was the only vaccine administered in five cases. Three reports involved coadministration of meningococcal vaccine, two with hepatitis A, one with TDaP, and one with varicella.
There were eight reports of Guillain-Barré.
There were 17 reports of postural orthostatic tachycardia syndrome, most of which (71%) did not meet diagnostic criteria. Five cases, however, did.
One possible case of complex regional pain syndrome was reported in a 13-year-old girl with comorbid anxiety.
There were two reports of acute disseminated encephalomyelitis, both in boys. There were no reports of transverse myelitis or chronic inflammatory demyelinating polyneuropathy.
Seven vaccine recipients died after vaccination. Five of these reports did not contain medical information or any proof-of-death confirmation. The other two were verified by autopsy. A 14-year-old girl who received a flu vaccination with 9vHPV died of a thoracic aorta dissection 7 days postvaccination. The other death was a 16-year-old boy who received a concurrent hepatitis A vaccine. Four days later, he died of a cerebellar hemorrhage.
“We did not identify any unusual or unexpected safety concerns in our review of 9vHPV reports to the VAERS; most (97%) reports were nonserious, and adverse events were analogous to those observed in the prelicensure clinical trials,” Dr. Shimabukuro and associates concluded.
Neither Dr. Shimabukuro nor Dr. Donahue had financial disclosures. Dr. Donahue’s study was funded by the Centers for Disease Control and Prevention. One coauthor had ties to several pharmaceutical companies. Dr. Shimabukuro’s study had no external funding. One coauthor is employed by Merck, but was not at the time of the study.
SOURCES: Shimabukuro T et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1791; Donahue J et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1808.
most of which cannot be definitively tied to the vaccine, according to two large studies published simultaneously in Pediatrics.
“The body of evidence on the safety of 9vHPV now includes prelicensure clinical trial data on 15,000 study subjects, reassuring results from postlicensure near real-time sequential monitoring by the Centers for Disease Control and Prevention’s Vaccine Safety Datalink, on approximately 839 000 doses administered, and our review of VAERS [Vaccine Adverse Event Reporting System] reports over a 3-year period, during which time approximately 28 million doses were distributed in the United States,” Tom T. Shimabukuro, MD, and colleagues reported in Pediatrics.
James G. Donahue, PhD, and colleagues, authors of the Vaccine Safety Datalink study published in the same issue, concluded much the same thing.
The new numbers bolster extant safety data on the vaccine, which was approved in 2015, wrote Dr. Donahue, an epidemiologist at the Marshfield (Wis.) Clinic Research Institute, and coauthors. “With this large observational study, we contribute reassuring postlicensure data that will help bolster the safety profile of 9vHPV. Although we detected several unexpected potential safety signals, none were confirmed after further evaluation.”
The Vaccine Safety Datalink study of 838,991 doses looked for safety signals in a prespecified group of potential events, including anaphylaxis, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, pancreatitis, seizures, stroke, and venous thromboembolism.
Dr. Donahue and coauthors used real-time vaccination data and time-matched historical controls to evaluate any changes in expected disease rates, compared with those occurring in vaccine recipients.
Most doses in the study (76%) were given to children aged 9-17 years, with 48% going to girls. The remaining 24% of doses were given to persons aged 18-26 years, with 64% going to women.
The analysis found potential safety signals in allergic reactions (43 cases), appendicitis (30 cases), pancreatitis (8 cases), and syncope (67). None of these were confirmed after further investigation.
“The safety profile of 9vHPV is favorable and comparable to that of its predecessor, 4vHPV,” Dr. Donahue and associates concluded.
The VAERS analysis was similarly reassuring. It examined all reported adverse events, not predetermined events.
Among 28 million doses, there were 7,244 adverse event reports – a rate of about 1 event per 7 million doses. Of these, 97% were nonserious, wrote Dr. Shimabukuro, deputy director of the CDC’s Immunization Safety Office, and colleagues.
The vaccine manufacturer submitted 64% of these to VAERS; health care providers submitted 27%. Adverse events were reported from postvaccine day 0 to 2 years afterward. 9vHPV was the only vaccine given in 75% of reports. Coadministered vaccines included meningococcal conjugate (1,028); tetanus and diphtheria (Td) or Tdap (673); and hepatitis A (434).
There were nine reports of anaphylaxis (five males, four females); 9vHPV was the only vaccine administered in five cases. Three reports involved coadministration of meningococcal vaccine, two with hepatitis A, one with TDaP, and one with varicella.
There were eight reports of Guillain-Barré.
There were 17 reports of postural orthostatic tachycardia syndrome, most of which (71%) did not meet diagnostic criteria. Five cases, however, did.
One possible case of complex regional pain syndrome was reported in a 13-year-old girl with comorbid anxiety.
There were two reports of acute disseminated encephalomyelitis, both in boys. There were no reports of transverse myelitis or chronic inflammatory demyelinating polyneuropathy.
Seven vaccine recipients died after vaccination. Five of these reports did not contain medical information or any proof-of-death confirmation. The other two were verified by autopsy. A 14-year-old girl who received a flu vaccination with 9vHPV died of a thoracic aorta dissection 7 days postvaccination. The other death was a 16-year-old boy who received a concurrent hepatitis A vaccine. Four days later, he died of a cerebellar hemorrhage.
“We did not identify any unusual or unexpected safety concerns in our review of 9vHPV reports to the VAERS; most (97%) reports were nonserious, and adverse events were analogous to those observed in the prelicensure clinical trials,” Dr. Shimabukuro and associates concluded.
Neither Dr. Shimabukuro nor Dr. Donahue had financial disclosures. Dr. Donahue’s study was funded by the Centers for Disease Control and Prevention. One coauthor had ties to several pharmaceutical companies. Dr. Shimabukuro’s study had no external funding. One coauthor is employed by Merck, but was not at the time of the study.
SOURCES: Shimabukuro T et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1791; Donahue J et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1808.
most of which cannot be definitively tied to the vaccine, according to two large studies published simultaneously in Pediatrics.
“The body of evidence on the safety of 9vHPV now includes prelicensure clinical trial data on 15,000 study subjects, reassuring results from postlicensure near real-time sequential monitoring by the Centers for Disease Control and Prevention’s Vaccine Safety Datalink, on approximately 839 000 doses administered, and our review of VAERS [Vaccine Adverse Event Reporting System] reports over a 3-year period, during which time approximately 28 million doses were distributed in the United States,” Tom T. Shimabukuro, MD, and colleagues reported in Pediatrics.
James G. Donahue, PhD, and colleagues, authors of the Vaccine Safety Datalink study published in the same issue, concluded much the same thing.
The new numbers bolster extant safety data on the vaccine, which was approved in 2015, wrote Dr. Donahue, an epidemiologist at the Marshfield (Wis.) Clinic Research Institute, and coauthors. “With this large observational study, we contribute reassuring postlicensure data that will help bolster the safety profile of 9vHPV. Although we detected several unexpected potential safety signals, none were confirmed after further evaluation.”
The Vaccine Safety Datalink study of 838,991 doses looked for safety signals in a prespecified group of potential events, including anaphylaxis, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, pancreatitis, seizures, stroke, and venous thromboembolism.
Dr. Donahue and coauthors used real-time vaccination data and time-matched historical controls to evaluate any changes in expected disease rates, compared with those occurring in vaccine recipients.
Most doses in the study (76%) were given to children aged 9-17 years, with 48% going to girls. The remaining 24% of doses were given to persons aged 18-26 years, with 64% going to women.
The analysis found potential safety signals in allergic reactions (43 cases), appendicitis (30 cases), pancreatitis (8 cases), and syncope (67). None of these were confirmed after further investigation.
“The safety profile of 9vHPV is favorable and comparable to that of its predecessor, 4vHPV,” Dr. Donahue and associates concluded.
The VAERS analysis was similarly reassuring. It examined all reported adverse events, not predetermined events.
Among 28 million doses, there were 7,244 adverse event reports – a rate of about 1 event per 7 million doses. Of these, 97% were nonserious, wrote Dr. Shimabukuro, deputy director of the CDC’s Immunization Safety Office, and colleagues.
The vaccine manufacturer submitted 64% of these to VAERS; health care providers submitted 27%. Adverse events were reported from postvaccine day 0 to 2 years afterward. 9vHPV was the only vaccine given in 75% of reports. Coadministered vaccines included meningococcal conjugate (1,028); tetanus and diphtheria (Td) or Tdap (673); and hepatitis A (434).
There were nine reports of anaphylaxis (five males, four females); 9vHPV was the only vaccine administered in five cases. Three reports involved coadministration of meningococcal vaccine, two with hepatitis A, one with TDaP, and one with varicella.
There were eight reports of Guillain-Barré.
There were 17 reports of postural orthostatic tachycardia syndrome, most of which (71%) did not meet diagnostic criteria. Five cases, however, did.
One possible case of complex regional pain syndrome was reported in a 13-year-old girl with comorbid anxiety.
There were two reports of acute disseminated encephalomyelitis, both in boys. There were no reports of transverse myelitis or chronic inflammatory demyelinating polyneuropathy.
Seven vaccine recipients died after vaccination. Five of these reports did not contain medical information or any proof-of-death confirmation. The other two were verified by autopsy. A 14-year-old girl who received a flu vaccination with 9vHPV died of a thoracic aorta dissection 7 days postvaccination. The other death was a 16-year-old boy who received a concurrent hepatitis A vaccine. Four days later, he died of a cerebellar hemorrhage.
“We did not identify any unusual or unexpected safety concerns in our review of 9vHPV reports to the VAERS; most (97%) reports were nonserious, and adverse events were analogous to those observed in the prelicensure clinical trials,” Dr. Shimabukuro and associates concluded.
Neither Dr. Shimabukuro nor Dr. Donahue had financial disclosures. Dr. Donahue’s study was funded by the Centers for Disease Control and Prevention. One coauthor had ties to several pharmaceutical companies. Dr. Shimabukuro’s study had no external funding. One coauthor is employed by Merck, but was not at the time of the study.
SOURCES: Shimabukuro T et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1791; Donahue J et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1808.
FROM PEDIATRICS
Key clinical point: Postlicensure studies confirm the safety of the 9vHPV vaccine.
Major finding: The adverse event rate is 1 in 7 million doses. Most of these events were not definitively tied to the vaccine.
Study details: The two studies covered all doses given in the United States since vaccine approval in 2015.
Disclosures: Neither Dr. Shimabukuro nor Dr. Donahue had financial disclosures. Dr. Donahue’s study was funded by the Centers for Disease Control and Prevention. One coauthor on his study had ties to several pharmaceutical companies. Dr. Shimabukuro’s study had no external funding. One coauthor is employed by Merck, but was not at the time of the study.
Sources: Shimabukuro T et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1791; Donahue J et al. Pediatrics. 2019 Nov 1. doi: 10.1542/peds.2019-1808.
Alzheimer’s disease subtypes follow neuropathologic patterns seen in the nucleus basalis of Meynert
Cholinergic neurons in the nucleus basalis of Meynert appear more susceptible to neurofibrillary tangles and neuronal destruction in women, patients carrying the apolipoprotein E–epsilon 4 (APOE4) allele, and people with hippocampal-sparing Alzheimer’s disease, a subtype characterized by early onset and rapid cognitive decline.
Those findings and others from a postmortem study published in JAMA Neurology also suggests that the nucleus basalis of Meynert (nbM) could be the first place that neuronal damage appears in Alzheimer’s disease (AD), according to first author Fadi S. Hanna Al-Shaikh and colleagues.
The study also confirmed the authors’ previous categorization of three AD subtypes: early-onset, rapidly declining hippocampal-sparing AD (HpSp), typical sporadic AD, and limbic predominant AD, a later-onset form with a slower rate of decline.
“We observed a wave of vulnerability in which the exacerbation of nbM neurofibrillary tangles [NFTs] in HpSp AD may leave the cortex more vulnerable to [tangle] accumulation, perhaps via a biologically accelerated process or through a mechanism of disinhibition,” wrote Mr. Al-Shaikh, of the Mayo Clinic, Jacksonville, Fla., and colleagues. “By contrast, the limbic predominant AD cases had an exacerbation of areas vulnerable early in the Braak-like pattern of NFT accumulation, perhaps via a biologically restrictive process that relatively confines pathology to limbic areas.”
The nbM is of interest to researchers because 90% of its neurons are cholinergic with cortical penetration. “Postmortem studies of AD and more recent neuroimaging studies provide evidence that involvement of the nucleus basalis of Meynert may be critical and early in the molecular cascade of events,” the authors said. “The accumulation of NFTs in the nbM may precede entorhinal cortex and locus coeruleus involvement, making the nbM potentially one of the earliest sites where NFT accumulation occurs.”
Previously, this team had identified three AD subtypes based on patterns of corticolimbic neurofibrillary tangling. In HpSp, the hippocampus is relatively spared, while the cortex has a greater number of tangles. In limbic predominant AD, the cortex is relatively spared, and the hippocampus is severely involved. Typical AD shows the expected patterns of hippocampal and cortical tangling.
Cases in this study came from the Florida Autopsied Multi-Ethnic (FLAME) cohort, comprising 1,361 brain tissue samples from confirmed AD cases and 103 nondemented controls. The investigators sought to understand the patterns of neuronal demise in the nbM, and any associations with clinical signs, demographics, and the recently described three subtypes.
In the cohort, AD subtypes included 175 with HpSp, 1,014 with typical AD, and 172 with limbic predominant AD. Patients with HpSp were the youngest, with a median disease onset age of 65 years, compared with 71 years in typical AD and 78 in limbic predominant. There were fewer women in the HpSp group (35%), compared with the typical AD group (54%) and the limbic group (70%). More patients with HpSp had atypical presentation (38%) in comparison with typical (11%) and limbic predominant AD (2%). But patients with HpSp were less likely to be APOE4 positive (46%), whereas those with limbic predominant AD were most likely to be APOE4 positive (72%).
Cognitively, HpSp patients declined more rapidly, losing a median of 4 points per year on the Mini Mental State Exam (MMSE), compared with 2 and 1 points in those with typical and limbic predominant AD. At death, the HpSp patients had a median MMSE score of 7, versus 13 in the typical AD group and 18 in the limbic group.
Patients with HpSp had the highest concentration of tangles and the lowest neuronal density in the nbM. Limbic predominant cases had the lowest tangle burden and the highest neuronal density. Typical AD cases lay between these extremes on both measures.
A multivariate regression analysis determined the overlap of neuronal findings and AD subtypes. A younger age at symptom onset was significantly associated with higher tangle counts in the nbM regions among patients with HpSp. In women with typical AD, there were 2.5 times more tangles than in men. APOE4 carriers had 1.3 times more tangles than did noncarriers.
There were also associations with cognition. “For every 10-point decrease in final MMSE of typical AD cases, the number of nbM NFTs was expected to increase by 1.8,” the authors wrote.
Although limbic predominant AD wasn’t associated with any clinical or demographic variables in this analysis, it was associated with neuronal changes in the nbM. “For every 10 years’ younger age at onset, the number of neurons was expected to be lower by 4.6 [per mm2]. … In addition, limbic predominant cases were observed to have 4.3 [per mm2] fewer neurons for every 10-point decrease in MMSE,” the authors said.
This study was supported by the National Institute on Aging, the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program, a Gerstner Family Career Development Award, and the Alzheimer’s Association. Two authors reported financial relationships with industry outside the submitted work.
SOURCE: Al Shaikh FSH et al. JAMA Neurol. 2019 Oct 28. doi: 10.1001/jamaneurol.2019.3606.
Cholinergic neurons in the nucleus basalis of Meynert appear more susceptible to neurofibrillary tangles and neuronal destruction in women, patients carrying the apolipoprotein E–epsilon 4 (APOE4) allele, and people with hippocampal-sparing Alzheimer’s disease, a subtype characterized by early onset and rapid cognitive decline.
Those findings and others from a postmortem study published in JAMA Neurology also suggests that the nucleus basalis of Meynert (nbM) could be the first place that neuronal damage appears in Alzheimer’s disease (AD), according to first author Fadi S. Hanna Al-Shaikh and colleagues.
The study also confirmed the authors’ previous categorization of three AD subtypes: early-onset, rapidly declining hippocampal-sparing AD (HpSp), typical sporadic AD, and limbic predominant AD, a later-onset form with a slower rate of decline.
“We observed a wave of vulnerability in which the exacerbation of nbM neurofibrillary tangles [NFTs] in HpSp AD may leave the cortex more vulnerable to [tangle] accumulation, perhaps via a biologically accelerated process or through a mechanism of disinhibition,” wrote Mr. Al-Shaikh, of the Mayo Clinic, Jacksonville, Fla., and colleagues. “By contrast, the limbic predominant AD cases had an exacerbation of areas vulnerable early in the Braak-like pattern of NFT accumulation, perhaps via a biologically restrictive process that relatively confines pathology to limbic areas.”
The nbM is of interest to researchers because 90% of its neurons are cholinergic with cortical penetration. “Postmortem studies of AD and more recent neuroimaging studies provide evidence that involvement of the nucleus basalis of Meynert may be critical and early in the molecular cascade of events,” the authors said. “The accumulation of NFTs in the nbM may precede entorhinal cortex and locus coeruleus involvement, making the nbM potentially one of the earliest sites where NFT accumulation occurs.”
Previously, this team had identified three AD subtypes based on patterns of corticolimbic neurofibrillary tangling. In HpSp, the hippocampus is relatively spared, while the cortex has a greater number of tangles. In limbic predominant AD, the cortex is relatively spared, and the hippocampus is severely involved. Typical AD shows the expected patterns of hippocampal and cortical tangling.
Cases in this study came from the Florida Autopsied Multi-Ethnic (FLAME) cohort, comprising 1,361 brain tissue samples from confirmed AD cases and 103 nondemented controls. The investigators sought to understand the patterns of neuronal demise in the nbM, and any associations with clinical signs, demographics, and the recently described three subtypes.
In the cohort, AD subtypes included 175 with HpSp, 1,014 with typical AD, and 172 with limbic predominant AD. Patients with HpSp were the youngest, with a median disease onset age of 65 years, compared with 71 years in typical AD and 78 in limbic predominant. There were fewer women in the HpSp group (35%), compared with the typical AD group (54%) and the limbic group (70%). More patients with HpSp had atypical presentation (38%) in comparison with typical (11%) and limbic predominant AD (2%). But patients with HpSp were less likely to be APOE4 positive (46%), whereas those with limbic predominant AD were most likely to be APOE4 positive (72%).
Cognitively, HpSp patients declined more rapidly, losing a median of 4 points per year on the Mini Mental State Exam (MMSE), compared with 2 and 1 points in those with typical and limbic predominant AD. At death, the HpSp patients had a median MMSE score of 7, versus 13 in the typical AD group and 18 in the limbic group.
Patients with HpSp had the highest concentration of tangles and the lowest neuronal density in the nbM. Limbic predominant cases had the lowest tangle burden and the highest neuronal density. Typical AD cases lay between these extremes on both measures.
A multivariate regression analysis determined the overlap of neuronal findings and AD subtypes. A younger age at symptom onset was significantly associated with higher tangle counts in the nbM regions among patients with HpSp. In women with typical AD, there were 2.5 times more tangles than in men. APOE4 carriers had 1.3 times more tangles than did noncarriers.
There were also associations with cognition. “For every 10-point decrease in final MMSE of typical AD cases, the number of nbM NFTs was expected to increase by 1.8,” the authors wrote.
Although limbic predominant AD wasn’t associated with any clinical or demographic variables in this analysis, it was associated with neuronal changes in the nbM. “For every 10 years’ younger age at onset, the number of neurons was expected to be lower by 4.6 [per mm2]. … In addition, limbic predominant cases were observed to have 4.3 [per mm2] fewer neurons for every 10-point decrease in MMSE,” the authors said.
This study was supported by the National Institute on Aging, the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program, a Gerstner Family Career Development Award, and the Alzheimer’s Association. Two authors reported financial relationships with industry outside the submitted work.
SOURCE: Al Shaikh FSH et al. JAMA Neurol. 2019 Oct 28. doi: 10.1001/jamaneurol.2019.3606.
Cholinergic neurons in the nucleus basalis of Meynert appear more susceptible to neurofibrillary tangles and neuronal destruction in women, patients carrying the apolipoprotein E–epsilon 4 (APOE4) allele, and people with hippocampal-sparing Alzheimer’s disease, a subtype characterized by early onset and rapid cognitive decline.
Those findings and others from a postmortem study published in JAMA Neurology also suggests that the nucleus basalis of Meynert (nbM) could be the first place that neuronal damage appears in Alzheimer’s disease (AD), according to first author Fadi S. Hanna Al-Shaikh and colleagues.
The study also confirmed the authors’ previous categorization of three AD subtypes: early-onset, rapidly declining hippocampal-sparing AD (HpSp), typical sporadic AD, and limbic predominant AD, a later-onset form with a slower rate of decline.
“We observed a wave of vulnerability in which the exacerbation of nbM neurofibrillary tangles [NFTs] in HpSp AD may leave the cortex more vulnerable to [tangle] accumulation, perhaps via a biologically accelerated process or through a mechanism of disinhibition,” wrote Mr. Al-Shaikh, of the Mayo Clinic, Jacksonville, Fla., and colleagues. “By contrast, the limbic predominant AD cases had an exacerbation of areas vulnerable early in the Braak-like pattern of NFT accumulation, perhaps via a biologically restrictive process that relatively confines pathology to limbic areas.”
The nbM is of interest to researchers because 90% of its neurons are cholinergic with cortical penetration. “Postmortem studies of AD and more recent neuroimaging studies provide evidence that involvement of the nucleus basalis of Meynert may be critical and early in the molecular cascade of events,” the authors said. “The accumulation of NFTs in the nbM may precede entorhinal cortex and locus coeruleus involvement, making the nbM potentially one of the earliest sites where NFT accumulation occurs.”
Previously, this team had identified three AD subtypes based on patterns of corticolimbic neurofibrillary tangling. In HpSp, the hippocampus is relatively spared, while the cortex has a greater number of tangles. In limbic predominant AD, the cortex is relatively spared, and the hippocampus is severely involved. Typical AD shows the expected patterns of hippocampal and cortical tangling.
Cases in this study came from the Florida Autopsied Multi-Ethnic (FLAME) cohort, comprising 1,361 brain tissue samples from confirmed AD cases and 103 nondemented controls. The investigators sought to understand the patterns of neuronal demise in the nbM, and any associations with clinical signs, demographics, and the recently described three subtypes.
In the cohort, AD subtypes included 175 with HpSp, 1,014 with typical AD, and 172 with limbic predominant AD. Patients with HpSp were the youngest, with a median disease onset age of 65 years, compared with 71 years in typical AD and 78 in limbic predominant. There were fewer women in the HpSp group (35%), compared with the typical AD group (54%) and the limbic group (70%). More patients with HpSp had atypical presentation (38%) in comparison with typical (11%) and limbic predominant AD (2%). But patients with HpSp were less likely to be APOE4 positive (46%), whereas those with limbic predominant AD were most likely to be APOE4 positive (72%).
Cognitively, HpSp patients declined more rapidly, losing a median of 4 points per year on the Mini Mental State Exam (MMSE), compared with 2 and 1 points in those with typical and limbic predominant AD. At death, the HpSp patients had a median MMSE score of 7, versus 13 in the typical AD group and 18 in the limbic group.
Patients with HpSp had the highest concentration of tangles and the lowest neuronal density in the nbM. Limbic predominant cases had the lowest tangle burden and the highest neuronal density. Typical AD cases lay between these extremes on both measures.
A multivariate regression analysis determined the overlap of neuronal findings and AD subtypes. A younger age at symptom onset was significantly associated with higher tangle counts in the nbM regions among patients with HpSp. In women with typical AD, there were 2.5 times more tangles than in men. APOE4 carriers had 1.3 times more tangles than did noncarriers.
There were also associations with cognition. “For every 10-point decrease in final MMSE of typical AD cases, the number of nbM NFTs was expected to increase by 1.8,” the authors wrote.
Although limbic predominant AD wasn’t associated with any clinical or demographic variables in this analysis, it was associated with neuronal changes in the nbM. “For every 10 years’ younger age at onset, the number of neurons was expected to be lower by 4.6 [per mm2]. … In addition, limbic predominant cases were observed to have 4.3 [per mm2] fewer neurons for every 10-point decrease in MMSE,” the authors said.
This study was supported by the National Institute on Aging, the Florida Department of Health, the Ed and Ethel Moore Alzheimer’s Disease Research Program, a Gerstner Family Career Development Award, and the Alzheimer’s Association. Two authors reported financial relationships with industry outside the submitted work.
SOURCE: Al Shaikh FSH et al. JAMA Neurol. 2019 Oct 28. doi: 10.1001/jamaneurol.2019.3606.
FROM JAMA NEUROLOGY
Seaweed floats to the top of Alzheimer’s news
China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.
Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.
A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.
Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.
In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.
“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”
“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.
Preclinical findings on GV-971
In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.
“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”
Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.
Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.
The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.
First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.
Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.
After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.
“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”
The phase 3 study
The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.
Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.
Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.
But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.
“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”
He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”
Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.
“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”
Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.
China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.
Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.
A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.
Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.
In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.
“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”
“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.
Preclinical findings on GV-971
In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.
“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”
Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.
Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.
The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.
First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.
Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.
After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.
“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”
The phase 3 study
The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.
Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.
Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.
But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.
“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”
He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”
Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.
“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”
Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.
China’s National Medical Products Administration has approved a new therapy for patients with mild to moderate Alzheimer’s disease – a seaweed extract thought to alter the gut microbiome profile and subsequently decrease microbiome-driven neuroinflammation.
Sodium oligomannate – dubbed GV-971 – won approval based on a 36-week, placebo-controlled, phase 3 study of 818 patients with mild to moderate Alzheimer’s disease (AD). The study hit its primary endpoint of change on the Alzheimer’s Disease Assessment Scale cognitive portion (ADAS-cog12). It did not meet any of the trial’s other cognitive or functional secondary endpoints.
A portion of the data were presented last year at the Clinical Trials on Alzheimer’s Disease meeting in Barcelona. But the full study has never appeared in a peer-reviewed journal. A truncated version is publicly available on the website of Shanghai Green Valley Pharmaceuticals, the company developing the molecule.
Shanghai Green Valley contends that it reduces neuroinflammation by improving a proinflammatory microbiome profile that it says is characteristic of AD. However, the mechanism by which GV-971 alters intestinal bacterial composition is unclear – or at least it is not fully described in the public literature.
In the United States, some key researchers appraised the news with a cautiously optimistic eye, while others pointed noted that the AD-microbiome link is an unproven concept, and that it was evaluated in a study of questionable worth.
“The company has presented data that suggest there is a modest cognitive benefit to this treatment,” Paul S. Aisen, MD, said in an interview. “The key secondary endpoint was missed, and the other secondary endpoints showed no benefit. It’s a single trial and the mechanism is still unclear.”
“We do need to pursue all possible leads, and I’m glad the company is pursuing additional studies, but I wouldn’t draw a firm conclusion from these data. And they certainly would not be enough to win approval in the U.S.,” said Dr. Aisen, founding director Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.
Preclinical findings on GV-971
In commenting on preclinical findings of GV-971 published in Cell Research in September 2019, David Holtzman, MD, associate director of the Alzheimer’s disease research center at Washington University, St. Louis, and coauthors observed that the data support research exploring treatments that modulate the gut microbiome but leave it unclear as to whether GV-971 has AD-specific effects.
“[The company shows] that GV-971 decreases amyloid beta-related pathologies by reconditioning the gut microbiota, providing further evidence that gut-targeted interventions may serve as novel strategies to tackle AD,” Dr. Holtzman and coauthors wrote. “Whether this potential mechanism represents an AD-specific process is not clear, since there is great overlap in immunological changes and gut dysbiosis with other diseases. … In addition, although this study reveals that gut reconditioning may be one mechanism of action of the drug GV-971, it does not rule out other possible mechanisms. For example, GV-971 may attenuate AD pathogenesis by directly inhibiting neuroinflammation or amyloid-beta fibril formation. However, there is no question that [these] data further [support] the emerging idea that modulation of the gut microbiome via treatments such as GV-971 or other strategies should be further explored as novel strategies to slow the progression of AD.”
Sodium oligomannate is a long-chain saccharide extracted from brown sea algae and consists of acidic linear oligosaccharides with structures ranging from dimers to decamers. Related molecules without the sugar backbone were inactive, suggesting that the saccharides are the active portion, Xinyi Wang of Shanghai Green Valley and colleagues wrote in the Cell Research paper.
Based on these studies, the company contends that Alzheimer’s progression is accompanied by a characteristic microbiome change to a proinflammatory profile. And indeed, two transgenic Alzheimer’s mouse models – one with five familial AD mutations (5xFAD) and one with mutations of amyloid precursor protein and presenilin 1 (APP/PS1) – showed similar gradual age- and progression-related decreases of Bacteroides and Verrucomicrobia, two components of a normal microbiome. Bacteroides species perform key functions necessary for survival, including sensing and adapting to nutrient variability, expelling toxins, and stimulating the immune system). Species of the Verrucomicrobia phylum are important in glucose homeostasis. The decline in Bacteroides and Verrucomicrobia species is accompanied by an increase in concomitant proinflammatory species.
The investigators then explored the relationship between the microbiome composition and cognitive function in both transgenic models and a wild-type mouse.
First, they showed that the bacterial populations shifted as the mice aged and their AD pathology developed. This was accompanied by an uptick in activated microglia and, in turn, proinflammatory T1 helper cells that migrated through the intestinal membranes and into the periphery, then cross the blood-brain barrier to enter the brain.
Then the investigators used a cocktail of powerful antibiotics to disturb the intestinal flora in both transgenic and wild-type mice. After this, the 5xFAD mice showed fewer activated microglia and fewer infiltrating T cells. Later, they gave wild-type mice a fecal transplant from the 5xFAD mice. The wild-type mice developed more activated and infiltrating cells and their microbiome began to resemble that of the transgenic mice. Conversely, when the transgenic mice received a transplant from the wild-type mice, their microbiome changed to resemble the donors’, and their activated and infiltrating cells declined.
After this, the team gave GV-971 to the mice. The APP/PS1 mice improved cognitively, and the 5xFAD mice had fewer activated and infiltrating cells, fewer amyloid brain plaques, and less tau phosphorylation. These changes were accompanied by higher levels of two amino acids, phenylalanine and isoleucine. These proteins appear to act on T-cell proliferation and differentiation, they said.
“Taken together, these analyses suggest the idea that gut dysbiosis contributes to [phenylalanine and isoleucine] elevation, which drives the proliferation/differentiation and brain infiltration of [T1 helper] cells,” Dr. Holtzman and coauthors wrote. “These infiltrating Th1 cells may then further activate microglia and contribute to amyloid-related pathogenesis.”
The phase 3 study
The approval of GV-971 was based on the subsequent 36-week phase 3, placebo-controlled study of 818 patients with mild to moderate AD, which was reported last year. Patients were randomized to placebo or to GV-971 450 mg twice daily. Amyloid PET imaging was not required at entrance to the study, so there was no measure of baseline amyloid load. However, all patients showed MRI evidence of cortical atrophy. The Mini Mental State Exam (MMSE) ranged from 11 to 26, indicating mild to moderate AD.
Secondary endpoints included change on the Alzheimer’s Disease Cooperative Study Activities of Daily Living, the Clinician’s Interview-Based Impression of Change–Plus, and the Neuropsychiatric Index.
Patients taking GV-971 experienced a statistically significant 2.54-point difference on the ADAS-cog12, compared with placebo. The difference was apparent by week 4 and was seen at every clinical visit. When patients were grouped according to baseline MMSE (11-14, 15-19, and 20-26), the drug performed similarly.
But none of the secondary endpoints significantly favored of GV-971. And the placebo group behaved in an unexpected way, which could throw the data interpretation off-kilter somewhat, David Knopman, MD, said in an interview.
“It was a very weird and unusual-looking trajectory of the placebo and treated groups,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn., with those taking placebo staying relatively stable for some time before the cognitive scores dropped precipitously. “The data were unconvincing to me.”
He also pointed out that although the extensive preclinical data appeared in the recent peer-reviewed Cell Research paper, the phase 3 data has not appeared in any peer-reviewed forum, “even though the trial has been completed for some time now. Furthermore, the duration of the study was inadequate.”
Finally, none of the study subjects were taking the standard-of-care cholinesterase inhibitors, which virtually every AD patient in the United States does take.
“This makes it almost completely inapplicable to the U.S.,” he said. “It’s not bad news. I’m just not convinced.”
Dr. Holtzman is a cofounder of C2N Diagnostics. He is on the scientific advisory board of Genentech, Denali, and C2N Diagnostics. He consults for Idorsia. Dr. Knopman is a consultant for the Bluefield Project to Cure Frontotemporal Dementia and for Lundbeck.
Survey asks adults: How likely are you to develop dementia?
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
I do not find it surprising that older adults fear dementia. Since they correctly perceive that there is no disease-modifying therapy (and maybe also that “getting caught with memory loss” would lead to a loss of driving privileges and other restrictions), they may be trying not to focus on it. As for asking about strategies to “prevent” dementia, that question implies unwarranted optimism about the effectiveness of any such strategy, especially in an older adult. I think we can say that a lifetime of healthy habits (regular physical exercise and careful control of any chronic conditions like diabetes being particularly important) may reduce our risk of dementia a bit, but the idea that anything a 75-year-old does is going to prevent it at that point is probably wishful thinking. Supplements and the like seem to have their own followers. It amazes me how many people suspect what they are taking probably does no good but they do it anyway out of blind hope. Sometimes we can talk them out of spending their money on such things – but not always.
Richard Caselli, MD, is associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Scottsdale, Ariz.
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
Donovan T. Maust, MD, and colleagues reported in a research letter published in JAMA Neurology.
More than half of study participants used crossword puzzles as a memory exercise, but only 5% said they spoke to their physician about how to reduce risk. Ironically, this lack of communication was also associated with buying unproven over-the-counter memory supplements, while still remaining ignorant of proven ways to head off dementia and other contributing chronic conditions, wrote Dr. Maust of the University of Michigan, Ann Arbor, and coauthors.
Their analysis of the Michigan National Poll on Healthy Aging found that close to half of respondents (48.5%) reported that they were at least somewhat likely to develop dementia. Another 4.2% thought dementia was “very likely” in their future.
The study comprised survey responses from 1,019 adults aged 50-64 years. Most rated their physical health either excellent (445 respondents) or good (413 respondents). Most also reported excellent or very good mental health (721 respondents); 234 reported good mental health. Many (678) were affluent, with annual incomes of $60,000 or higher. They tended to be well educated; only 337 were without at least some college education. More than half were white (753); there were 101 Hispanic respondents and 93 black respondents. Other groups made up the remainder.
A multivariate analysis found that black respondents were about half as likely to believe they would develop dementia, compared with whites – an assumption contrary to epidemiologic findings that blacks are more likely than whites to develop dementia.
People who reported fair or poor mental health were more than twice as likely to feel dementia was in their future (odds ratio, 2.3). But fair or poor physical health was not significantly associated with that concern.
“Those with fair to poor physical health did not accurately perceive that their likelihood of developing dementia was potentially higher than respondents with very good or excellent physical health,” the authors wrote. “In contrast, fair to poor mental health had the largest association with perceived likelihood of dementia, even though less evidence suggests that poor mental health is causally linked with dementia.”
Despite the concerns, just 5% of respondents said that they had spoken to their physician. Those who believed they had a high likelihood of dementia were more likely to talk with their clinician (7.1%) than those who believed they had a low risk (3.6%).
Many more, however, were using non–evidence-based compounds touted as memory supporting. These included fish oil or omega-3 fatty acids (31.6%) and vitamins or supplements (32.9%). Crossword puzzles were a very popular prevention strategy, employed by about 55% in both belief groups.
“While managing chronic medical conditions, such as diabetes or cardiovascular disease, could reduce dementia risk, few respondents appear to have discussed this with their physician. Given repeated failures of disease-preventing or disease-modifying treatments for dementia, interest in treatment and prevention has shifted earlier in the disease process. Adults in middle age may not accurately estimate their risk of developing dementia, which could lead to both overuse and underuse if preclinical dementia treatments become available. Policy and physicians should emphasize current evidence-based strategies of managing lifestyle and chronic medical conditions to reduce the risk of dementia,” the investigators wrote.
Dr. Maust had no financial disclosures.
SOURCE: Maust D et al. JAMA Neurol. 2019 Nov 15. doi: 10.1001/jamaneurol.2019.3946
FROM JAMA NEUROLOGY
Bempedoic acid cuts LDL by 15% in patients already on maximal treatment
When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.
The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).
The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.
The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.
The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.
After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)
Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).
Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.
Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.
Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.
New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.
In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.
Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.
SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.
Bempedoic acid may fill a niche for patients who don’t experience sufficient LDL cholesterol (LDL-C) reductions despite maximally tolerated statin treatment, Michael C. Honigberg, MD,and Pradeep Natarajan, MD, wrote in an accompany editorial.
“Given encouraging results from clinical trials, nonstatin LDL-C–lowering medicines are now guideline-recommended when the degree of LDL-C lowering attained by maximally tolerated statins is deemed insufficient,” they wrote (JAMA. 2019 Nov 12;322:1769-71).
However, other drugs in this category are available and have already been incorporated into practice. In view of this trend, the role of bempedoic acid is not yet clear. The picture may come more into focus in 2022, when the results of the related CLEAR Outcomes trial are reported. CLEAR Outcomes will assess how much bempedoic acid reduces cardiovascular risk in 12,600 patients.
“Given the results from all CLEAR trials for LDL-C–lowering efficacy and safety, should bempedoic acid similarly be used in clinical practice before results from CLEAR Outcomes are reported? If so, with the availability of several LDL-C–lowering agents, when should patients and their physicians consider bempedoic acid?”
One factor could be the increasing effort to reduce LDL cholesterol even further than the current target. In 2013, the American College of Cardiology/American Heart Association endorsed high-potency statins for the secondary prevention of atherosclerotic cardiovascular disease, with a target LDL cholesterol reduction of more than 50%. But recently, an even greater target reduction has been advised.
“Without an obvious ‘floor’ of efficacy or safety, the ... guidelines extended prior recommendations by establishing an LDL-C goal of less than 70 mg/dL for secondary prevention for individuals at very high risk of future [atherosclerotic cardiovascular disease] events. The 2018 guidelines now support the use of nonstatin LDL-C–lowering medicines, specifically ezetimibe, alirocumab, and evolocumab, to further reduce LDL-C levels as necessary among such very-high-risk individuals. ... The next few years will see results from trials of additional nonstatin LDL-C–reducing agents. After focusing the last three decades exclusively on statins, the increasingly diverse options to attain maximally tolerated LDL-C reduction are welcome additions for management of high-risk patients.”
Dr Natarajan and Dr. Honiberg are both from the Massachusetts General Hospital, Boston. Dr. Natarajan reported receiving research grant support from Amgen, Apple, and Boston Scientific and serving as a scientific adviser to Apple and Blackstone LifeSciences, all unrelated to the present work. Dr Honigberg reported no disclosure
Bempedoic acid may fill a niche for patients who don’t experience sufficient LDL cholesterol (LDL-C) reductions despite maximally tolerated statin treatment, Michael C. Honigberg, MD,and Pradeep Natarajan, MD, wrote in an accompany editorial.
“Given encouraging results from clinical trials, nonstatin LDL-C–lowering medicines are now guideline-recommended when the degree of LDL-C lowering attained by maximally tolerated statins is deemed insufficient,” they wrote (JAMA. 2019 Nov 12;322:1769-71).
However, other drugs in this category are available and have already been incorporated into practice. In view of this trend, the role of bempedoic acid is not yet clear. The picture may come more into focus in 2022, when the results of the related CLEAR Outcomes trial are reported. CLEAR Outcomes will assess how much bempedoic acid reduces cardiovascular risk in 12,600 patients.
“Given the results from all CLEAR trials for LDL-C–lowering efficacy and safety, should bempedoic acid similarly be used in clinical practice before results from CLEAR Outcomes are reported? If so, with the availability of several LDL-C–lowering agents, when should patients and their physicians consider bempedoic acid?”
One factor could be the increasing effort to reduce LDL cholesterol even further than the current target. In 2013, the American College of Cardiology/American Heart Association endorsed high-potency statins for the secondary prevention of atherosclerotic cardiovascular disease, with a target LDL cholesterol reduction of more than 50%. But recently, an even greater target reduction has been advised.
“Without an obvious ‘floor’ of efficacy or safety, the ... guidelines extended prior recommendations by establishing an LDL-C goal of less than 70 mg/dL for secondary prevention for individuals at very high risk of future [atherosclerotic cardiovascular disease] events. The 2018 guidelines now support the use of nonstatin LDL-C–lowering medicines, specifically ezetimibe, alirocumab, and evolocumab, to further reduce LDL-C levels as necessary among such very-high-risk individuals. ... The next few years will see results from trials of additional nonstatin LDL-C–reducing agents. After focusing the last three decades exclusively on statins, the increasingly diverse options to attain maximally tolerated LDL-C reduction are welcome additions for management of high-risk patients.”
Dr Natarajan and Dr. Honiberg are both from the Massachusetts General Hospital, Boston. Dr. Natarajan reported receiving research grant support from Amgen, Apple, and Boston Scientific and serving as a scientific adviser to Apple and Blackstone LifeSciences, all unrelated to the present work. Dr Honigberg reported no disclosure
Bempedoic acid may fill a niche for patients who don’t experience sufficient LDL cholesterol (LDL-C) reductions despite maximally tolerated statin treatment, Michael C. Honigberg, MD,and Pradeep Natarajan, MD, wrote in an accompany editorial.
“Given encouraging results from clinical trials, nonstatin LDL-C–lowering medicines are now guideline-recommended when the degree of LDL-C lowering attained by maximally tolerated statins is deemed insufficient,” they wrote (JAMA. 2019 Nov 12;322:1769-71).
However, other drugs in this category are available and have already been incorporated into practice. In view of this trend, the role of bempedoic acid is not yet clear. The picture may come more into focus in 2022, when the results of the related CLEAR Outcomes trial are reported. CLEAR Outcomes will assess how much bempedoic acid reduces cardiovascular risk in 12,600 patients.
“Given the results from all CLEAR trials for LDL-C–lowering efficacy and safety, should bempedoic acid similarly be used in clinical practice before results from CLEAR Outcomes are reported? If so, with the availability of several LDL-C–lowering agents, when should patients and their physicians consider bempedoic acid?”
One factor could be the increasing effort to reduce LDL cholesterol even further than the current target. In 2013, the American College of Cardiology/American Heart Association endorsed high-potency statins for the secondary prevention of atherosclerotic cardiovascular disease, with a target LDL cholesterol reduction of more than 50%. But recently, an even greater target reduction has been advised.
“Without an obvious ‘floor’ of efficacy or safety, the ... guidelines extended prior recommendations by establishing an LDL-C goal of less than 70 mg/dL for secondary prevention for individuals at very high risk of future [atherosclerotic cardiovascular disease] events. The 2018 guidelines now support the use of nonstatin LDL-C–lowering medicines, specifically ezetimibe, alirocumab, and evolocumab, to further reduce LDL-C levels as necessary among such very-high-risk individuals. ... The next few years will see results from trials of additional nonstatin LDL-C–reducing agents. After focusing the last three decades exclusively on statins, the increasingly diverse options to attain maximally tolerated LDL-C reduction are welcome additions for management of high-risk patients.”
Dr Natarajan and Dr. Honiberg are both from the Massachusetts General Hospital, Boston. Dr. Natarajan reported receiving research grant support from Amgen, Apple, and Boston Scientific and serving as a scientific adviser to Apple and Blackstone LifeSciences, all unrelated to the present work. Dr Honigberg reported no disclosure
When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.
The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).
The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.
The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.
The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.
After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)
Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).
Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.
Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.
Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.
New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.
In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.
Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.
SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.
When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.
The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).
The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.
The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.
The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.
After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)
Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).
Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.
Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.
Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.
New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.
In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.
Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.
SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.
FROM JAMA
Observational secukinumab data reflect clinical trial results in patients with moderate to severe psoriasis
A in a report published in the Journal of the European Academy of Dermatology and Venereology.
“The safety profile of secukinumab was similar to that reported in previous clinical trials, and no new or unexpected safety signals were observed,” according to Diamant Thaci, MD, of the Comprehensive Centre of Inflammation Medicine, University of Lübeck (Germany) and coauthors. Moreover, effectiveness in those who started treatment with secukinumab at baseline, they added, “was comparable to that observed in Phase 3 trials. High levels of effectiveness were observed also in subjects who had received previous biologic therapies, although the response rates were numerically lower, as might be expected in a difficult to treat population. In addition, lower baseline PASI [Psoriasis Area and Severity Index] in patients with prior biologic treatment could also reduce the relative decrease in PASI observed over the course of the study.”
They reported on an interim analysis of the first 1,988 patients enrolled in the PROSPECT study, an observational 24-week study conducted in Germany; 1,323 patients completed the 24 week study; total cumulative exposure to secukinumab was 746.3 patient-years. Their mean baseline PASI was 17.7, slightly lower than those in typical clinical trials, and most (91%) had received systemic therapies before.
Almost half the patients (46%) experienced an adverse event during treatment, and about 4% experienced a serious adverse event; only 1% of serious adverse events were considered related to the study drug. About 7% discontinued treatment with secukinumab because of an adverse event. The most common reasons for discontinuation were lack of benefit in 2.4%, psoriasis in 2.3%, and upper respiratory tract viral infection in 0.5%.
The most common adverse events were nasopharyngitis (8.7%), pruritus (2.9%), and headache (2.4%). Rates of neoplastic disorders and major cerebrovascular events were similar to published data, with 5 patients (0.3%) experiencing a major adverse cardiovascular event and 10 (0.5%) experiencing a malignancy. Four patients (0.2%) developed inflammatory bowel disease, 42 (2.1%) developed Candida infection, 2 (0.1%) developed hepatotoxicity, and 11 (0.6%) an injection-site reaction. There were three deaths, determined not to be related to secukinumab, the authors wrote.
Efficacy was also similar to that observed in earlier studies, they noted, with positive results regardless of concomitant medication. Overall, 44% of the cohort used concomitant medications.
Of the 829 patients using concomitant topical treatments, 73% had started before baseline. In all, 110 patients were also using conventional systemic medications and phototherapy; 77 started treatment before baseline. The most commonly employed concomitant therapies were topical steroids and phototherapy.
Overall, most patients (86%) achieved a PASI 75 by week 24, with 68.5% achieving a PASI 90, and 40% achieving a PASI 100 at that time point.
Secukinumab was most effective among the 83 patients who were naive to systemic therapies; in these patients, results at week 24 were as follows: PASI 75, 93%; PASI 90, 84%; and PASI 100, 66%. Among patients who had previously received a biologic, scores were slightly lower: PASI 75, 78%; PASI 90, 55%; and PASI 100, 29%.
“These interim data from PROSPECT confirm the effectiveness and safety of secukinumab in the routine clinical setting, in a large cohort of psoriasis patients with high disease severity,” the investigators concluded.
Initially approved in the United States in 2015, secukinumab, an interleukin-17A antagonist, is indicated for treating moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis.
The study was funded by Novartis, Germany; four authors are employees of the company. Dr. Thaci has served as an investigator and/or consultant for multiple pharmaceutical companies, including Novartis, AbbVie, Amgen, Arena, Biogen Idec, Boehringer Ingelheim, and Celgene. Other authors also disclosed serving as investigators, consultants, and/or speakers for Novartis and other companies.
SOURCE: J Eur Acad Dermatol Venereol. 2019 Sep 21. doi: 10.1111/jdv.15962.
A in a report published in the Journal of the European Academy of Dermatology and Venereology.
“The safety profile of secukinumab was similar to that reported in previous clinical trials, and no new or unexpected safety signals were observed,” according to Diamant Thaci, MD, of the Comprehensive Centre of Inflammation Medicine, University of Lübeck (Germany) and coauthors. Moreover, effectiveness in those who started treatment with secukinumab at baseline, they added, “was comparable to that observed in Phase 3 trials. High levels of effectiveness were observed also in subjects who had received previous biologic therapies, although the response rates were numerically lower, as might be expected in a difficult to treat population. In addition, lower baseline PASI [Psoriasis Area and Severity Index] in patients with prior biologic treatment could also reduce the relative decrease in PASI observed over the course of the study.”
They reported on an interim analysis of the first 1,988 patients enrolled in the PROSPECT study, an observational 24-week study conducted in Germany; 1,323 patients completed the 24 week study; total cumulative exposure to secukinumab was 746.3 patient-years. Their mean baseline PASI was 17.7, slightly lower than those in typical clinical trials, and most (91%) had received systemic therapies before.
Almost half the patients (46%) experienced an adverse event during treatment, and about 4% experienced a serious adverse event; only 1% of serious adverse events were considered related to the study drug. About 7% discontinued treatment with secukinumab because of an adverse event. The most common reasons for discontinuation were lack of benefit in 2.4%, psoriasis in 2.3%, and upper respiratory tract viral infection in 0.5%.
The most common adverse events were nasopharyngitis (8.7%), pruritus (2.9%), and headache (2.4%). Rates of neoplastic disorders and major cerebrovascular events were similar to published data, with 5 patients (0.3%) experiencing a major adverse cardiovascular event and 10 (0.5%) experiencing a malignancy. Four patients (0.2%) developed inflammatory bowel disease, 42 (2.1%) developed Candida infection, 2 (0.1%) developed hepatotoxicity, and 11 (0.6%) an injection-site reaction. There were three deaths, determined not to be related to secukinumab, the authors wrote.
Efficacy was also similar to that observed in earlier studies, they noted, with positive results regardless of concomitant medication. Overall, 44% of the cohort used concomitant medications.
Of the 829 patients using concomitant topical treatments, 73% had started before baseline. In all, 110 patients were also using conventional systemic medications and phototherapy; 77 started treatment before baseline. The most commonly employed concomitant therapies were topical steroids and phototherapy.
Overall, most patients (86%) achieved a PASI 75 by week 24, with 68.5% achieving a PASI 90, and 40% achieving a PASI 100 at that time point.
Secukinumab was most effective among the 83 patients who were naive to systemic therapies; in these patients, results at week 24 were as follows: PASI 75, 93%; PASI 90, 84%; and PASI 100, 66%. Among patients who had previously received a biologic, scores were slightly lower: PASI 75, 78%; PASI 90, 55%; and PASI 100, 29%.
“These interim data from PROSPECT confirm the effectiveness and safety of secukinumab in the routine clinical setting, in a large cohort of psoriasis patients with high disease severity,” the investigators concluded.
Initially approved in the United States in 2015, secukinumab, an interleukin-17A antagonist, is indicated for treating moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis.
The study was funded by Novartis, Germany; four authors are employees of the company. Dr. Thaci has served as an investigator and/or consultant for multiple pharmaceutical companies, including Novartis, AbbVie, Amgen, Arena, Biogen Idec, Boehringer Ingelheim, and Celgene. Other authors also disclosed serving as investigators, consultants, and/or speakers for Novartis and other companies.
SOURCE: J Eur Acad Dermatol Venereol. 2019 Sep 21. doi: 10.1111/jdv.15962.
A in a report published in the Journal of the European Academy of Dermatology and Venereology.
“The safety profile of secukinumab was similar to that reported in previous clinical trials, and no new or unexpected safety signals were observed,” according to Diamant Thaci, MD, of the Comprehensive Centre of Inflammation Medicine, University of Lübeck (Germany) and coauthors. Moreover, effectiveness in those who started treatment with secukinumab at baseline, they added, “was comparable to that observed in Phase 3 trials. High levels of effectiveness were observed also in subjects who had received previous biologic therapies, although the response rates were numerically lower, as might be expected in a difficult to treat population. In addition, lower baseline PASI [Psoriasis Area and Severity Index] in patients with prior biologic treatment could also reduce the relative decrease in PASI observed over the course of the study.”
They reported on an interim analysis of the first 1,988 patients enrolled in the PROSPECT study, an observational 24-week study conducted in Germany; 1,323 patients completed the 24 week study; total cumulative exposure to secukinumab was 746.3 patient-years. Their mean baseline PASI was 17.7, slightly lower than those in typical clinical trials, and most (91%) had received systemic therapies before.
Almost half the patients (46%) experienced an adverse event during treatment, and about 4% experienced a serious adverse event; only 1% of serious adverse events were considered related to the study drug. About 7% discontinued treatment with secukinumab because of an adverse event. The most common reasons for discontinuation were lack of benefit in 2.4%, psoriasis in 2.3%, and upper respiratory tract viral infection in 0.5%.
The most common adverse events were nasopharyngitis (8.7%), pruritus (2.9%), and headache (2.4%). Rates of neoplastic disorders and major cerebrovascular events were similar to published data, with 5 patients (0.3%) experiencing a major adverse cardiovascular event and 10 (0.5%) experiencing a malignancy. Four patients (0.2%) developed inflammatory bowel disease, 42 (2.1%) developed Candida infection, 2 (0.1%) developed hepatotoxicity, and 11 (0.6%) an injection-site reaction. There were three deaths, determined not to be related to secukinumab, the authors wrote.
Efficacy was also similar to that observed in earlier studies, they noted, with positive results regardless of concomitant medication. Overall, 44% of the cohort used concomitant medications.
Of the 829 patients using concomitant topical treatments, 73% had started before baseline. In all, 110 patients were also using conventional systemic medications and phototherapy; 77 started treatment before baseline. The most commonly employed concomitant therapies were topical steroids and phototherapy.
Overall, most patients (86%) achieved a PASI 75 by week 24, with 68.5% achieving a PASI 90, and 40% achieving a PASI 100 at that time point.
Secukinumab was most effective among the 83 patients who were naive to systemic therapies; in these patients, results at week 24 were as follows: PASI 75, 93%; PASI 90, 84%; and PASI 100, 66%. Among patients who had previously received a biologic, scores were slightly lower: PASI 75, 78%; PASI 90, 55%; and PASI 100, 29%.
“These interim data from PROSPECT confirm the effectiveness and safety of secukinumab in the routine clinical setting, in a large cohort of psoriasis patients with high disease severity,” the investigators concluded.
Initially approved in the United States in 2015, secukinumab, an interleukin-17A antagonist, is indicated for treating moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, adults with psoriatic arthritis, and adults with active ankylosing spondylitis.
The study was funded by Novartis, Germany; four authors are employees of the company. Dr. Thaci has served as an investigator and/or consultant for multiple pharmaceutical companies, including Novartis, AbbVie, Amgen, Arena, Biogen Idec, Boehringer Ingelheim, and Celgene. Other authors also disclosed serving as investigators, consultants, and/or speakers for Novartis and other companies.
SOURCE: J Eur Acad Dermatol Venereol. 2019 Sep 21. doi: 10.1111/jdv.15962.
FROM THE JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
Lung cancer on the decline, but still higher among men than women
according to the Centers for Disease Control and Prevention.
From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.
Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”
The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.
In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).
Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).
There were different declines in different age groups by region, the authors noted.
Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).
Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.
Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.
There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).
Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.
Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.
“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”
However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”
SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.
according to the Centers for Disease Control and Prevention.
From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.
Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”
The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.
In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).
Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).
There were different declines in different age groups by region, the authors noted.
Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).
Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.
Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.
There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).
Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.
Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.
“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”
However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”
SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.
according to the Centers for Disease Control and Prevention.
From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.
Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”
The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.
In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).
Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).
There were different declines in different age groups by region, the authors noted.
Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).
Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.
Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.
There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).
Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.
Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.
“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”
However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”
SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.
FROM MMWR
Adverse childhood experiences increase the risk of poor long-term health
and societal outcomes, according to a new report by the Centers for Disease Control and Prevention.
“Our analysis suggests that preventing or reducing these adverse childhood experiences [ACEs] could potentially reduce the annual number of coronary heart disease cases by up to 13%,” said Ann Schuchat, MD, the CDC’s principal deputy director. “If we apply this analysis to other national disease estimates, preventing ACEs could prevent 1.9 million cases of heart disease, 2.5 million cases of overweight or obesity, 21 million cases of depression, and 1.5 million high-school incompletions.”
The analysis, conducted by Melissa T. Merrick, PhD, and colleagues at the National Center for Injury Prevention and Control at the CDC, Atlanta, is based on data acquired from more than 144,000 adults in 27 states.
It’s the first time the CDC has waded into this territory, Dr. Schuchat said during a press briefing. But a hard look into the data is long overdue. ACEs have been linked to at least 5 of the top 10 leading causes of death in the United States: heart disease, cancer, respiratory disease, diabetes, and suicide.
“It’s been proven that exposure to abuse, violence, and familial substance abuse and mental health problems can lead to health and social problems during the entire lifespan. Multiple exposures can produce toxic stress and chronic activation of the stress response system,” Dr. Schuchat continued. “Our report found that more than half of adults have experienced at least one type of ACE, and one in six adults has been exposed to four or more. The effects add up – the more types of ACE encountered, the higher the risk for negative outcomes that limit their entire lives.”
Dr. Merrick, a behavioral scientist with the CDC, and her team reviewed data collected from the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey of noninstitutionalized adults administered every year within each state. During the 2015-2017 data collection years, 27 states included questions about ACEs. The experiences included childhood exposure to three types of abuse (physical, emotional, and sexual) and five types of household challenges (household member substance misuse, incarceration, mental illness, parental divorce, or witnessing intimate partner violence) before age 18 years.
In all, 61% of respondents reported experiencing at least one of the events; 16% reported experiencing four or more. Women, Native Americans, Native Alaskans, and blacks were more likely to have these experiences than were men and whites.
A multivariate regression analysis found that adults with the highest level of ACE exposure had significantly elevated risks of several chronic health issues and social challenges, compared with nonexposed subjects. These included increased risk of overweight or obesity (adjusted odds ratio, 1.2), chronic obstructive pulmonary disease (aOR, 2.8), depression (aOR 5.3), smoking (aOR 3.1), heavy drinking (aOR 1.8), and underemployment (aOR 1.7), compared with adults reporting no ACEs.
Reducing ACE exposures could in turn reduce many of these challenges, especially among people with the highest number of exposures. Among this group, preventing all ACE exposure could cut overweight and obesity by up to 1.7%, chronic obstructive pulmonary disease by up to 27%, depression by up to 44%, smoking by up to 33%, and heavy drinking by 24%. Preventing ACE exposure also could reduce lack of health insurance by 4% and unemployment by 15%, the researchers said.
The good news, Dr. Merrick and associates said, is that ACE exposure can be at least partially offset by positive interactions with adults and in social and community settings.
“Prevention of adverse childhood experiences is possible with state and community efforts to build resilient families and communities, provide parental support to develop positive parenting and coping skills, and increase access to, and use of, comprehensive health services,” they said.
The CDC recommends a comprehensive approach to preventing ACEs and mitigating their impact. The data-driven suggestions include:
- Promoting family economic health, including tax credits and family-focused work policy.
- Endorsing programs to mitigate violence and adversity, including public education programs that support parents.
- Promoting early childhood development with high-quality child care and preschool programs.
- Recommending stress reduction skills for parents and young people, and programs that teach safe dating and healthy relationship skills.
- Supporting youth development by connecting youth to adult mentors and after-school programs.
- Encouraging clinicians to identify and address ACE exposure with screening, referral, and support.
“This is important for reducing the consequences of adverse childhood experiences and for helping to protect the next generation of children from exposure to violence and other adverse experiences, such as witnessing substance misuse in their household,” Dr. Merrick and associates said.
The researchers had no relevant financial disclosures.
SOURCE: Merrick M et al. MMWR. 2019 Nov 5. doi: 10.15585/mmwr.mm6844e1.
Adverse childhood experiences (ACEs) trigger pathophysiologic responses that exert real physical and psychological harm. Thus, clinicians can and should address them as part of good medical care, Christopher M. Jones, PharmD, Melissa T. Merrick, PhD, and Debra E. Houry, MD, MPH, said in a JAMA commentary.
“A large and growing body of research indicates that the underlying mechanism by which ACEs are associated with health outcomes is through the development of toxic stress, a chronic activation of the stress response system. Toxic stress results in dysregulation of the limbic-hypothalamic-pituitary-adrenal axis, elevating levels of catecholamines (“fight or flight” response), cortisol, and proinflammatory cytokines, leading to cascading effects on the nervous, endocrine, and immune systems. These changes can affect attention and other executive functioning, impulsive behavior, brain reward systems, decision-making, and response to stress throughout the life span,” they said.
While societies and communities at large must work together to reduce ACE exposure, clinicians also have a role. Research indicates that many don’t routinely ask questions about these issues, in a large part because they lack training in how and when to screen.
“Incorporating components of primary ACEs prevention into everyday clinical practice may be achievable through talking with parents and caregivers about creating safe, stable, nurturing environments and protective relationships, and reinforcing positive parenting techniques and coping skills at routine clinical visits,” the editorialists said. “In addition, clinicians can refer parents to parenting skills classes or refer higher-risk parents to home visitation programs such as Healthy Families America and Nurse-Family Partnership. Home visitation programs have demonstrated significant reductions in rates of child abuse and neglect and have improved substance use, violence, and parenting outcomes.”
Clinicians also may have a role to play in mitigating the harms of ACEs, by incorporating trauma-informed care and services into their daily practice.
“Important elements of trauma-informed care include understanding how trauma affects health, routinely screening for ACEs and trauma, using culturally responsive assessments, promoting resilience and protective factors, addressing trauma-related somatic and mental health issues, and ensuring appropriate linkage to services and supports for identified issues,” the editorialists concluded.
Dr. Jones is associate director in the Office of Strategy and Innovation in the CDC Injury Center. Dr. Merrick is president and CEO of Prevent Childhood Abuse America, Chicago. Dr. Houry is director of the National Center for Injury Prevention and Control at the CDC, Atlanta. They discussed the MMWR analysis in a commentary (JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.18499). They had no relevant financial disclosures.
Adverse childhood experiences (ACEs) trigger pathophysiologic responses that exert real physical and psychological harm. Thus, clinicians can and should address them as part of good medical care, Christopher M. Jones, PharmD, Melissa T. Merrick, PhD, and Debra E. Houry, MD, MPH, said in a JAMA commentary.
“A large and growing body of research indicates that the underlying mechanism by which ACEs are associated with health outcomes is through the development of toxic stress, a chronic activation of the stress response system. Toxic stress results in dysregulation of the limbic-hypothalamic-pituitary-adrenal axis, elevating levels of catecholamines (“fight or flight” response), cortisol, and proinflammatory cytokines, leading to cascading effects on the nervous, endocrine, and immune systems. These changes can affect attention and other executive functioning, impulsive behavior, brain reward systems, decision-making, and response to stress throughout the life span,” they said.
While societies and communities at large must work together to reduce ACE exposure, clinicians also have a role. Research indicates that many don’t routinely ask questions about these issues, in a large part because they lack training in how and when to screen.
“Incorporating components of primary ACEs prevention into everyday clinical practice may be achievable through talking with parents and caregivers about creating safe, stable, nurturing environments and protective relationships, and reinforcing positive parenting techniques and coping skills at routine clinical visits,” the editorialists said. “In addition, clinicians can refer parents to parenting skills classes or refer higher-risk parents to home visitation programs such as Healthy Families America and Nurse-Family Partnership. Home visitation programs have demonstrated significant reductions in rates of child abuse and neglect and have improved substance use, violence, and parenting outcomes.”
Clinicians also may have a role to play in mitigating the harms of ACEs, by incorporating trauma-informed care and services into their daily practice.
“Important elements of trauma-informed care include understanding how trauma affects health, routinely screening for ACEs and trauma, using culturally responsive assessments, promoting resilience and protective factors, addressing trauma-related somatic and mental health issues, and ensuring appropriate linkage to services and supports for identified issues,” the editorialists concluded.
Dr. Jones is associate director in the Office of Strategy and Innovation in the CDC Injury Center. Dr. Merrick is president and CEO of Prevent Childhood Abuse America, Chicago. Dr. Houry is director of the National Center for Injury Prevention and Control at the CDC, Atlanta. They discussed the MMWR analysis in a commentary (JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.18499). They had no relevant financial disclosures.
Adverse childhood experiences (ACEs) trigger pathophysiologic responses that exert real physical and psychological harm. Thus, clinicians can and should address them as part of good medical care, Christopher M. Jones, PharmD, Melissa T. Merrick, PhD, and Debra E. Houry, MD, MPH, said in a JAMA commentary.
“A large and growing body of research indicates that the underlying mechanism by which ACEs are associated with health outcomes is through the development of toxic stress, a chronic activation of the stress response system. Toxic stress results in dysregulation of the limbic-hypothalamic-pituitary-adrenal axis, elevating levels of catecholamines (“fight or flight” response), cortisol, and proinflammatory cytokines, leading to cascading effects on the nervous, endocrine, and immune systems. These changes can affect attention and other executive functioning, impulsive behavior, brain reward systems, decision-making, and response to stress throughout the life span,” they said.
While societies and communities at large must work together to reduce ACE exposure, clinicians also have a role. Research indicates that many don’t routinely ask questions about these issues, in a large part because they lack training in how and when to screen.
“Incorporating components of primary ACEs prevention into everyday clinical practice may be achievable through talking with parents and caregivers about creating safe, stable, nurturing environments and protective relationships, and reinforcing positive parenting techniques and coping skills at routine clinical visits,” the editorialists said. “In addition, clinicians can refer parents to parenting skills classes or refer higher-risk parents to home visitation programs such as Healthy Families America and Nurse-Family Partnership. Home visitation programs have demonstrated significant reductions in rates of child abuse and neglect and have improved substance use, violence, and parenting outcomes.”
Clinicians also may have a role to play in mitigating the harms of ACEs, by incorporating trauma-informed care and services into their daily practice.
“Important elements of trauma-informed care include understanding how trauma affects health, routinely screening for ACEs and trauma, using culturally responsive assessments, promoting resilience and protective factors, addressing trauma-related somatic and mental health issues, and ensuring appropriate linkage to services and supports for identified issues,” the editorialists concluded.
Dr. Jones is associate director in the Office of Strategy and Innovation in the CDC Injury Center. Dr. Merrick is president and CEO of Prevent Childhood Abuse America, Chicago. Dr. Houry is director of the National Center for Injury Prevention and Control at the CDC, Atlanta. They discussed the MMWR analysis in a commentary (JAMA. 2019 Nov 5. doi: 10.1001/jama.2019.18499). They had no relevant financial disclosures.
and societal outcomes, according to a new report by the Centers for Disease Control and Prevention.
“Our analysis suggests that preventing or reducing these adverse childhood experiences [ACEs] could potentially reduce the annual number of coronary heart disease cases by up to 13%,” said Ann Schuchat, MD, the CDC’s principal deputy director. “If we apply this analysis to other national disease estimates, preventing ACEs could prevent 1.9 million cases of heart disease, 2.5 million cases of overweight or obesity, 21 million cases of depression, and 1.5 million high-school incompletions.”
The analysis, conducted by Melissa T. Merrick, PhD, and colleagues at the National Center for Injury Prevention and Control at the CDC, Atlanta, is based on data acquired from more than 144,000 adults in 27 states.
It’s the first time the CDC has waded into this territory, Dr. Schuchat said during a press briefing. But a hard look into the data is long overdue. ACEs have been linked to at least 5 of the top 10 leading causes of death in the United States: heart disease, cancer, respiratory disease, diabetes, and suicide.
“It’s been proven that exposure to abuse, violence, and familial substance abuse and mental health problems can lead to health and social problems during the entire lifespan. Multiple exposures can produce toxic stress and chronic activation of the stress response system,” Dr. Schuchat continued. “Our report found that more than half of adults have experienced at least one type of ACE, and one in six adults has been exposed to four or more. The effects add up – the more types of ACE encountered, the higher the risk for negative outcomes that limit their entire lives.”
Dr. Merrick, a behavioral scientist with the CDC, and her team reviewed data collected from the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey of noninstitutionalized adults administered every year within each state. During the 2015-2017 data collection years, 27 states included questions about ACEs. The experiences included childhood exposure to three types of abuse (physical, emotional, and sexual) and five types of household challenges (household member substance misuse, incarceration, mental illness, parental divorce, or witnessing intimate partner violence) before age 18 years.
In all, 61% of respondents reported experiencing at least one of the events; 16% reported experiencing four or more. Women, Native Americans, Native Alaskans, and blacks were more likely to have these experiences than were men and whites.
A multivariate regression analysis found that adults with the highest level of ACE exposure had significantly elevated risks of several chronic health issues and social challenges, compared with nonexposed subjects. These included increased risk of overweight or obesity (adjusted odds ratio, 1.2), chronic obstructive pulmonary disease (aOR, 2.8), depression (aOR 5.3), smoking (aOR 3.1), heavy drinking (aOR 1.8), and underemployment (aOR 1.7), compared with adults reporting no ACEs.
Reducing ACE exposures could in turn reduce many of these challenges, especially among people with the highest number of exposures. Among this group, preventing all ACE exposure could cut overweight and obesity by up to 1.7%, chronic obstructive pulmonary disease by up to 27%, depression by up to 44%, smoking by up to 33%, and heavy drinking by 24%. Preventing ACE exposure also could reduce lack of health insurance by 4% and unemployment by 15%, the researchers said.
The good news, Dr. Merrick and associates said, is that ACE exposure can be at least partially offset by positive interactions with adults and in social and community settings.
“Prevention of adverse childhood experiences is possible with state and community efforts to build resilient families and communities, provide parental support to develop positive parenting and coping skills, and increase access to, and use of, comprehensive health services,” they said.
The CDC recommends a comprehensive approach to preventing ACEs and mitigating their impact. The data-driven suggestions include:
- Promoting family economic health, including tax credits and family-focused work policy.
- Endorsing programs to mitigate violence and adversity, including public education programs that support parents.
- Promoting early childhood development with high-quality child care and preschool programs.
- Recommending stress reduction skills for parents and young people, and programs that teach safe dating and healthy relationship skills.
- Supporting youth development by connecting youth to adult mentors and after-school programs.
- Encouraging clinicians to identify and address ACE exposure with screening, referral, and support.
“This is important for reducing the consequences of adverse childhood experiences and for helping to protect the next generation of children from exposure to violence and other adverse experiences, such as witnessing substance misuse in their household,” Dr. Merrick and associates said.
The researchers had no relevant financial disclosures.
SOURCE: Merrick M et al. MMWR. 2019 Nov 5. doi: 10.15585/mmwr.mm6844e1.
and societal outcomes, according to a new report by the Centers for Disease Control and Prevention.
“Our analysis suggests that preventing or reducing these adverse childhood experiences [ACEs] could potentially reduce the annual number of coronary heart disease cases by up to 13%,” said Ann Schuchat, MD, the CDC’s principal deputy director. “If we apply this analysis to other national disease estimates, preventing ACEs could prevent 1.9 million cases of heart disease, 2.5 million cases of overweight or obesity, 21 million cases of depression, and 1.5 million high-school incompletions.”
The analysis, conducted by Melissa T. Merrick, PhD, and colleagues at the National Center for Injury Prevention and Control at the CDC, Atlanta, is based on data acquired from more than 144,000 adults in 27 states.
It’s the first time the CDC has waded into this territory, Dr. Schuchat said during a press briefing. But a hard look into the data is long overdue. ACEs have been linked to at least 5 of the top 10 leading causes of death in the United States: heart disease, cancer, respiratory disease, diabetes, and suicide.
“It’s been proven that exposure to abuse, violence, and familial substance abuse and mental health problems can lead to health and social problems during the entire lifespan. Multiple exposures can produce toxic stress and chronic activation of the stress response system,” Dr. Schuchat continued. “Our report found that more than half of adults have experienced at least one type of ACE, and one in six adults has been exposed to four or more. The effects add up – the more types of ACE encountered, the higher the risk for negative outcomes that limit their entire lives.”
Dr. Merrick, a behavioral scientist with the CDC, and her team reviewed data collected from the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey of noninstitutionalized adults administered every year within each state. During the 2015-2017 data collection years, 27 states included questions about ACEs. The experiences included childhood exposure to three types of abuse (physical, emotional, and sexual) and five types of household challenges (household member substance misuse, incarceration, mental illness, parental divorce, or witnessing intimate partner violence) before age 18 years.
In all, 61% of respondents reported experiencing at least one of the events; 16% reported experiencing four or more. Women, Native Americans, Native Alaskans, and blacks were more likely to have these experiences than were men and whites.
A multivariate regression analysis found that adults with the highest level of ACE exposure had significantly elevated risks of several chronic health issues and social challenges, compared with nonexposed subjects. These included increased risk of overweight or obesity (adjusted odds ratio, 1.2), chronic obstructive pulmonary disease (aOR, 2.8), depression (aOR 5.3), smoking (aOR 3.1), heavy drinking (aOR 1.8), and underemployment (aOR 1.7), compared with adults reporting no ACEs.
Reducing ACE exposures could in turn reduce many of these challenges, especially among people with the highest number of exposures. Among this group, preventing all ACE exposure could cut overweight and obesity by up to 1.7%, chronic obstructive pulmonary disease by up to 27%, depression by up to 44%, smoking by up to 33%, and heavy drinking by 24%. Preventing ACE exposure also could reduce lack of health insurance by 4% and unemployment by 15%, the researchers said.
The good news, Dr. Merrick and associates said, is that ACE exposure can be at least partially offset by positive interactions with adults and in social and community settings.
“Prevention of adverse childhood experiences is possible with state and community efforts to build resilient families and communities, provide parental support to develop positive parenting and coping skills, and increase access to, and use of, comprehensive health services,” they said.
The CDC recommends a comprehensive approach to preventing ACEs and mitigating their impact. The data-driven suggestions include:
- Promoting family economic health, including tax credits and family-focused work policy.
- Endorsing programs to mitigate violence and adversity, including public education programs that support parents.
- Promoting early childhood development with high-quality child care and preschool programs.
- Recommending stress reduction skills for parents and young people, and programs that teach safe dating and healthy relationship skills.
- Supporting youth development by connecting youth to adult mentors and after-school programs.
- Encouraging clinicians to identify and address ACE exposure with screening, referral, and support.
“This is important for reducing the consequences of adverse childhood experiences and for helping to protect the next generation of children from exposure to violence and other adverse experiences, such as witnessing substance misuse in their household,” Dr. Merrick and associates said.
The researchers had no relevant financial disclosures.
SOURCE: Merrick M et al. MMWR. 2019 Nov 5. doi: 10.15585/mmwr.mm6844e1.
FROM MMWR
ACP: Low-risk adults aged 50-75 should undergo regular screening for colorectal cancer
issued by the American College of Physicians.
Regular screening can be discontinued after age 75 years, Amir Qaseem, MD, president of clinical policy and the Center for Evidence Reviews at the American College of Physicians, and colleagues wrote in the Annals of Internal Medicine.
No one test is preferred over another, according to the guidance statement. Patients and physicians can select the test type together, based on individual needs and preferences, and each test carries its own screening interval. But regular testing has been proven time and again to reduce the risk of colorectal cancer mortality, and more people should have it, according to the guidance.
“Not enough people in the United States get screened for colorectal cancer,” ACP President Robert M. McLean, MD, said in a press statement. “Physicians should perform an individualized risk assessment for colorectal cancer in all adults. Doctors and patients should select the screening test based on a discussion of the benefits, harms, costs, availability, frequency, and patient preferences.”
The guidance is an attempt to balance existing guidelines authored by the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care (CTFPHC), but it also was developed following critical review of those from the American Cancer Society and other organizations.
The ACP guidance is for adults at average risk for colorectal cancer who do not have symptoms; it does not apply to adults with a family history of colorectal cancer, a long-standing history of inflammatory bowel disease, genetic syndromes such as familial cancerous polyps, a personal history of previous colorectal cancer or benign polyps, or other risk factors.
The guidance was based on evaluations of stool-based tests, including the fecal immunochemical test (FIT), also called the immunochemical-based fecal occult blood test (FOBT), and direct visualization with endoscopic and radiologic tests, including flexible sigmoidoscopy, colonoscopy, and CT colonography. The guidance includes the following recommendations:
Clinicians should regularly screen for colorectal cancer in average-risk adults between the ages of 50 and 75 years.
This recommendation is in line with those made by the U.S. Preventive Services Task Force and the CTFPHC. Data suggest that regular screening reduces colorectal cancer–specific mortality in this age group, with those aged 65-75 years likely to garner the most benefit.
The absolute risk reduction increases with age and varies with test type. For every-other-year FOBT, it rises from 0.037% in those younger than 60 years to 0.20% in those aged 60 years or older. For flexible sigmoidoscopy, the risk reduction rises from 0.05% in the younger group to 0.29% in the older group.
Data from the CTFPHC show that the net benefit in those aged 50-59 years is small, however. This may influence the decision about when to start screening.
Clinicians should select the colorectal cancer screening test with the patient based on a discussion of benefits, harms, costs, availability, frequency, and patient preferences.
The FIT or FOBT should be performed every 2 years, colonoscopy every 10 years, and flexible sigmoidoscopy every 10 years, plus FIT every 2 years.
No data suggest a benefit of one test over another; however, “all screening tests are associated with potential benefits as well as harms,” the document states. “Clinical decisions need to be individualized using patient clinical characteristics, patient preferences, and screening test frequency and availability. Because many eligible patients have never been screened and some may not adhere to recommendations about subsequent screening or follow-up of positive findings on screening tests (such as colonoscopy after a positive result on a stool-based screening test), patient informed decision making and adherence are important factors in selection of a [colorectal cancer] screening test.”
Discussions with patients should include topics like the recommended frequency of each test, bowel preparation, anesthesia, transportation to and from testing site, time commitments, and the necessary steps if a test result is positive.
Clinicians should discontinue screening for colorectal cancer in average-risk adults older than 75 years or in adults with a life expectancy of 10 years or less.
While the benefit from screening increases with age, so do the risks for harm, especially serious harm. Data show the balance of harms and benefits reaching a tipping point at around 75 years of age. But again, this isn’t a universal recommendation, the statement says.
“Persons with no history of [colorectal cancer] screening may benefit from screening after age 75 years, whereas those who have received regular screening with negative results may not.”
Cessation of testing considers life expectancy after age 75 years. The average life expectancy for healthy 75-year-old men and women in the United States is 9.9 and 12 years, respectively. But among men and women with serious medical comorbidities, average life expectancy after age 70 years drops to 8.9 and 10.8 years, respectively.
“Therefore, most persons aged 75 years or older, as well as most adults who are younger than 75 years but have serious comorbid conditions [such as chronic renal failure], are unlikely to benefit from screening but would undergo unnecessary, burdensome, potentially harmful, and costly screening tests.”
As in any testing discussion, personal preferences are important, but not just to make patients feel comfortable about their choice. Mindset about colorectal cancer testing has a very big effect on compliance, the statement noted.
“For example, a biennial stool test is not a good screening strategy for patients who may be unwilling or unlikely to follow up every other year. In addition, given the tradeoffs between benefits and harms, some patients may want less intensive screening, such as screening that begins at a later age, stops at an earlier age, or recurs less frequently regardless of modality selected.”
SOURCE: Qassam A et al. Ann Intern Med. 2019;171:643-54.
Cost-effectiveness is one more factor in the colorectal screening discussion, Michael Pignone, MD, said in an accompanying editorial.
Two studies by Ladabaum et al. reported cost-effectiveness modeling for various CRC screening techniques: “Comparative effectiveness and cost effectiveness of a multitarget stool DNA test to screen for colorectal neoplasia” (Gastroenterology. 2019;151,:427-39.e6) and “Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years” (Gastroenterology. 2019;157:137-48).
These reports concluded that annual stool testing is more effective – but also more costly – than biennial testing. However, the additional cost per unit of benefit (figured in quality-adjusted life-years) is about $33,000 per life-year gained – a reasonable cost. “Hence, annual testing is a viable screening option,” wrote Dr. Pignone.
Starting screening at age 45 years instead of 50 years also produced an additional cost per life-year, but again, it is reasonable at $33,900 for colonoscopy screening and $7,700 for stool testing.
“However, for the same amount of additional resources, increasing screening rates in 55- or 65-year-olds or improving the proportion of positive stool test results that are followed by colonoscopy from 60% to 90% would yield much more benefit in life-years gained than lowering the starting age to 45 years.”
Analyses such as these conditionally support earlier colorectal cancer screening only if the universal screening rate for 50- to 75-year-olds is more than 80%, he wrote. “They also reinforce the most important point in all of the major guidelines: Any recommended form of screening in the 50- to 75-year age range is likely to be very cost-effective (if not cost-saving) compared with no screening and should be strongly encouraged.”
Dr. Pignone is director of the program on cancer prevention and control at the LIVESTRONG Cancer Institutes at the University of Texas, Austin.
Cost-effectiveness is one more factor in the colorectal screening discussion, Michael Pignone, MD, said in an accompanying editorial.
Two studies by Ladabaum et al. reported cost-effectiveness modeling for various CRC screening techniques: “Comparative effectiveness and cost effectiveness of a multitarget stool DNA test to screen for colorectal neoplasia” (Gastroenterology. 2019;151,:427-39.e6) and “Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years” (Gastroenterology. 2019;157:137-48).
These reports concluded that annual stool testing is more effective – but also more costly – than biennial testing. However, the additional cost per unit of benefit (figured in quality-adjusted life-years) is about $33,000 per life-year gained – a reasonable cost. “Hence, annual testing is a viable screening option,” wrote Dr. Pignone.
Starting screening at age 45 years instead of 50 years also produced an additional cost per life-year, but again, it is reasonable at $33,900 for colonoscopy screening and $7,700 for stool testing.
“However, for the same amount of additional resources, increasing screening rates in 55- or 65-year-olds or improving the proportion of positive stool test results that are followed by colonoscopy from 60% to 90% would yield much more benefit in life-years gained than lowering the starting age to 45 years.”
Analyses such as these conditionally support earlier colorectal cancer screening only if the universal screening rate for 50- to 75-year-olds is more than 80%, he wrote. “They also reinforce the most important point in all of the major guidelines: Any recommended form of screening in the 50- to 75-year age range is likely to be very cost-effective (if not cost-saving) compared with no screening and should be strongly encouraged.”
Dr. Pignone is director of the program on cancer prevention and control at the LIVESTRONG Cancer Institutes at the University of Texas, Austin.
Cost-effectiveness is one more factor in the colorectal screening discussion, Michael Pignone, MD, said in an accompanying editorial.
Two studies by Ladabaum et al. reported cost-effectiveness modeling for various CRC screening techniques: “Comparative effectiveness and cost effectiveness of a multitarget stool DNA test to screen for colorectal neoplasia” (Gastroenterology. 2019;151,:427-39.e6) and “Cost-effectiveness and national effects of initiating colorectal cancer screening for average-risk persons at age 45 years instead of 50 years” (Gastroenterology. 2019;157:137-48).
These reports concluded that annual stool testing is more effective – but also more costly – than biennial testing. However, the additional cost per unit of benefit (figured in quality-adjusted life-years) is about $33,000 per life-year gained – a reasonable cost. “Hence, annual testing is a viable screening option,” wrote Dr. Pignone.
Starting screening at age 45 years instead of 50 years also produced an additional cost per life-year, but again, it is reasonable at $33,900 for colonoscopy screening and $7,700 for stool testing.
“However, for the same amount of additional resources, increasing screening rates in 55- or 65-year-olds or improving the proportion of positive stool test results that are followed by colonoscopy from 60% to 90% would yield much more benefit in life-years gained than lowering the starting age to 45 years.”
Analyses such as these conditionally support earlier colorectal cancer screening only if the universal screening rate for 50- to 75-year-olds is more than 80%, he wrote. “They also reinforce the most important point in all of the major guidelines: Any recommended form of screening in the 50- to 75-year age range is likely to be very cost-effective (if not cost-saving) compared with no screening and should be strongly encouraged.”
Dr. Pignone is director of the program on cancer prevention and control at the LIVESTRONG Cancer Institutes at the University of Texas, Austin.
issued by the American College of Physicians.
Regular screening can be discontinued after age 75 years, Amir Qaseem, MD, president of clinical policy and the Center for Evidence Reviews at the American College of Physicians, and colleagues wrote in the Annals of Internal Medicine.
No one test is preferred over another, according to the guidance statement. Patients and physicians can select the test type together, based on individual needs and preferences, and each test carries its own screening interval. But regular testing has been proven time and again to reduce the risk of colorectal cancer mortality, and more people should have it, according to the guidance.
“Not enough people in the United States get screened for colorectal cancer,” ACP President Robert M. McLean, MD, said in a press statement. “Physicians should perform an individualized risk assessment for colorectal cancer in all adults. Doctors and patients should select the screening test based on a discussion of the benefits, harms, costs, availability, frequency, and patient preferences.”
The guidance is an attempt to balance existing guidelines authored by the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care (CTFPHC), but it also was developed following critical review of those from the American Cancer Society and other organizations.
The ACP guidance is for adults at average risk for colorectal cancer who do not have symptoms; it does not apply to adults with a family history of colorectal cancer, a long-standing history of inflammatory bowel disease, genetic syndromes such as familial cancerous polyps, a personal history of previous colorectal cancer or benign polyps, or other risk factors.
The guidance was based on evaluations of stool-based tests, including the fecal immunochemical test (FIT), also called the immunochemical-based fecal occult blood test (FOBT), and direct visualization with endoscopic and radiologic tests, including flexible sigmoidoscopy, colonoscopy, and CT colonography. The guidance includes the following recommendations:
Clinicians should regularly screen for colorectal cancer in average-risk adults between the ages of 50 and 75 years.
This recommendation is in line with those made by the U.S. Preventive Services Task Force and the CTFPHC. Data suggest that regular screening reduces colorectal cancer–specific mortality in this age group, with those aged 65-75 years likely to garner the most benefit.
The absolute risk reduction increases with age and varies with test type. For every-other-year FOBT, it rises from 0.037% in those younger than 60 years to 0.20% in those aged 60 years or older. For flexible sigmoidoscopy, the risk reduction rises from 0.05% in the younger group to 0.29% in the older group.
Data from the CTFPHC show that the net benefit in those aged 50-59 years is small, however. This may influence the decision about when to start screening.
Clinicians should select the colorectal cancer screening test with the patient based on a discussion of benefits, harms, costs, availability, frequency, and patient preferences.
The FIT or FOBT should be performed every 2 years, colonoscopy every 10 years, and flexible sigmoidoscopy every 10 years, plus FIT every 2 years.
No data suggest a benefit of one test over another; however, “all screening tests are associated with potential benefits as well as harms,” the document states. “Clinical decisions need to be individualized using patient clinical characteristics, patient preferences, and screening test frequency and availability. Because many eligible patients have never been screened and some may not adhere to recommendations about subsequent screening or follow-up of positive findings on screening tests (such as colonoscopy after a positive result on a stool-based screening test), patient informed decision making and adherence are important factors in selection of a [colorectal cancer] screening test.”
Discussions with patients should include topics like the recommended frequency of each test, bowel preparation, anesthesia, transportation to and from testing site, time commitments, and the necessary steps if a test result is positive.
Clinicians should discontinue screening for colorectal cancer in average-risk adults older than 75 years or in adults with a life expectancy of 10 years or less.
While the benefit from screening increases with age, so do the risks for harm, especially serious harm. Data show the balance of harms and benefits reaching a tipping point at around 75 years of age. But again, this isn’t a universal recommendation, the statement says.
“Persons with no history of [colorectal cancer] screening may benefit from screening after age 75 years, whereas those who have received regular screening with negative results may not.”
Cessation of testing considers life expectancy after age 75 years. The average life expectancy for healthy 75-year-old men and women in the United States is 9.9 and 12 years, respectively. But among men and women with serious medical comorbidities, average life expectancy after age 70 years drops to 8.9 and 10.8 years, respectively.
“Therefore, most persons aged 75 years or older, as well as most adults who are younger than 75 years but have serious comorbid conditions [such as chronic renal failure], are unlikely to benefit from screening but would undergo unnecessary, burdensome, potentially harmful, and costly screening tests.”
As in any testing discussion, personal preferences are important, but not just to make patients feel comfortable about their choice. Mindset about colorectal cancer testing has a very big effect on compliance, the statement noted.
“For example, a biennial stool test is not a good screening strategy for patients who may be unwilling or unlikely to follow up every other year. In addition, given the tradeoffs between benefits and harms, some patients may want less intensive screening, such as screening that begins at a later age, stops at an earlier age, or recurs less frequently regardless of modality selected.”
SOURCE: Qassam A et al. Ann Intern Med. 2019;171:643-54.
issued by the American College of Physicians.
Regular screening can be discontinued after age 75 years, Amir Qaseem, MD, president of clinical policy and the Center for Evidence Reviews at the American College of Physicians, and colleagues wrote in the Annals of Internal Medicine.
No one test is preferred over another, according to the guidance statement. Patients and physicians can select the test type together, based on individual needs and preferences, and each test carries its own screening interval. But regular testing has been proven time and again to reduce the risk of colorectal cancer mortality, and more people should have it, according to the guidance.
“Not enough people in the United States get screened for colorectal cancer,” ACP President Robert M. McLean, MD, said in a press statement. “Physicians should perform an individualized risk assessment for colorectal cancer in all adults. Doctors and patients should select the screening test based on a discussion of the benefits, harms, costs, availability, frequency, and patient preferences.”
The guidance is an attempt to balance existing guidelines authored by the U.S. Preventive Services Task Force and the Canadian Task Force on Preventive Health Care (CTFPHC), but it also was developed following critical review of those from the American Cancer Society and other organizations.
The ACP guidance is for adults at average risk for colorectal cancer who do not have symptoms; it does not apply to adults with a family history of colorectal cancer, a long-standing history of inflammatory bowel disease, genetic syndromes such as familial cancerous polyps, a personal history of previous colorectal cancer or benign polyps, or other risk factors.
The guidance was based on evaluations of stool-based tests, including the fecal immunochemical test (FIT), also called the immunochemical-based fecal occult blood test (FOBT), and direct visualization with endoscopic and radiologic tests, including flexible sigmoidoscopy, colonoscopy, and CT colonography. The guidance includes the following recommendations:
Clinicians should regularly screen for colorectal cancer in average-risk adults between the ages of 50 and 75 years.
This recommendation is in line with those made by the U.S. Preventive Services Task Force and the CTFPHC. Data suggest that regular screening reduces colorectal cancer–specific mortality in this age group, with those aged 65-75 years likely to garner the most benefit.
The absolute risk reduction increases with age and varies with test type. For every-other-year FOBT, it rises from 0.037% in those younger than 60 years to 0.20% in those aged 60 years or older. For flexible sigmoidoscopy, the risk reduction rises from 0.05% in the younger group to 0.29% in the older group.
Data from the CTFPHC show that the net benefit in those aged 50-59 years is small, however. This may influence the decision about when to start screening.
Clinicians should select the colorectal cancer screening test with the patient based on a discussion of benefits, harms, costs, availability, frequency, and patient preferences.
The FIT or FOBT should be performed every 2 years, colonoscopy every 10 years, and flexible sigmoidoscopy every 10 years, plus FIT every 2 years.
No data suggest a benefit of one test over another; however, “all screening tests are associated with potential benefits as well as harms,” the document states. “Clinical decisions need to be individualized using patient clinical characteristics, patient preferences, and screening test frequency and availability. Because many eligible patients have never been screened and some may not adhere to recommendations about subsequent screening or follow-up of positive findings on screening tests (such as colonoscopy after a positive result on a stool-based screening test), patient informed decision making and adherence are important factors in selection of a [colorectal cancer] screening test.”
Discussions with patients should include topics like the recommended frequency of each test, bowel preparation, anesthesia, transportation to and from testing site, time commitments, and the necessary steps if a test result is positive.
Clinicians should discontinue screening for colorectal cancer in average-risk adults older than 75 years or in adults with a life expectancy of 10 years or less.
While the benefit from screening increases with age, so do the risks for harm, especially serious harm. Data show the balance of harms and benefits reaching a tipping point at around 75 years of age. But again, this isn’t a universal recommendation, the statement says.
“Persons with no history of [colorectal cancer] screening may benefit from screening after age 75 years, whereas those who have received regular screening with negative results may not.”
Cessation of testing considers life expectancy after age 75 years. The average life expectancy for healthy 75-year-old men and women in the United States is 9.9 and 12 years, respectively. But among men and women with serious medical comorbidities, average life expectancy after age 70 years drops to 8.9 and 10.8 years, respectively.
“Therefore, most persons aged 75 years or older, as well as most adults who are younger than 75 years but have serious comorbid conditions [such as chronic renal failure], are unlikely to benefit from screening but would undergo unnecessary, burdensome, potentially harmful, and costly screening tests.”
As in any testing discussion, personal preferences are important, but not just to make patients feel comfortable about their choice. Mindset about colorectal cancer testing has a very big effect on compliance, the statement noted.
“For example, a biennial stool test is not a good screening strategy for patients who may be unwilling or unlikely to follow up every other year. In addition, given the tradeoffs between benefits and harms, some patients may want less intensive screening, such as screening that begins at a later age, stops at an earlier age, or recurs less frequently regardless of modality selected.”
SOURCE: Qassam A et al. Ann Intern Med. 2019;171:643-54.
FROM THE ANNALS OF INTERNAL MEDICINE
Severe psoriasis associated with increased cancer risk, mortality
according to a meta-analysis of cohort and case-control studies.
Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.
The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.
Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.
“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”
The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.
Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.
Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.
In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”
Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.
according to a meta-analysis of cohort and case-control studies.
Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.
The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.
Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.
“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”
The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.
Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.
Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.
In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”
Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.
according to a meta-analysis of cohort and case-control studies.
Compared with a psoriasis-free population, having a diagnosis of severe psoriasis was associated with a 22% increase in cancer risk, Alex Trafford of the University of Manchester (England) and colleagues reported in JAMA Dermatology. The risk of cancer mortality was also increased by 22% among those with severe psoriasis.
The site-specific risks ranged from a low of 18% for colon cancer to more than a twofold increased risk for oral and esophageal cancer, according to the investigators.
Since these were associations only, any underlying mechanism is still unclear, they wrote. The chronic inflammation that drives psoriasis can also drive the development of cancer, but immunomodulatory therapies may also play a part, they suggested.
“Of particular relevance in this regard are biological therapies, which are being increasingly used for the management of psoriasis,” they added. “Although preliminary studies have suggested little to no increased risk of cancer incidence in patients with psoriasis receiving these therapies, further study allowing greater follow-up and increased power is required to properly examine the potential cancer risk, particularly for site-specific cancers.”
The analysis included 58 studies, published between 1983 and 2017. Nine of these reported risks for cancer incidence among patients with severe psoriasis, and seven reported the risk of cancer mortality among patients with all severities of psoriasis.
Overall, severe psoriasis was associated with an increased cancer risk of 22%; for all severities of psoriasis combined, the risk increase was 18%. Relative risks for specific cancer types were as follows: colon, 1.18; colorectal, 1.34; kidney, 1.58; laryngeal, 1.79; liver, 1.83; lymphoma, 1.40; non-Hodgkin lymphoma, 1.28; keratinocyte cancers, 1.71; esophageal 2.05; oral cavity, 2.80; and pancreatic, 1.41.
Overall cancer mortality risk was 22% higher in patients with severe psoriasis than the general population. Site-specific relative mortality risks included liver, 1.43; esophageal 2.53; and pancreatic, 1.31.
In light of these findings, clinicians should stress lifestyle modifications known to decrease cancer risk, the investigators said. “Although it has been noted that lifestyle behavior change is challenging for healthcare professionals to implement, the importance of a more holistic approach to psoriasis care involving lifestyle behavior change is reinforced through the results of this meta-analysis.”
Among the coauthors were Darren M. Ashcroft, PhD, the senior author, and Christopher Griffiths, MD, both of the University of Manchester. Dr. Ashcroft reported receiving research grants from AbbVie, Almirall, Celgene, Eli Lilly, Novartis, UCB, and the Leo Foundation. Dr. Griffiths reported receiving honoraria and/or research grants from AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Sandoz, and UCB. The lead author and the other authors had no disclosures. The Global Psoriasis Atlas (GPA) Collaborating Organizations (the International Federation of Psoriasis Associations, the International League of Dermatological Societies, and the International Psoriasis Council) were involved with funding of the study.
SOURCE: Trafford A et al. JAMA Dermatol. 2019 Oct 16. doi:10.1001/jamadermatol.2019.3056.
FROM JAMA DERMATOLOGY