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Mild cognitive impairment risk slashed by 19% in SPRINT MIND
CHICAGO – Lowering systolic blood pressure to a target of 120 mm Hg or lower in people with cardiovascular risk factors reduced the risk of mild cognitive impairment by 19% and probable all-cause dementia by 17% relative to those who achieved a less intensive target of less than 140 mm Hg
Drug class didn’t matter. Cheap generics were just as effective as expensive name brands. It equally benefited men and women, whites, blacks, and Hispanics. And keeping systolic blood pressure at 120 mm Hg or lower prevented MCI just as well in those older than 75 as it did for younger subjects.
The stunning announcement came during a press briefing at the Alzheimer’s Association International Conference, as Jeff D. Williamson, MD, unveiled the results of the 4-year SPRINT MIND study. Strict blood pressure control for 3.2 years, with a systolic target of 120 mm Hg or lower, reduced the incidence of mild cognitive impairment by a magnitude of benefit that no amyloid-targeting investigational drug has ever approached.
“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during at the briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude. Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”
Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. People in the strict BP arm had 18% fewer white matter hyperintensities after 4 years of follow-up.
The news is an incredible step forward for the field that has stumbled repeatedly, clinicians agreed. Generic antihypertensives can be very inexpensive. They are almost globally available, and confer a host of other benefits, not only on cardiovascular health but on kidney health as well, said Dr. Williamson, chief of geriatric medicine at Wake Forest University, Winston-Salem, N.C.
“Hypertension is a highly prevalent condition, with 60%-70% having it. The 19% overall risk reduction for MCI will have a huge impact,” he said.
Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was somewhat more guarded, but still very enthusiastic.
“I think the most we can say right now is we are able to reduce risk,” she said in an interview. “But the reality is that reducing the risk of MCI by 19% will have a huge impact on dementia overall. And slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, the I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.
SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, and standard care, a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 American Heart Association and American College of Cardiology high blood pressure clinical guidelines.
The SPRINT MIND substudy looked at whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume.
It comprised 9,361 SPRINT subjects who were 50 years or older (mean 68; 28% at least 75) and had at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia.
In SPRINT, physicians could choose any appropriate antihypertensive regimen, but they were encouraged to use drugs with the strongest evidence of cardiovascular benefit: thiazide-type diuretics encouraged as first-line, and then loop diuretics and beta-adrenergic blockers. About 90% of the drugs used during the study were generics.
Subjects were seen monthly for the first 3 months, during which medications were adjusted to achieve the target, and then every 3 months after that. Medications could be adjusted monthly to keep on target.
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped in August 2015 due to the observed cardiovascular disease benefit, after a median follow up of 3.26 years, but cognitive assessment continued until the end of June (N Engl J Med. 2015 Nov 26; 373:2103-16).
The SPRINT MIND study did not meet its primary endpoint. Adjudicated cases of probable all-cause dementia developed in 175 of the standard care group and 147 of the intensive treatment group; the 17% risk reduction was not statistically significant (P = .10).
However, it did hit both secondary endpoints. Adjudicated cases of MCI developed in 348 of the standard treatment groups and 285 of the intensive treatment group: a statistically significant 19% risk reduction (P = .01). The combined secondary endpoint of MCI and probable dementia was a significant 15% risk reduction (P = .02), with 463 cases in the standard care group and 398 in the intensive care group.
The imaging study comprised 454 subjects who had brain MRI at baseline and 4 years after randomization. There was no change in total brain volume, said Ilya Nasrallah, MD, of the University of Pennsylvania. But those in the intensively managed group had 18% lower white matter lesion load than those in the standard care group (P = .004).
White matter lesions often point to small vessel disease, which is conclusively linked to vascular dementia, and may also linked to Alzheimer’s disease. Most AD patients, in fact, have a mixed dementia that often includes a vascular component, Dr. Carillo said.
SPRINT MIND didn’t follow subjects past 4 years, and didn’t include any follow-up for amyloid or Alzheimer’s diagnosis. But preventing MCI is no trivial thing, according to David Knopman, MD, who moderated the session.
“There’s nothing that is benign about MCI,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “it’s the first sign of overt cognitive dysfunction, and although the rate at which MCI progress to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think is going to change clinical practice for people in primary care and the benefits at the population level are going to be substantial.”
Dr. Williamson drove this point home in a later interview, suggesting that physicians may want to think about how the SPRINT MIND results might apply to even younger patients with hypertension, and even if they don’t have other cardiovascular risk factors.
“I can’t say as a scientist that we have evidence to do that, yet. But as a physician, and for my own self and my own patients, I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg, and certainly start treating people in their 50s, and probably in their 40s.”
***This article was updated 7/31/18.
SOURCE: Williamson et al. AAIC 2018 DT-0202 Nasrallah et al. AAIC 2018 DT-03-03
CHICAGO – Lowering systolic blood pressure to a target of 120 mm Hg or lower in people with cardiovascular risk factors reduced the risk of mild cognitive impairment by 19% and probable all-cause dementia by 17% relative to those who achieved a less intensive target of less than 140 mm Hg
Drug class didn’t matter. Cheap generics were just as effective as expensive name brands. It equally benefited men and women, whites, blacks, and Hispanics. And keeping systolic blood pressure at 120 mm Hg or lower prevented MCI just as well in those older than 75 as it did for younger subjects.
The stunning announcement came during a press briefing at the Alzheimer’s Association International Conference, as Jeff D. Williamson, MD, unveiled the results of the 4-year SPRINT MIND study. Strict blood pressure control for 3.2 years, with a systolic target of 120 mm Hg or lower, reduced the incidence of mild cognitive impairment by a magnitude of benefit that no amyloid-targeting investigational drug has ever approached.
“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during at the briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude. Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”
Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. People in the strict BP arm had 18% fewer white matter hyperintensities after 4 years of follow-up.
The news is an incredible step forward for the field that has stumbled repeatedly, clinicians agreed. Generic antihypertensives can be very inexpensive. They are almost globally available, and confer a host of other benefits, not only on cardiovascular health but on kidney health as well, said Dr. Williamson, chief of geriatric medicine at Wake Forest University, Winston-Salem, N.C.
“Hypertension is a highly prevalent condition, with 60%-70% having it. The 19% overall risk reduction for MCI will have a huge impact,” he said.
Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was somewhat more guarded, but still very enthusiastic.
“I think the most we can say right now is we are able to reduce risk,” she said in an interview. “But the reality is that reducing the risk of MCI by 19% will have a huge impact on dementia overall. And slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, the I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.
SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, and standard care, a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 American Heart Association and American College of Cardiology high blood pressure clinical guidelines.
The SPRINT MIND substudy looked at whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume.
It comprised 9,361 SPRINT subjects who were 50 years or older (mean 68; 28% at least 75) and had at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia.
In SPRINT, physicians could choose any appropriate antihypertensive regimen, but they were encouraged to use drugs with the strongest evidence of cardiovascular benefit: thiazide-type diuretics encouraged as first-line, and then loop diuretics and beta-adrenergic blockers. About 90% of the drugs used during the study were generics.
Subjects were seen monthly for the first 3 months, during which medications were adjusted to achieve the target, and then every 3 months after that. Medications could be adjusted monthly to keep on target.
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped in August 2015 due to the observed cardiovascular disease benefit, after a median follow up of 3.26 years, but cognitive assessment continued until the end of June (N Engl J Med. 2015 Nov 26; 373:2103-16).
The SPRINT MIND study did not meet its primary endpoint. Adjudicated cases of probable all-cause dementia developed in 175 of the standard care group and 147 of the intensive treatment group; the 17% risk reduction was not statistically significant (P = .10).
However, it did hit both secondary endpoints. Adjudicated cases of MCI developed in 348 of the standard treatment groups and 285 of the intensive treatment group: a statistically significant 19% risk reduction (P = .01). The combined secondary endpoint of MCI and probable dementia was a significant 15% risk reduction (P = .02), with 463 cases in the standard care group and 398 in the intensive care group.
The imaging study comprised 454 subjects who had brain MRI at baseline and 4 years after randomization. There was no change in total brain volume, said Ilya Nasrallah, MD, of the University of Pennsylvania. But those in the intensively managed group had 18% lower white matter lesion load than those in the standard care group (P = .004).
White matter lesions often point to small vessel disease, which is conclusively linked to vascular dementia, and may also linked to Alzheimer’s disease. Most AD patients, in fact, have a mixed dementia that often includes a vascular component, Dr. Carillo said.
SPRINT MIND didn’t follow subjects past 4 years, and didn’t include any follow-up for amyloid or Alzheimer’s diagnosis. But preventing MCI is no trivial thing, according to David Knopman, MD, who moderated the session.
“There’s nothing that is benign about MCI,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “it’s the first sign of overt cognitive dysfunction, and although the rate at which MCI progress to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think is going to change clinical practice for people in primary care and the benefits at the population level are going to be substantial.”
Dr. Williamson drove this point home in a later interview, suggesting that physicians may want to think about how the SPRINT MIND results might apply to even younger patients with hypertension, and even if they don’t have other cardiovascular risk factors.
“I can’t say as a scientist that we have evidence to do that, yet. But as a physician, and for my own self and my own patients, I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg, and certainly start treating people in their 50s, and probably in their 40s.”
***This article was updated 7/31/18.
SOURCE: Williamson et al. AAIC 2018 DT-0202 Nasrallah et al. AAIC 2018 DT-03-03
CHICAGO – Lowering systolic blood pressure to a target of 120 mm Hg or lower in people with cardiovascular risk factors reduced the risk of mild cognitive impairment by 19% and probable all-cause dementia by 17% relative to those who achieved a less intensive target of less than 140 mm Hg
Drug class didn’t matter. Cheap generics were just as effective as expensive name brands. It equally benefited men and women, whites, blacks, and Hispanics. And keeping systolic blood pressure at 120 mm Hg or lower prevented MCI just as well in those older than 75 as it did for younger subjects.
The stunning announcement came during a press briefing at the Alzheimer’s Association International Conference, as Jeff D. Williamson, MD, unveiled the results of the 4-year SPRINT MIND study. Strict blood pressure control for 3.2 years, with a systolic target of 120 mm Hg or lower, reduced the incidence of mild cognitive impairment by a magnitude of benefit that no amyloid-targeting investigational drug has ever approached.
“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during at the briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude. Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”
Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. People in the strict BP arm had 18% fewer white matter hyperintensities after 4 years of follow-up.
The news is an incredible step forward for the field that has stumbled repeatedly, clinicians agreed. Generic antihypertensives can be very inexpensive. They are almost globally available, and confer a host of other benefits, not only on cardiovascular health but on kidney health as well, said Dr. Williamson, chief of geriatric medicine at Wake Forest University, Winston-Salem, N.C.
“Hypertension is a highly prevalent condition, with 60%-70% having it. The 19% overall risk reduction for MCI will have a huge impact,” he said.
Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was somewhat more guarded, but still very enthusiastic.
“I think the most we can say right now is we are able to reduce risk,” she said in an interview. “But the reality is that reducing the risk of MCI by 19% will have a huge impact on dementia overall. And slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, the I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.
SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, and standard care, a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 American Heart Association and American College of Cardiology high blood pressure clinical guidelines.
The SPRINT MIND substudy looked at whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume.
It comprised 9,361 SPRINT subjects who were 50 years or older (mean 68; 28% at least 75) and had at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia.
In SPRINT, physicians could choose any appropriate antihypertensive regimen, but they were encouraged to use drugs with the strongest evidence of cardiovascular benefit: thiazide-type diuretics encouraged as first-line, and then loop diuretics and beta-adrenergic blockers. About 90% of the drugs used during the study were generics.
Subjects were seen monthly for the first 3 months, during which medications were adjusted to achieve the target, and then every 3 months after that. Medications could be adjusted monthly to keep on target.
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped in August 2015 due to the observed cardiovascular disease benefit, after a median follow up of 3.26 years, but cognitive assessment continued until the end of June (N Engl J Med. 2015 Nov 26; 373:2103-16).
The SPRINT MIND study did not meet its primary endpoint. Adjudicated cases of probable all-cause dementia developed in 175 of the standard care group and 147 of the intensive treatment group; the 17% risk reduction was not statistically significant (P = .10).
However, it did hit both secondary endpoints. Adjudicated cases of MCI developed in 348 of the standard treatment groups and 285 of the intensive treatment group: a statistically significant 19% risk reduction (P = .01). The combined secondary endpoint of MCI and probable dementia was a significant 15% risk reduction (P = .02), with 463 cases in the standard care group and 398 in the intensive care group.
The imaging study comprised 454 subjects who had brain MRI at baseline and 4 years after randomization. There was no change in total brain volume, said Ilya Nasrallah, MD, of the University of Pennsylvania. But those in the intensively managed group had 18% lower white matter lesion load than those in the standard care group (P = .004).
White matter lesions often point to small vessel disease, which is conclusively linked to vascular dementia, and may also linked to Alzheimer’s disease. Most AD patients, in fact, have a mixed dementia that often includes a vascular component, Dr. Carillo said.
SPRINT MIND didn’t follow subjects past 4 years, and didn’t include any follow-up for amyloid or Alzheimer’s diagnosis. But preventing MCI is no trivial thing, according to David Knopman, MD, who moderated the session.
“There’s nothing that is benign about MCI,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “it’s the first sign of overt cognitive dysfunction, and although the rate at which MCI progress to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think is going to change clinical practice for people in primary care and the benefits at the population level are going to be substantial.”
Dr. Williamson drove this point home in a later interview, suggesting that physicians may want to think about how the SPRINT MIND results might apply to even younger patients with hypertension, and even if they don’t have other cardiovascular risk factors.
“I can’t say as a scientist that we have evidence to do that, yet. But as a physician, and for my own self and my own patients, I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg, and certainly start treating people in their 50s, and probably in their 40s.”
***This article was updated 7/31/18.
SOURCE: Williamson et al. AAIC 2018 DT-0202 Nasrallah et al. AAIC 2018 DT-03-03
AT AAIC 2018
Key clinical point: Keeping systolic blood pressure at less than 120 mm Hg reduced the risk of MCI and all-cause dementia more effectively than keeping it less than 140 mm Hg.
Major finding: After 3.2 years of treatment, there was a 19% lower risk of MCI in the intensively managed group relative to the standard of care group.
Study details: SPRINT MIND comprised more than 9,000 subjects treated for 3.2 years.
Disclosures: The study was funded by the National Institutes of Health. Neither presenter had any relevant financial disclosures.
Source: Williamson et al. AAIC 2018 DT-0202
Pregnancy and years of reproductive capability linked to dementia risk
CHICAGO – More pregnancies and a longer span of reproductive years appear to confer some level of protection against dementia, suggesting that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study, presented at the Alzheimer’s Association International Conference, is the first to examine this question in a large cohort, comprising more than 14,500 women with up to 50 years of follow-up data. It is one of the first explorations in a renewed interest in the link between hormones and cognition, said Suzanne Craft, PhD, who moderated a press briefing on the topic.
“WHI [Women’s Heath Initiative] had a completely chilling effect on research into estrogen and cognition completely,” Dr. Craft of Wake Forest University, Winston-Salem, N.C., said in an interview. “Many well-regarded researchers simply couldn’t get funding and had to close their programs and move on to other areas. But now I think the pendulum is slowly moving back. It’s clear that something is going on, that there is a link. I’m glad we’re starting to explore this again.”
The investigation of women’s total reproductive experience affects dementia risk found several intriguing associations, said Paola Gilsanz, ScD, of Kaiser Permanente, Oakland, Calif. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Her study comprised 14,595 women, all members of the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup sometime between 1964 and 1973, when they were 40-55 years old. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the group (68%) was white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996-2017, when the women were 62-86 years old.
A multivariate regression model controlled for age, race, education, midlife health issues (hypertension, smoking, and body mass index), hysterectomy, and late-life health issues (stroke, heart failure, and diabetes).
Half of the cohort (50%) had at least three children, and 75% had experienced at least one miscarriage. The average age at menarche was 13 years, and the average age at last natural menstrual period was 47 years. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed some type of dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child (hazard ratio, 0.88). The association remained significant even after researchers controlled for age, race, educational level, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who didn’t report one were 20% less likely to develop dementia than were those who had experienced at least one (HR, 0.81). The benefit of no miscarriage was even greater among women with at least three children, conferring a 28% reduced risk (HR, 0.72).
A shortened reproductive period increased the risk of dementia. Those who experienced menarche at 16 years or older had a 31% increased risk of dementia (HR, 1.31), and those who experienced their last period at age 45 or younger faced a 28% greater risk (HR, 1.28). Each additional year of reproductive capability was associated with a 2% decreased risk (HR, 0.98).
Women with a reproductive period of 21-30 years were 33% more likely to develop dementia than were those with a longer period (HR, 1.33)
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieu that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
She had no financial disclosures.
SOURCE: Gilsanz P et al. AAIC 2018, Abstract P3-587
CHICAGO – More pregnancies and a longer span of reproductive years appear to confer some level of protection against dementia, suggesting that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study, presented at the Alzheimer’s Association International Conference, is the first to examine this question in a large cohort, comprising more than 14,500 women with up to 50 years of follow-up data. It is one of the first explorations in a renewed interest in the link between hormones and cognition, said Suzanne Craft, PhD, who moderated a press briefing on the topic.
“WHI [Women’s Heath Initiative] had a completely chilling effect on research into estrogen and cognition completely,” Dr. Craft of Wake Forest University, Winston-Salem, N.C., said in an interview. “Many well-regarded researchers simply couldn’t get funding and had to close their programs and move on to other areas. But now I think the pendulum is slowly moving back. It’s clear that something is going on, that there is a link. I’m glad we’re starting to explore this again.”
The investigation of women’s total reproductive experience affects dementia risk found several intriguing associations, said Paola Gilsanz, ScD, of Kaiser Permanente, Oakland, Calif. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Her study comprised 14,595 women, all members of the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup sometime between 1964 and 1973, when they were 40-55 years old. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the group (68%) was white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996-2017, when the women were 62-86 years old.
A multivariate regression model controlled for age, race, education, midlife health issues (hypertension, smoking, and body mass index), hysterectomy, and late-life health issues (stroke, heart failure, and diabetes).
Half of the cohort (50%) had at least three children, and 75% had experienced at least one miscarriage. The average age at menarche was 13 years, and the average age at last natural menstrual period was 47 years. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed some type of dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child (hazard ratio, 0.88). The association remained significant even after researchers controlled for age, race, educational level, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who didn’t report one were 20% less likely to develop dementia than were those who had experienced at least one (HR, 0.81). The benefit of no miscarriage was even greater among women with at least three children, conferring a 28% reduced risk (HR, 0.72).
A shortened reproductive period increased the risk of dementia. Those who experienced menarche at 16 years or older had a 31% increased risk of dementia (HR, 1.31), and those who experienced their last period at age 45 or younger faced a 28% greater risk (HR, 1.28). Each additional year of reproductive capability was associated with a 2% decreased risk (HR, 0.98).
Women with a reproductive period of 21-30 years were 33% more likely to develop dementia than were those with a longer period (HR, 1.33)
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieu that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
She had no financial disclosures.
SOURCE: Gilsanz P et al. AAIC 2018, Abstract P3-587
CHICAGO – More pregnancies and a longer span of reproductive years appear to confer some level of protection against dementia, suggesting that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study, presented at the Alzheimer’s Association International Conference, is the first to examine this question in a large cohort, comprising more than 14,500 women with up to 50 years of follow-up data. It is one of the first explorations in a renewed interest in the link between hormones and cognition, said Suzanne Craft, PhD, who moderated a press briefing on the topic.
“WHI [Women’s Heath Initiative] had a completely chilling effect on research into estrogen and cognition completely,” Dr. Craft of Wake Forest University, Winston-Salem, N.C., said in an interview. “Many well-regarded researchers simply couldn’t get funding and had to close their programs and move on to other areas. But now I think the pendulum is slowly moving back. It’s clear that something is going on, that there is a link. I’m glad we’re starting to explore this again.”
The investigation of women’s total reproductive experience affects dementia risk found several intriguing associations, said Paola Gilsanz, ScD, of Kaiser Permanente, Oakland, Calif. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Her study comprised 14,595 women, all members of the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup sometime between 1964 and 1973, when they were 40-55 years old. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the group (68%) was white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996-2017, when the women were 62-86 years old.
A multivariate regression model controlled for age, race, education, midlife health issues (hypertension, smoking, and body mass index), hysterectomy, and late-life health issues (stroke, heart failure, and diabetes).
Half of the cohort (50%) had at least three children, and 75% had experienced at least one miscarriage. The average age at menarche was 13 years, and the average age at last natural menstrual period was 47 years. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed some type of dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child (hazard ratio, 0.88). The association remained significant even after researchers controlled for age, race, educational level, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who didn’t report one were 20% less likely to develop dementia than were those who had experienced at least one (HR, 0.81). The benefit of no miscarriage was even greater among women with at least three children, conferring a 28% reduced risk (HR, 0.72).
A shortened reproductive period increased the risk of dementia. Those who experienced menarche at 16 years or older had a 31% increased risk of dementia (HR, 1.31), and those who experienced their last period at age 45 or younger faced a 28% greater risk (HR, 1.28). Each additional year of reproductive capability was associated with a 2% decreased risk (HR, 0.98).
Women with a reproductive period of 21-30 years were 33% more likely to develop dementia than were those with a longer period (HR, 1.33)
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieu that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
She had no financial disclosures.
SOURCE: Gilsanz P et al. AAIC 2018, Abstract P3-587
AT AAIC 2018
Key clinical point: More pregnancies and a longer reproductive period were associated with a significantly reduced risk of late-life dementia among women.
Major finding: Women with at least three children were 12% less likely to develop dementia than were those who had just one child.
Study details: The retrospective observational study comprised 14,595 women.
Disclosures: Dr. Gilsanz had no financial disclosures.
Source: Gilsanz P et al. AAIC 2018, Abstract P3-587.
Gates Foundation, Lauder family launch $30 million Alzheimer’s biomarker search
Two billionaires have joined forces in a $30 million effort to develop peripheral biomarkers for the early detection of Alzheimer’s disease and other dementias.
Bill Gates and Leonard Lauder, cofounder of the Alzheimer’s Drug Discovery Foundation (ADDF) and chairman emeritus of Estée Lauder, provided initial funding for the project, dubbed Diagnostics Accelerator. Support from other philanthropists, including the Dolby family and the Charles and Helen Schwab Foundation, will bring the initiative up to its full funding capacity, according to an ADDF press statement.
“Over the next 3 years, we will provide more than $30 million in grants to researchers who are working on the most promising and innovative ideas to help diagnose Alzheimer’s disease [AD] early before the more devastating symptoms occur,” Mr. Lauder said in the statement.
Researchers at academic centers and nonprofit organizations are eligible to apply for the program; biotech companies and startups are also invited. Letters of intent for the first round of funding are due by Sept. 14, and the final proposals are due Nov. 16. Conducted under the auspices of the ADDF, the program will employ strict scientific review of all proposals and grant priority to blood and other peripheral markers, including saliva, urine, and ocular biomarkers. Neuroimaging and cerebrospinal fluid biomarkers won’t be considered, although researchers may use these as validation tests for their investigational markers.
Target areas include, but aren’t limited to:
- Neuroprotection
- Neurodegeneration
- Protein misfolding
- Synaptic integrity and/or activity
- Vascular injury and blood-brain barrier integrity
- Mitochondria and metabolic function
- Oxidative stress
- White matter changes
The initiative reflects recent emphasis on the critical role of biomarkers in drug development; this is especially important because emerging data paint a clear picture of a long AD prodrome during which the disease might be more amenable to treatment, ADDF’s Howard Fillit, MD, said in the press statement.
“The significance of biomarkers in Alzheimer’s disease research is underscored by recent FDA [Food and Drug Administration] guidelines that recognize the critical role of biomarkers in drug development and shift the research definition of the early stages of the disease to include biomarkers, even before clinical symptoms become apparent. ... Like in cancer today, using the biomarker-specific model of precision medicine, we will be able to predict more accurately which treatment and prevention strategies will work in different at-risk populations of people who have Alzheimer’s disease or other forms of dementia.”
Diagnostics Accelerator will award two general types of grants. Proof-of-principle awards of up to $500,000 will support exploratory analyses of biomarkers in smaller human sample sizes of 50-100. Proposals must be supported by human data that demonstrate that the candidate markers correspond with disease pathophysiology. Preliminary assay validation data for the proposed studies should be included. Successful proof-of principle projects may be eligible for follow-on funding in the form of a validation award.
Validation awards will support exploring biomarkers that need to be tested at a larger scale (500-1,000 samples). These must be supported by a significant extant body of human data that demonstrate that the biomarker corresponds to disease pathophysiology. Validation studies should compare peripheral analytes to quantitative measurements using PET imaging and/or cerebrospinal fluid testing, and not cognition alone. Award amounts will be based on stage and scope of research.
The announcement drew praise from researchers and clinicians.
“I think this is a terrific initiative,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s so important to identify those at high risk of developing AD well before the onset of symptoms. All clinical trials for disease-modifying therapies have failed because these have enrolled subjects who already have AD or MCI. Preventing or delaying disease onset [i.e., prophylaxis] is the way forward, but this will require specific predictive biomarkers.”
Richard J. Caselli, MD, a professor of neurology at the Mayo Clinic Arizona in Scottsdale and clinical core director of the Arizona Alzheimer’s Disease Center, agreed.
“I would add that we are still trying to understand how various ‘experiences’ might push us toward Alzheimer’s disease; head injury, diabetes, and air pollution, for example. We know already, based on existing genomic and acquired risk factors, that AD is a complex disease and that many disparate things can influence our risk. Are each of these equally important in each of us or do we each have our own unique vulnerability profile? New biomarkers can help us determine that, and if we are in fact each unique, then maybe prevention strategies need to be personalized.”
Two billionaires have joined forces in a $30 million effort to develop peripheral biomarkers for the early detection of Alzheimer’s disease and other dementias.
Bill Gates and Leonard Lauder, cofounder of the Alzheimer’s Drug Discovery Foundation (ADDF) and chairman emeritus of Estée Lauder, provided initial funding for the project, dubbed Diagnostics Accelerator. Support from other philanthropists, including the Dolby family and the Charles and Helen Schwab Foundation, will bring the initiative up to its full funding capacity, according to an ADDF press statement.
“Over the next 3 years, we will provide more than $30 million in grants to researchers who are working on the most promising and innovative ideas to help diagnose Alzheimer’s disease [AD] early before the more devastating symptoms occur,” Mr. Lauder said in the statement.
Researchers at academic centers and nonprofit organizations are eligible to apply for the program; biotech companies and startups are also invited. Letters of intent for the first round of funding are due by Sept. 14, and the final proposals are due Nov. 16. Conducted under the auspices of the ADDF, the program will employ strict scientific review of all proposals and grant priority to blood and other peripheral markers, including saliva, urine, and ocular biomarkers. Neuroimaging and cerebrospinal fluid biomarkers won’t be considered, although researchers may use these as validation tests for their investigational markers.
Target areas include, but aren’t limited to:
- Neuroprotection
- Neurodegeneration
- Protein misfolding
- Synaptic integrity and/or activity
- Vascular injury and blood-brain barrier integrity
- Mitochondria and metabolic function
- Oxidative stress
- White matter changes
The initiative reflects recent emphasis on the critical role of biomarkers in drug development; this is especially important because emerging data paint a clear picture of a long AD prodrome during which the disease might be more amenable to treatment, ADDF’s Howard Fillit, MD, said in the press statement.
“The significance of biomarkers in Alzheimer’s disease research is underscored by recent FDA [Food and Drug Administration] guidelines that recognize the critical role of biomarkers in drug development and shift the research definition of the early stages of the disease to include biomarkers, even before clinical symptoms become apparent. ... Like in cancer today, using the biomarker-specific model of precision medicine, we will be able to predict more accurately which treatment and prevention strategies will work in different at-risk populations of people who have Alzheimer’s disease or other forms of dementia.”
Diagnostics Accelerator will award two general types of grants. Proof-of-principle awards of up to $500,000 will support exploratory analyses of biomarkers in smaller human sample sizes of 50-100. Proposals must be supported by human data that demonstrate that the candidate markers correspond with disease pathophysiology. Preliminary assay validation data for the proposed studies should be included. Successful proof-of principle projects may be eligible for follow-on funding in the form of a validation award.
Validation awards will support exploring biomarkers that need to be tested at a larger scale (500-1,000 samples). These must be supported by a significant extant body of human data that demonstrate that the biomarker corresponds to disease pathophysiology. Validation studies should compare peripheral analytes to quantitative measurements using PET imaging and/or cerebrospinal fluid testing, and not cognition alone. Award amounts will be based on stage and scope of research.
The announcement drew praise from researchers and clinicians.
“I think this is a terrific initiative,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s so important to identify those at high risk of developing AD well before the onset of symptoms. All clinical trials for disease-modifying therapies have failed because these have enrolled subjects who already have AD or MCI. Preventing or delaying disease onset [i.e., prophylaxis] is the way forward, but this will require specific predictive biomarkers.”
Richard J. Caselli, MD, a professor of neurology at the Mayo Clinic Arizona in Scottsdale and clinical core director of the Arizona Alzheimer’s Disease Center, agreed.
“I would add that we are still trying to understand how various ‘experiences’ might push us toward Alzheimer’s disease; head injury, diabetes, and air pollution, for example. We know already, based on existing genomic and acquired risk factors, that AD is a complex disease and that many disparate things can influence our risk. Are each of these equally important in each of us or do we each have our own unique vulnerability profile? New biomarkers can help us determine that, and if we are in fact each unique, then maybe prevention strategies need to be personalized.”
Two billionaires have joined forces in a $30 million effort to develop peripheral biomarkers for the early detection of Alzheimer’s disease and other dementias.
Bill Gates and Leonard Lauder, cofounder of the Alzheimer’s Drug Discovery Foundation (ADDF) and chairman emeritus of Estée Lauder, provided initial funding for the project, dubbed Diagnostics Accelerator. Support from other philanthropists, including the Dolby family and the Charles and Helen Schwab Foundation, will bring the initiative up to its full funding capacity, according to an ADDF press statement.
“Over the next 3 years, we will provide more than $30 million in grants to researchers who are working on the most promising and innovative ideas to help diagnose Alzheimer’s disease [AD] early before the more devastating symptoms occur,” Mr. Lauder said in the statement.
Researchers at academic centers and nonprofit organizations are eligible to apply for the program; biotech companies and startups are also invited. Letters of intent for the first round of funding are due by Sept. 14, and the final proposals are due Nov. 16. Conducted under the auspices of the ADDF, the program will employ strict scientific review of all proposals and grant priority to blood and other peripheral markers, including saliva, urine, and ocular biomarkers. Neuroimaging and cerebrospinal fluid biomarkers won’t be considered, although researchers may use these as validation tests for their investigational markers.
Target areas include, but aren’t limited to:
- Neuroprotection
- Neurodegeneration
- Protein misfolding
- Synaptic integrity and/or activity
- Vascular injury and blood-brain barrier integrity
- Mitochondria and metabolic function
- Oxidative stress
- White matter changes
The initiative reflects recent emphasis on the critical role of biomarkers in drug development; this is especially important because emerging data paint a clear picture of a long AD prodrome during which the disease might be more amenable to treatment, ADDF’s Howard Fillit, MD, said in the press statement.
“The significance of biomarkers in Alzheimer’s disease research is underscored by recent FDA [Food and Drug Administration] guidelines that recognize the critical role of biomarkers in drug development and shift the research definition of the early stages of the disease to include biomarkers, even before clinical symptoms become apparent. ... Like in cancer today, using the biomarker-specific model of precision medicine, we will be able to predict more accurately which treatment and prevention strategies will work in different at-risk populations of people who have Alzheimer’s disease or other forms of dementia.”
Diagnostics Accelerator will award two general types of grants. Proof-of-principle awards of up to $500,000 will support exploratory analyses of biomarkers in smaller human sample sizes of 50-100. Proposals must be supported by human data that demonstrate that the candidate markers correspond with disease pathophysiology. Preliminary assay validation data for the proposed studies should be included. Successful proof-of principle projects may be eligible for follow-on funding in the form of a validation award.
Validation awards will support exploring biomarkers that need to be tested at a larger scale (500-1,000 samples). These must be supported by a significant extant body of human data that demonstrate that the biomarker corresponds to disease pathophysiology. Validation studies should compare peripheral analytes to quantitative measurements using PET imaging and/or cerebrospinal fluid testing, and not cognition alone. Award amounts will be based on stage and scope of research.
The announcement drew praise from researchers and clinicians.
“I think this is a terrific initiative,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s so important to identify those at high risk of developing AD well before the onset of symptoms. All clinical trials for disease-modifying therapies have failed because these have enrolled subjects who already have AD or MCI. Preventing or delaying disease onset [i.e., prophylaxis] is the way forward, but this will require specific predictive biomarkers.”
Richard J. Caselli, MD, a professor of neurology at the Mayo Clinic Arizona in Scottsdale and clinical core director of the Arizona Alzheimer’s Disease Center, agreed.
“I would add that we are still trying to understand how various ‘experiences’ might push us toward Alzheimer’s disease; head injury, diabetes, and air pollution, for example. We know already, based on existing genomic and acquired risk factors, that AD is a complex disease and that many disparate things can influence our risk. Are each of these equally important in each of us or do we each have our own unique vulnerability profile? New biomarkers can help us determine that, and if we are in fact each unique, then maybe prevention strategies need to be personalized.”
Dementia epidemiology in LGB community examined for first time
CHICAGO – The first comprehensive analysis of dementia prevalence among sexual minorities has found a rate of 8% in this population.
While only marginally lower than the 9% prevalence among a heterosexual comparator group, the disorder manifested at an earlier age and occurred more often among men, Jason Flatt, PhD, said at the Alzheimer’s Association International Conference. In addition, higher education didn’t exert the protective influence seen in general populations, said Dr. Flatt of the University of California, San Francisco.
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, he said. It’s an important quest because the age-risk curve is rising just as quickly among the LGB population as it is in the heterosexual population.
“We do know there are 2-3 million people who identify as LGB [lesbian, gay, or bisexual] in the U.S., and are 60 years old or older, and with the continued aging of our entire population, we expect this number to increase to about 6 million by 2040,” he said. “Given the gaps in collection of sexual orientation and gender identification, we haven’t been able to look at this issue before.”
Sexual minorities face unique dementia risks, Dr. Flatt noted. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “The often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress.”
These experiences make the LGB population less likely to seek out medical care, he said. “All of these things impact health over the life course.”
Dr. Flatt and his colleagues drew their data from the Kaiser Permanente Research Program on Genes, Environment, and Health. The study examined dementia prevalence and comorbidities among 4,337 LGB subjects aged 60 years or older, compared with 195,264 age-matched heterosexual subjects. Dementia diagnoses occurred from 1996 to 2015, and the mean follow-up time was 9 years. A quarter of the sample identified as lesbian, 37% identified as gay men, and 38% as bisexual; among these, 48% were women. Depression was more common among the LGB group (35% vs. 28%), as was posttraumatic stress disorder (1.9% vs. 1%). Both are well documented risk factors for dementia.
However, there were no significant difference in other risk factors, including hypertension, stroke, and heart disease, Dr. Flatt noted. He and his associates did not examine midlife obesity, physical inactivity, or low educational attainment, but will do so in a future analysis.
A dementia diagnosis occurred among 343 (8%) of the LGB group and 18,060 (9.2%) of the heterosexual group. The disorder manifested earlier in the LGB group (average 69 vs. 71 years). Self-identified men were overrepresented in the sample (63% vs. 44%) – a key difference, since women are generally found to have a significantly increased risk compared with men. However, Dr. Flatt noted, the study didn’t collect information that would show biological sex, so that number could be skewed.
Higher education didn’t seem to be as protective in the LGB population, with 62% having a college education, compared with 40% of the heterosexual sample.
In a regression analysis that adjusted for age and education, Dr. Flatt reported that depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (OR, 2.5).
These initial findings highlight the need for more research into this population, he said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs.” This might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
SOURCE: Flatt J et al. AAIC 2018, Abstract P1-619.
CHICAGO – The first comprehensive analysis of dementia prevalence among sexual minorities has found a rate of 8% in this population.
While only marginally lower than the 9% prevalence among a heterosexual comparator group, the disorder manifested at an earlier age and occurred more often among men, Jason Flatt, PhD, said at the Alzheimer’s Association International Conference. In addition, higher education didn’t exert the protective influence seen in general populations, said Dr. Flatt of the University of California, San Francisco.
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, he said. It’s an important quest because the age-risk curve is rising just as quickly among the LGB population as it is in the heterosexual population.
“We do know there are 2-3 million people who identify as LGB [lesbian, gay, or bisexual] in the U.S., and are 60 years old or older, and with the continued aging of our entire population, we expect this number to increase to about 6 million by 2040,” he said. “Given the gaps in collection of sexual orientation and gender identification, we haven’t been able to look at this issue before.”
Sexual minorities face unique dementia risks, Dr. Flatt noted. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “The often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress.”
These experiences make the LGB population less likely to seek out medical care, he said. “All of these things impact health over the life course.”
Dr. Flatt and his colleagues drew their data from the Kaiser Permanente Research Program on Genes, Environment, and Health. The study examined dementia prevalence and comorbidities among 4,337 LGB subjects aged 60 years or older, compared with 195,264 age-matched heterosexual subjects. Dementia diagnoses occurred from 1996 to 2015, and the mean follow-up time was 9 years. A quarter of the sample identified as lesbian, 37% identified as gay men, and 38% as bisexual; among these, 48% were women. Depression was more common among the LGB group (35% vs. 28%), as was posttraumatic stress disorder (1.9% vs. 1%). Both are well documented risk factors for dementia.
However, there were no significant difference in other risk factors, including hypertension, stroke, and heart disease, Dr. Flatt noted. He and his associates did not examine midlife obesity, physical inactivity, or low educational attainment, but will do so in a future analysis.
A dementia diagnosis occurred among 343 (8%) of the LGB group and 18,060 (9.2%) of the heterosexual group. The disorder manifested earlier in the LGB group (average 69 vs. 71 years). Self-identified men were overrepresented in the sample (63% vs. 44%) – a key difference, since women are generally found to have a significantly increased risk compared with men. However, Dr. Flatt noted, the study didn’t collect information that would show biological sex, so that number could be skewed.
Higher education didn’t seem to be as protective in the LGB population, with 62% having a college education, compared with 40% of the heterosexual sample.
In a regression analysis that adjusted for age and education, Dr. Flatt reported that depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (OR, 2.5).
These initial findings highlight the need for more research into this population, he said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs.” This might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
SOURCE: Flatt J et al. AAIC 2018, Abstract P1-619.
CHICAGO – The first comprehensive analysis of dementia prevalence among sexual minorities has found a rate of 8% in this population.
While only marginally lower than the 9% prevalence among a heterosexual comparator group, the disorder manifested at an earlier age and occurred more often among men, Jason Flatt, PhD, said at the Alzheimer’s Association International Conference. In addition, higher education didn’t exert the protective influence seen in general populations, said Dr. Flatt of the University of California, San Francisco.
The analysis of a large California health care database is the first step in learning more about dementia in this diverse population, he said. It’s an important quest because the age-risk curve is rising just as quickly among the LGB population as it is in the heterosexual population.
“We do know there are 2-3 million people who identify as LGB [lesbian, gay, or bisexual] in the U.S., and are 60 years old or older, and with the continued aging of our entire population, we expect this number to increase to about 6 million by 2040,” he said. “Given the gaps in collection of sexual orientation and gender identification, we haven’t been able to look at this issue before.”
Sexual minorities face unique dementia risks, Dr. Flatt noted. They are less likely to marry and have children than are heterosexuals, and twice as likely to live alone. “The often have little or no caregiver support, and are likely to have experienced stigma, discrimination, trauma, and high lifelong stress.”
These experiences make the LGB population less likely to seek out medical care, he said. “All of these things impact health over the life course.”
Dr. Flatt and his colleagues drew their data from the Kaiser Permanente Research Program on Genes, Environment, and Health. The study examined dementia prevalence and comorbidities among 4,337 LGB subjects aged 60 years or older, compared with 195,264 age-matched heterosexual subjects. Dementia diagnoses occurred from 1996 to 2015, and the mean follow-up time was 9 years. A quarter of the sample identified as lesbian, 37% identified as gay men, and 38% as bisexual; among these, 48% were women. Depression was more common among the LGB group (35% vs. 28%), as was posttraumatic stress disorder (1.9% vs. 1%). Both are well documented risk factors for dementia.
However, there were no significant difference in other risk factors, including hypertension, stroke, and heart disease, Dr. Flatt noted. He and his associates did not examine midlife obesity, physical inactivity, or low educational attainment, but will do so in a future analysis.
A dementia diagnosis occurred among 343 (8%) of the LGB group and 18,060 (9.2%) of the heterosexual group. The disorder manifested earlier in the LGB group (average 69 vs. 71 years). Self-identified men were overrepresented in the sample (63% vs. 44%) – a key difference, since women are generally found to have a significantly increased risk compared with men. However, Dr. Flatt noted, the study didn’t collect information that would show biological sex, so that number could be skewed.
Higher education didn’t seem to be as protective in the LGB population, with 62% having a college education, compared with 40% of the heterosexual sample.
In a regression analysis that adjusted for age and education, Dr. Flatt reported that depression almost tripled the risk of dementia among sexual minorities (odds ratio, 2.7). Depression was also a significant dementia risk factor for heterosexual subjects (OR, 2.5).
These initial findings highlight the need for more research into this population, he said.
“We need to provide more LGB-affirming health care services, and this means training health care providers to meet these needs.” This might include improved community outreach that could result in earlier detection and treatment, as well as training medical staff to provide more culturally sensitive care.
SOURCE: Flatt J et al. AAIC 2018, Abstract P1-619.
AT AAIC 2018
Key clinical point: AAIC 2018 highlighted the first study of dementia prevalence among subjects who identified as lesbian, gay, or bisexual.
Major finding: The disorder occurred in 8%, and manifested at an earlier age (69 vs. 71 years).
Study details: The database study comprised 4,337 LGB subjects and 195,264 heterosexual subjects.
Disclosures: Dr. Flatt had no financial disclosures.
Source: Flatt J et al. AAIC 2018, Abstract P1-619.
Breast cancer patients don’t get the financial counseling they want from their clinicians
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer. 
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer.
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
About half of medical oncologists – and even fewer surgeons and radiation oncologists – have someone in their practice to discuss the financial implications of treating breast cancer, a physician-patient survey has found.
Patients are feeling that lack of service, too; 73% of women in the survey said their providers didn’t offer much, or even any, help in tackling the potentially devastating financial impact of their cancer. Women reported a variety of these issues, including increased debt, lost time at work, skimping on their food budget, and even losing their homes as the medical bills added up.
“The privations observed in the current study are sobering and consistent with studies published before the widespread awareness of the potential for financial toxicity after the diagnosis and treatment of cancer,” wrote Reshma Jagsi, MD, and coauthors. The report was published in Cancer.
“… Unfortunately, unmet needs for discussion persist, as does unresolved worry. The percentage of patients who perceive meaningful clinician engagement is low, with far fewer than one-quarter of respondents reporting more than a little discussion of these issues, which is strikingly lower than the percentage of providers who perceive routinely making services available,” they wrote.
Dr. Jagsi, of the University of Michigan, Ann Arbor, and her colleagues used the Surveillance, Epidemiology, and End Results (SEER) database to identify 2,502 women in Georgia and Los Angeles County who were diagnosed with early-stage breast cancer from 2013 to 2015. They contacted these women, who were at least 1 year out from diagnosis, and their oncology providers with a survey designed to determine how both groups communicated about financial issues, and how those issues affected patients’ day-to-day lives.
Most of the clinicians were surgeons (370); the rest were medical oncologists (306) or radiation oncologists (169). About a quarter of each group was in a teaching practice.
Among the medical oncologists, 50.9% reported that someone in their practice often or always discussed financial burden with patients, as did 15.6% of surgeons and 43.2% of radiation oncologists. Medical oncologists were also more likely to respond that they were very aware of out-of-pocket costs for patients, as did 27.3% of surgeons and 34.3% of radiation oncologists.
About 57% of medical oncologists thought it was quite or extremely important to save their patients money; 35.3% of surgeons and 55.8% of radiation oncologists also responded so.
Many women reported at least some measure of financial toxicity related to their cancer and its treatment, and this varied widely by ethnicity and race. Debt was common, noted by 58.9% of black patients, 33.5% of Latina patients, and about 28% of both white and Asian patients.
“Many patients also had substantial lost income and out-of-pocket expenses that they attributed to breast cancer,” the authors wrote. “Overall, 14% of patients reported lost income that was [at least] 10% of their household income, 17% of patients reported spending [at least] 10% of household income on out-of-pocket medical expenses, and 7% of patients reported spending [at least] 10% of household income on out-of-pocket nonmedical expenses.
Housing loss attributed to breast cancer was most common among blacks (6%) and Latinas (4.7%), and less so among whites and Asians (about 1% each).
Blacks and Latinas also were more likely to report a utility disconnection due to unpaid bills (5.9% and 3.2%, respectively) compared with whites and Asians (1.7% and 0.5%).
One way women financially coped, the survey found, was to cut the food budget. “One in five whites [21.5%] and Asians [22.5%] cut down spending on food, as did nearly one-half of black individuals [45.2%] and greater than one-third of Latinas [35.8%].”
Worry about finances was most common among blacks and Latinas (about 50%), but about a third of white and Asian women also reported worry. Survey results suggested that clinicians were not addressing these issues.
Women – especially nonwhite women – wanted to have these talks, with 15.2% of whites, 31.1% of blacks, 30.3% of Latinas, and 25.4% of Asians reporting this desire.
“Unmet patient needs for engagement with physicians regarding financial concerns were common. Of the 945 women who expressed worrying at least somewhat, 679 (72.8%) indicated that cancer physicians and their staff did not help at least somewhat,” the authors said.
More than half of the 523 women who expressed a desire to talk to health care providers regarding the impact of breast cancer on employment or finances (55.4%) reported that this discussion never took place, either with the oncologist, primary care provider, social worker, or any other professional involved in their care.
A multivariate analysis examined patient characteristics associated with the desire to discuss financial toxicity with a health care provider. Younger age, nonwhite race, lower income, being employed, receiving chemotherapy, and living in Georgia all showed significant, independent interaction.
“Given these findings, it is clear that thoughtfully designed, prospective interventions are necessary to address the remarkably common experiences of financial burden that patients report even in the modern era,” the investigators wrote. “These interventions might include training for physicians and their staff regarding how to have effective conversations in this context, in ways that are sensitive to cultural differences and needs. Other promising approaches might include the use of advanced technology to engage patients in interactive exercises that elicit their financial concerns and experiences and alert providers to their needs.”
The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
SOURCE: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
FROM CANCER
Key clinical point: Oncology care providers aren’t providing adequate financial counseling for patients with breast cancer.
Major finding: Half of medical oncologists say they don’t have a staff member routinely discuss the financial impact of breast cancer, and 73% of patients say they’ve never had this discussion with their doctor.
Study details: The survey comprised 2,502 patients and 845 physicians.
Disclosures: The study was largely funded by a grant from the National Cancer Institute and the University of Michigan. Dr. Jagsi disclosed that she has been a consultant for Amgen but not relative to this study.
Source: Jagsi R et al. Cancer 2018 Jul 23. doi: 10.1002/cncr.31532.
Deaths from liver disease surged in U.S. since 1999
Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.
“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”
The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.
Cirrhosis
During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).
Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.
Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.
The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.
Hepatocellular carcinoma
Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.
Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).
The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.
“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).
“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”
However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”
Neither author had any financial disclosure relevant to the work.
SOURCE: Tapper EB et al. BMJ 2018;362:k2817.
Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.
“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”
The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.
Cirrhosis
During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).
Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.
Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.
The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.
Hepatocellular carcinoma
Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.
Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).
The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.
“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).
“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”
However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”
Neither author had any financial disclosure relevant to the work.
SOURCE: Tapper EB et al. BMJ 2018;362:k2817.
Cirrhosis mortality showed a sharp rise beginning in 2009, with a 3.6% annual increase driven entirely by a surge in alcoholic cirrhosis among young people aged 25-34 years, Elliot B. Tapper, MD, and Neehar D. Parikh, MD, reported in the BMJ. The uptick in hepatocellular carcinoma, however, was gradual and consistent, with a 2% annual increase felt mostly in older people, wrote Dr. Tapper and Dr. Parikh, both at the University of Michigan, Ann Arbor.
“The increasing mortality due to cirrhosis and hepatocellular carcinoma speaks to the expanding socioeconomic impact of liver disease,” the colleagues wrote. “Adverse trends in liver-related mortality are particularly unfortunate given that in most cases the liver disease is preventable. Understanding the factors associated with mortality due to these conditions will inform how best to allocate resources.”
The study extracted its data from the Vital Statistic Cooperative and the Centers for Disease Control and Prevention. The investigators not only examined raw mortality numbers, but analyzed them for demographic and geographic trends, in analyses that controlled for age.
Cirrhosis
During the study period, 460,760 patients died from cirrhosis (20,661 in 1999 and 34,174 in 2016, an increase of 65.4%).
Men were twice as likely to die from cirrhosis. Young people aged 25-34 years had the highest rate of increase (3.7% over the entire period and 10.5% from 2009 to 2016). This was directly driven by parallel increases in both alcohol use disorder and alcohol-related liver diseases, which increased by about 16% and 10%, respectively, in this group.
Native Americans had the highest mortality rate (25.8 per 100,000) followed by whites (12.7 per 100,000). “Notably, by 2016, cirrhosis accounted for 6.3% [up from 4.3% in 2009] and 7% [up from 5.8% in 2009] of deaths for Native Americans aged 25-34 and 35 or more, respectively,” and 2.3% of all deaths among adults aged 25-34 years, the authors wrote.
The increases were largely felt in the southern and western states (about 13 per 100,000 in each region). The greatest increases occurred in Kentucky (6.8%), New Mexico (6%), Arkansas (5.7%), Indiana (5%), and Alabama (5%). There was a statistically significant 1.2% decrease in deaths from cirrhosis in Maryland.
Hepatocellular carcinoma
Hepatocellular carcinoma accounted for 136,442 deaths during the study period (5,112 in 1999 and 11,073 in 2016 – an increase of 116.6%). This represented an average annual increase of 2%.
Men were four times more likely to die from hepatocellular carcinoma. The increase manifested mostly in older people, decreasing in those younger than 55 years. Mortality was highest among Asians and Pacific Islanders (6 per 100,000), followed by blacks (4.94 per 100,000).
The increases were largely felt in western states, with an overall increase of 4.2 per 100,000.
“Many of the same states with worsening cirrhosis-related mortality also experienced worsening mortality from hepatocellular carcinoma, including Oregon and Iowa,” the authors wrote. But mortality from the disease also increased significantly in Arizona (5.1%), Kansas (4.3%), Kentucky (4%), and Washington (3.9%).
“Potential explanations supported by these data include increasing early detection of hepatocellular carcinoma, application of curative or locoregional therapies, and, because hepatitis B is the principal cause of hepatocellular carcinoma worldwide and among Asian Americans, effectiveness of vaccination programs and the efficacy of antiviral therapy for hepatitis B in preventing the development of hepatocellular carcinoma.”
However, they noted, “it is unclear how these trends are, or will be, affected by direct-acting antivirals for hepatitis C virus ... eradication of hepatitis C virus will prevent the development of cirrhosis and its complications, potentially changing these trends in the next 5-10 years. However, therapy for hepatitis C viral infection cannot modify the statistically significant trends observed related to alcohol or the expected increase in the burden of nonalcoholic fatty liver disease.”
Neither author had any financial disclosure relevant to the work.
SOURCE: Tapper EB et al. BMJ 2018;362:k2817.
FROM BMJ
Key clinical point: Deaths from cirrhosis and hepatocellular carcinoma have surged in the United States since 1999.
Major finding: Liver cirrhosis mortality increased by 65% and hepatocellular carcinoma mortality by about 117%.
Study details: The study extracted data from the National Vital Statistics database and the CDC.
Disclosures: Neither author had relevant financial disclosures.
Source: Tapper EB et al. BMJ 2018;362:k2817.
New PET imaging agent shows loss of synaptic density in Alzheimer’s brains
Patients with mild Alzheimer’s disease dementia or amnestic mild cognitive impairment due to Alzheimer’s showed 41% less binding of an investigational PET imaging marker of synaptic density when compared with cognitively normal control patients.
“Synaptic loss in the association cortex and the limbic system is a robust and consistent pathology in AD [Alzheimer’s disease] and is closely correlated with cognitive impairment,” wrote Dr. Chen of Yale University, New Haven, Conn., and his associates. “However, until now, the assessment of synaptic density and the quantification of pre-synaptic proteins in AD could only be performed in postmortem brain tissues. The present study demonstrated, for the first time, that noninvasive PET imaging with 11C-UCB-J is capable of measuring reductions in synaptic density in vivo in the hippocampus of individuals with amnestic MCI [mild cognitive impairment] and AD dementia.”
The marker could potentially be used to identify early synaptic loss and track disease progression and therapeutic response, the authors suggested.
The team that created 11C-UCB-J, also known as ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), conducted this study. The agent binds to synaptic vesicle glycoprotein 2A (SV2A), which is the only one of three isoforms that is expressed only in brain synapses. The team’s earlier work showed that SV2A is a marker of synaptic density and that 11C-UCB-J can effectively track changes in the glycoprotein’s presence.
The study comprised 5 patients with amnestic MCI due to AD, 5 with mild AD dementia, and 11 cognitively normal matched controls; they were a mean of 72 years old. All underwent amyloid PET scanning to confirm Alzheimer’s pathology, and then additional PET imaging with 11C-UCB-J.
In a model that corrected for age and brain atrophy, AD patients showed a 41% decrease in hippocampal binding with the agent. The decrease correlated positively with a composite score of episodic memory, the investigators noted.
Dr. Chen disclosed research support from Eli Lilly and Merck; two of his coauthors have a patent pending for a version of the agent.
SOURCE: Chen M-K et al. JAMA Neurol. 2018 July 16. doi: 10.1001/jamaneurol.2018.1836.
The work by Chen et al. could open a new avenue in the research of Alzheimer’s pathophysiology, Elizabeth C. Mormino, PhD, and William J. Jagust, MD, wrote in an editorial (JAMA Neurol. 2018 Jul 16. doi: 10.1001/jamaneurol.2018.1643).
“An examination of synaptic density in conjunction with spatial patterns of beta amyloid and tau (also measurable with PET) will improve our understanding of the long course of AD, beginning with the clinically asymptomatic stages of the disease,” they wrote. “Such studies could support or refute numerous proposed mechanisms of disease causation by these two protein aggregates, as well as many other pathological processes.”
Those lines of investigation might include when synaptic density changes in relation to AB and tau aggregation, and whether anti-amyloid and anti-tau drugs could rescue synapses.
“Given the strong associations between synaptic density and clinical symptoms, a reliable measurement of synaptic density in clinical trials could help establish mechanisms of drug efficacy and even potentially shorten the duration of trials,” Dr. Mormino and Dr. Jagust suggested. “... The addition of a PET ligand that measures synaptic density can provide a tool for disease monitoring and assessing treatment effects in people throughout the spectrum of AD. This approach could also be useful in examining synaptic loss as a disease mechanism in many other neurological disorders that involve brain degeneration,” including psychiatric illnesses that manifest synaptic alterations, such as autism and schizophrenia.
“These developments offer the potential for a much more complete understanding of AD, and potentially other neurodegenerative and psychiatric conditions.”
Dr. Mormino is with Stanford (Calif.) University and Dr. Jagust is with the University of California, Berkeley. They had no disclosures to report.
The work by Chen et al. could open a new avenue in the research of Alzheimer’s pathophysiology, Elizabeth C. Mormino, PhD, and William J. Jagust, MD, wrote in an editorial (JAMA Neurol. 2018 Jul 16. doi: 10.1001/jamaneurol.2018.1643).
“An examination of synaptic density in conjunction with spatial patterns of beta amyloid and tau (also measurable with PET) will improve our understanding of the long course of AD, beginning with the clinically asymptomatic stages of the disease,” they wrote. “Such studies could support or refute numerous proposed mechanisms of disease causation by these two protein aggregates, as well as many other pathological processes.”
Those lines of investigation might include when synaptic density changes in relation to AB and tau aggregation, and whether anti-amyloid and anti-tau drugs could rescue synapses.
“Given the strong associations between synaptic density and clinical symptoms, a reliable measurement of synaptic density in clinical trials could help establish mechanisms of drug efficacy and even potentially shorten the duration of trials,” Dr. Mormino and Dr. Jagust suggested. “... The addition of a PET ligand that measures synaptic density can provide a tool for disease monitoring and assessing treatment effects in people throughout the spectrum of AD. This approach could also be useful in examining synaptic loss as a disease mechanism in many other neurological disorders that involve brain degeneration,” including psychiatric illnesses that manifest synaptic alterations, such as autism and schizophrenia.
“These developments offer the potential for a much more complete understanding of AD, and potentially other neurodegenerative and psychiatric conditions.”
Dr. Mormino is with Stanford (Calif.) University and Dr. Jagust is with the University of California, Berkeley. They had no disclosures to report.
The work by Chen et al. could open a new avenue in the research of Alzheimer’s pathophysiology, Elizabeth C. Mormino, PhD, and William J. Jagust, MD, wrote in an editorial (JAMA Neurol. 2018 Jul 16. doi: 10.1001/jamaneurol.2018.1643).
“An examination of synaptic density in conjunction with spatial patterns of beta amyloid and tau (also measurable with PET) will improve our understanding of the long course of AD, beginning with the clinically asymptomatic stages of the disease,” they wrote. “Such studies could support or refute numerous proposed mechanisms of disease causation by these two protein aggregates, as well as many other pathological processes.”
Those lines of investigation might include when synaptic density changes in relation to AB and tau aggregation, and whether anti-amyloid and anti-tau drugs could rescue synapses.
“Given the strong associations between synaptic density and clinical symptoms, a reliable measurement of synaptic density in clinical trials could help establish mechanisms of drug efficacy and even potentially shorten the duration of trials,” Dr. Mormino and Dr. Jagust suggested. “... The addition of a PET ligand that measures synaptic density can provide a tool for disease monitoring and assessing treatment effects in people throughout the spectrum of AD. This approach could also be useful in examining synaptic loss as a disease mechanism in many other neurological disorders that involve brain degeneration,” including psychiatric illnesses that manifest synaptic alterations, such as autism and schizophrenia.
“These developments offer the potential for a much more complete understanding of AD, and potentially other neurodegenerative and psychiatric conditions.”
Dr. Mormino is with Stanford (Calif.) University and Dr. Jagust is with the University of California, Berkeley. They had no disclosures to report.
Patients with mild Alzheimer’s disease dementia or amnestic mild cognitive impairment due to Alzheimer’s showed 41% less binding of an investigational PET imaging marker of synaptic density when compared with cognitively normal control patients.
“Synaptic loss in the association cortex and the limbic system is a robust and consistent pathology in AD [Alzheimer’s disease] and is closely correlated with cognitive impairment,” wrote Dr. Chen of Yale University, New Haven, Conn., and his associates. “However, until now, the assessment of synaptic density and the quantification of pre-synaptic proteins in AD could only be performed in postmortem brain tissues. The present study demonstrated, for the first time, that noninvasive PET imaging with 11C-UCB-J is capable of measuring reductions in synaptic density in vivo in the hippocampus of individuals with amnestic MCI [mild cognitive impairment] and AD dementia.”
The marker could potentially be used to identify early synaptic loss and track disease progression and therapeutic response, the authors suggested.
The team that created 11C-UCB-J, also known as ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), conducted this study. The agent binds to synaptic vesicle glycoprotein 2A (SV2A), which is the only one of three isoforms that is expressed only in brain synapses. The team’s earlier work showed that SV2A is a marker of synaptic density and that 11C-UCB-J can effectively track changes in the glycoprotein’s presence.
The study comprised 5 patients with amnestic MCI due to AD, 5 with mild AD dementia, and 11 cognitively normal matched controls; they were a mean of 72 years old. All underwent amyloid PET scanning to confirm Alzheimer’s pathology, and then additional PET imaging with 11C-UCB-J.
In a model that corrected for age and brain atrophy, AD patients showed a 41% decrease in hippocampal binding with the agent. The decrease correlated positively with a composite score of episodic memory, the investigators noted.
Dr. Chen disclosed research support from Eli Lilly and Merck; two of his coauthors have a patent pending for a version of the agent.
SOURCE: Chen M-K et al. JAMA Neurol. 2018 July 16. doi: 10.1001/jamaneurol.2018.1836.
Patients with mild Alzheimer’s disease dementia or amnestic mild cognitive impairment due to Alzheimer’s showed 41% less binding of an investigational PET imaging marker of synaptic density when compared with cognitively normal control patients.
“Synaptic loss in the association cortex and the limbic system is a robust and consistent pathology in AD [Alzheimer’s disease] and is closely correlated with cognitive impairment,” wrote Dr. Chen of Yale University, New Haven, Conn., and his associates. “However, until now, the assessment of synaptic density and the quantification of pre-synaptic proteins in AD could only be performed in postmortem brain tissues. The present study demonstrated, for the first time, that noninvasive PET imaging with 11C-UCB-J is capable of measuring reductions in synaptic density in vivo in the hippocampus of individuals with amnestic MCI [mild cognitive impairment] and AD dementia.”
The marker could potentially be used to identify early synaptic loss and track disease progression and therapeutic response, the authors suggested.
The team that created 11C-UCB-J, also known as ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), conducted this study. The agent binds to synaptic vesicle glycoprotein 2A (SV2A), which is the only one of three isoforms that is expressed only in brain synapses. The team’s earlier work showed that SV2A is a marker of synaptic density and that 11C-UCB-J can effectively track changes in the glycoprotein’s presence.
The study comprised 5 patients with amnestic MCI due to AD, 5 with mild AD dementia, and 11 cognitively normal matched controls; they were a mean of 72 years old. All underwent amyloid PET scanning to confirm Alzheimer’s pathology, and then additional PET imaging with 11C-UCB-J.
In a model that corrected for age and brain atrophy, AD patients showed a 41% decrease in hippocampal binding with the agent. The decrease correlated positively with a composite score of episodic memory, the investigators noted.
Dr. Chen disclosed research support from Eli Lilly and Merck; two of his coauthors have a patent pending for a version of the agent.
SOURCE: Chen M-K et al. JAMA Neurol. 2018 July 16. doi: 10.1001/jamaneurol.2018.1836.
FROM JAMA NEUROLOGY
Key clinical point:
Major finding: Compared to controls, patients with amnestic MCI due to AD or mild AD dementia had a 41% decrease in hippocampal binding with 11C-UCB-J.
Study details: The study comprised 5 patients with amnestic MCI due to AD, 5 with mild AD dementia, and 11 age-matched, cognitively normal controls.
Disclosures: Dr. Chen disclosed research support from Eli Lilly and Merck; two of his coauthors have a patent pending for a version of the agent.
Source: Chen M-K et al. JAMA Neurol. 2018 Jul 16. doi: 10.1001/jamaneurol.2018.1836.
About half of FDA expedited approvals lack double-blind trials
About half of the drugs approved under the Food and Drug Administrations’s Breakthrough Therapy designation have lacked the gold-standard evidence of a double-blind, randomized, placebo-controlled trial, according to a new JAMA report.
“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” wrote Jeremy Puthumana and his coauthors. “Furthermore, more than half were based on a single, pivotal trial.”
The average premarket development time was about 5 years, but regulatory review of these agents took less than 7 months on average, the report found.
Mr. Puthumana, of Yale University, New Haven, Conn., and his coauthors, reviewed all 46 of the drugs and biologics approved by the FDA from 2012 to 2017 under the designation. The Breakthrough Therapy designation allows for the rapid review of drugs and biologics for serious or life-threatening conditions where there is preliminary evidence demonstrating a substantial improvement over existing therapies. The researchers identified all pivotal trials supporting approval, looking at randomization, blinding, comparator group, primary endpoint, and patient numbers.
Of these drugs, most (25) were oncologic agents. Other indications were infectious disease (8), genetic or metabolic disorders (5), and other unspecified purposes (8). The median number of patients enrolled among all pivotal trials supporting an indication approval was 222.
Most of the approvals (27) were based on randomized trials, 21 (45.7%) were based on double-blind randomization, 25 (54.3%) employed an active or placebo comparator group, and 10 (21.7%) used a clinical primary endpoint.
Compared with drugs without accelerated approval, drugs with accelerated approval status were less likely to be examined in randomized or double-blinded trials(24 vs. 3 and 20 vs. 1, respectively), and were less likely to include a control group (32 vs. 3).
However, all drugs with Accelerated Approval status underwent at least one clinical safety or efficacy-focused postmarketing requirement, as did 64.3% of those without that status.
“Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals,” the authors wrote. “FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.”
Mr. Puthumana reported having no financial disclosures.
SOURCE: Puthumana J et al. JAMA. 2018;320(3):301-3.
Expedited drug approvals raise concerns that important questions about safety and effectiveness might be insufficiently answered before an agent makes it to pharmacy shelves, Austin B. Frakt, PhD, wrote in an accompanying editorial.
Several key facts suggest that the Food and Drug Administration’s expedited review programs may invite greater risks than benefits, he wrote.
Most new drugs are approved with relatively little data about long-term outcomes.
More than two-thirds of approvals are based on studies lasting less than 6 months.
The FDA approves novel therapeutic agents more quickly than do similar regulatory bodies in Europe and Canada, with a median time of 6 months for cancer drug approval.
Expedited reviews have increased in the last 2 decades. The increase is driven by drugs that are not first in their class, implying that they aren’t addressing unmet needs.
“The idea that doing something more quickly means it is not done as well has considerable face validity,” Dr. Frakt wrote. Nevertheless, at least one study suggests that expedited FDA approvals do confer substantial gains in quality of life. “[The study suggests] that the FDA’s expedited drug review programs include drugs that provide greater benefits than those undergoing conventional review. Indeed, to the extent the expedited programs handle drugs for conditions for which there is unmet medical need, relatively larger QALY [quality-adjusted life-year] gains are to be expected.”
However, drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings. But in some cases, at least, the trade-off seems worth it.
“Because expedited review programs are intended for drugs that treat serious conditions and address unmet medical needs, accepting greater risk may be reasonable and more consistent with patients’ preferences,” he said. “However, because many of these drugs also come with high price tags, financed with public funds through Medicare, Medicaid, and other programs, the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.”
Dr. Frakt is director of the Partnered Evidence-based Policy Resource Center at the Boston Veterans Affairs Healthcare System. His remarks are adapted from an accompanying editorial (JAMA. 2018;320[3]:225-6).
Expedited drug approvals raise concerns that important questions about safety and effectiveness might be insufficiently answered before an agent makes it to pharmacy shelves, Austin B. Frakt, PhD, wrote in an accompanying editorial.
Several key facts suggest that the Food and Drug Administration’s expedited review programs may invite greater risks than benefits, he wrote.
Most new drugs are approved with relatively little data about long-term outcomes.
More than two-thirds of approvals are based on studies lasting less than 6 months.
The FDA approves novel therapeutic agents more quickly than do similar regulatory bodies in Europe and Canada, with a median time of 6 months for cancer drug approval.
Expedited reviews have increased in the last 2 decades. The increase is driven by drugs that are not first in their class, implying that they aren’t addressing unmet needs.
“The idea that doing something more quickly means it is not done as well has considerable face validity,” Dr. Frakt wrote. Nevertheless, at least one study suggests that expedited FDA approvals do confer substantial gains in quality of life. “[The study suggests] that the FDA’s expedited drug review programs include drugs that provide greater benefits than those undergoing conventional review. Indeed, to the extent the expedited programs handle drugs for conditions for which there is unmet medical need, relatively larger QALY [quality-adjusted life-year] gains are to be expected.”
However, drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings. But in some cases, at least, the trade-off seems worth it.
“Because expedited review programs are intended for drugs that treat serious conditions and address unmet medical needs, accepting greater risk may be reasonable and more consistent with patients’ preferences,” he said. “However, because many of these drugs also come with high price tags, financed with public funds through Medicare, Medicaid, and other programs, the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.”
Dr. Frakt is director of the Partnered Evidence-based Policy Resource Center at the Boston Veterans Affairs Healthcare System. His remarks are adapted from an accompanying editorial (JAMA. 2018;320[3]:225-6).
Expedited drug approvals raise concerns that important questions about safety and effectiveness might be insufficiently answered before an agent makes it to pharmacy shelves, Austin B. Frakt, PhD, wrote in an accompanying editorial.
Several key facts suggest that the Food and Drug Administration’s expedited review programs may invite greater risks than benefits, he wrote.
Most new drugs are approved with relatively little data about long-term outcomes.
More than two-thirds of approvals are based on studies lasting less than 6 months.
The FDA approves novel therapeutic agents more quickly than do similar regulatory bodies in Europe and Canada, with a median time of 6 months for cancer drug approval.
Expedited reviews have increased in the last 2 decades. The increase is driven by drugs that are not first in their class, implying that they aren’t addressing unmet needs.
“The idea that doing something more quickly means it is not done as well has considerable face validity,” Dr. Frakt wrote. Nevertheless, at least one study suggests that expedited FDA approvals do confer substantial gains in quality of life. “[The study suggests] that the FDA’s expedited drug review programs include drugs that provide greater benefits than those undergoing conventional review. Indeed, to the extent the expedited programs handle drugs for conditions for which there is unmet medical need, relatively larger QALY [quality-adjusted life-year] gains are to be expected.”
However, drugs subject to less FDA scrutiny are more likely to exhibit safety problems, be withdrawn from the market, or carry black box warnings. But in some cases, at least, the trade-off seems worth it.
“Because expedited review programs are intended for drugs that treat serious conditions and address unmet medical needs, accepting greater risk may be reasonable and more consistent with patients’ preferences,” he said. “However, because many of these drugs also come with high price tags, financed with public funds through Medicare, Medicaid, and other programs, the patients’ point of view is not the only one of relevance. A consideration of cost is also reasonable from the point of view of taxpayers.”
Dr. Frakt is director of the Partnered Evidence-based Policy Resource Center at the Boston Veterans Affairs Healthcare System. His remarks are adapted from an accompanying editorial (JAMA. 2018;320[3]:225-6).
About half of the drugs approved under the Food and Drug Administrations’s Breakthrough Therapy designation have lacked the gold-standard evidence of a double-blind, randomized, placebo-controlled trial, according to a new JAMA report.
“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” wrote Jeremy Puthumana and his coauthors. “Furthermore, more than half were based on a single, pivotal trial.”
The average premarket development time was about 5 years, but regulatory review of these agents took less than 7 months on average, the report found.
Mr. Puthumana, of Yale University, New Haven, Conn., and his coauthors, reviewed all 46 of the drugs and biologics approved by the FDA from 2012 to 2017 under the designation. The Breakthrough Therapy designation allows for the rapid review of drugs and biologics for serious or life-threatening conditions where there is preliminary evidence demonstrating a substantial improvement over existing therapies. The researchers identified all pivotal trials supporting approval, looking at randomization, blinding, comparator group, primary endpoint, and patient numbers.
Of these drugs, most (25) were oncologic agents. Other indications were infectious disease (8), genetic or metabolic disorders (5), and other unspecified purposes (8). The median number of patients enrolled among all pivotal trials supporting an indication approval was 222.
Most of the approvals (27) were based on randomized trials, 21 (45.7%) were based on double-blind randomization, 25 (54.3%) employed an active or placebo comparator group, and 10 (21.7%) used a clinical primary endpoint.
Compared with drugs without accelerated approval, drugs with accelerated approval status were less likely to be examined in randomized or double-blinded trials(24 vs. 3 and 20 vs. 1, respectively), and were less likely to include a control group (32 vs. 3).
However, all drugs with Accelerated Approval status underwent at least one clinical safety or efficacy-focused postmarketing requirement, as did 64.3% of those without that status.
“Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals,” the authors wrote. “FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.”
Mr. Puthumana reported having no financial disclosures.
SOURCE: Puthumana J et al. JAMA. 2018;320(3):301-3.
About half of the drugs approved under the Food and Drug Administrations’s Breakthrough Therapy designation have lacked the gold-standard evidence of a double-blind, randomized, placebo-controlled trial, according to a new JAMA report.
“This study of all FDA approvals granted Breakthrough Therapy designation from 2012 through 2017 suggests that pivotal trials supporting these approvals commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary end points, and enrolled small numbers of patients,” wrote Jeremy Puthumana and his coauthors. “Furthermore, more than half were based on a single, pivotal trial.”
The average premarket development time was about 5 years, but regulatory review of these agents took less than 7 months on average, the report found.
Mr. Puthumana, of Yale University, New Haven, Conn., and his coauthors, reviewed all 46 of the drugs and biologics approved by the FDA from 2012 to 2017 under the designation. The Breakthrough Therapy designation allows for the rapid review of drugs and biologics for serious or life-threatening conditions where there is preliminary evidence demonstrating a substantial improvement over existing therapies. The researchers identified all pivotal trials supporting approval, looking at randomization, blinding, comparator group, primary endpoint, and patient numbers.
Of these drugs, most (25) were oncologic agents. Other indications were infectious disease (8), genetic or metabolic disorders (5), and other unspecified purposes (8). The median number of patients enrolled among all pivotal trials supporting an indication approval was 222.
Most of the approvals (27) were based on randomized trials, 21 (45.7%) were based on double-blind randomization, 25 (54.3%) employed an active or placebo comparator group, and 10 (21.7%) used a clinical primary endpoint.
Compared with drugs without accelerated approval, drugs with accelerated approval status were less likely to be examined in randomized or double-blinded trials(24 vs. 3 and 20 vs. 1, respectively), and were less likely to include a control group (32 vs. 3).
However, all drugs with Accelerated Approval status underwent at least one clinical safety or efficacy-focused postmarketing requirement, as did 64.3% of those without that status.
“Patients and physicians may have misconceptions about the strength of evidence supporting breakthrough approvals,” the authors wrote. “FDA-required postmarketing studies will be critical to confirm the clinical benefit and safety of these promising, newly approved therapies.”
Mr. Puthumana reported having no financial disclosures.
SOURCE: Puthumana J et al. JAMA. 2018;320(3):301-3.
FROM JAMA
Key clinical point:
Major finding: Just 45.7% of drugs granted Breakthrough Therapy approval by the Food and Drug Administration went through a double-blind, randomized study.
Study details: The review comprised 46 drugs granted Breakthrough status from 2012 to 2017.
Disclosures: Mr. Puthumana reported having no financial disclosures.
Source: Puthumana J et al. JAMA. 2018;320[3]:301-3.
Better ICU staff communication with family may improve end-of-life choices
A nurse-led support intervention for the families of critically ill patients did little to ease families’ psychological symptoms, but it did improve their perception of staff communication and family-centered care in the intensive care unit.
The length of ICU stay was also significantly shorter and the in-unit death rate higher among patients whose families received the intervention – a finding that suggests difficult end-of-life choices may have been eased, reported Douglas B. White, MD, and his colleagues (N Engl J Med. 2018;378:2365-75).
“The intervention resulted in significant improvements in markers of the quality of decision making, including the patient- and family-centeredness of care and the quality of clinician-family communication. Taken together, these findings suggest that the intervention allowed surrogates to transition a patient’s treatment to comfort-focused care when doing so aligned with the patient’s values,” wrote Dr. White of the University of Pittsburgh. “A previous study that was conducted in the context of advanced illness suggested that treatment that accords with the patient’s preferences may lead to shorter survival among those who prioritize comfort over longevity.”
The trial randomized 1,420 patients and their family surrogates in five ICUs to usual care, or to the multicomponent family-support intervention. The primary outcome was change in the surrogates’ scores on the Hospital Anxiety Depression Scale (HADS) at 6 months. The secondary outcomes were changes in Impact of Event Scale (IES; a measure of posttraumatic stress) the Quality of Communication (QOC) scale, quality of clinician-family communication measured by the Patient Perception of Patient Centeredness (PPPC) scale and the mean length of ICU stay.
The intervention was delivered by nurses who received special training on communication and other skills needed to support the families of critically ill patients. Nurses met with families every day and arranged regular meetings with ICU clinicians. A quality improvement specialist incorporated the family support into daily work flow.
In a fully adjusted model, there was no significant between-group difference in the 6-month HADS scores (11.7 vs. 12 points). Likewise, there was no significant difference between the groups in the mean IES score at 6 months.
Family members in the active group did rate the quality of clinician-family communication as significantly better, and they also gave significantly higher ratings to the quality of patient- and family-centered care during the ICU stay.
The shorter length of stay was reflected in the time to death among patients who died during the stay (4.4 days in the intervention group vs. 6.8 days in the control group), although there was no significant difference in length of stay among patients who survived to discharge. Significantly more patients in the intervention group died in the ICU as well (36% vs. 28.5%); however, there was no significant difference in 6-month mortality (60.4% vs. 55.4%).
The study was supported by an Innovation Award from the University of Pittsburgh Medical Center Health System and by the Greenwell Foundation. Dr. White reported having no financial disclosures
Although the results by White and colleagues “cannot be interpreted as clinically directive,” the study offers a glimpse of the path forward in improving the experience of families with critically ill loved ones, Daniela Lamas, MD, wrote in an accompanying editorial (N Engl J Med. 2018; 378:2431-2).
The study didn’t meet its primary endpoint of reducing surrogates’ psychological symptoms at 6 months, but it did lead to an improved ICU experience, with better clinician communication. There was another finding that deserves a close look: In the intervention group, ICU length of stay was shorter and in-hospital mortality greater, although mortality among those who survived to discharge was similar at 6 months.
These findings suggest that the intervention did not lead to the premature death of patients who would have otherwise done well, but rather was associated with a shorter dying process for those who faced a dismal prognosis, according to Dr. Lamas.
“As we increasingly look beyond mortality as the primary outcome that matters, seeking to maximize quality of life and minimize suffering, this work represents an ‘end of the beginning’ by suggesting the next steps in moving closer to achieving these goals.”
Dr. Lamas is a pulmonary and critical care doctor at Brigham & Women’s Hospital and on the faculty at Harvard Medical School, Boston.
Although the results by White and colleagues “cannot be interpreted as clinically directive,” the study offers a glimpse of the path forward in improving the experience of families with critically ill loved ones, Daniela Lamas, MD, wrote in an accompanying editorial (N Engl J Med. 2018; 378:2431-2).
The study didn’t meet its primary endpoint of reducing surrogates’ psychological symptoms at 6 months, but it did lead to an improved ICU experience, with better clinician communication. There was another finding that deserves a close look: In the intervention group, ICU length of stay was shorter and in-hospital mortality greater, although mortality among those who survived to discharge was similar at 6 months.
These findings suggest that the intervention did not lead to the premature death of patients who would have otherwise done well, but rather was associated with a shorter dying process for those who faced a dismal prognosis, according to Dr. Lamas.
“As we increasingly look beyond mortality as the primary outcome that matters, seeking to maximize quality of life and minimize suffering, this work represents an ‘end of the beginning’ by suggesting the next steps in moving closer to achieving these goals.”
Dr. Lamas is a pulmonary and critical care doctor at Brigham & Women’s Hospital and on the faculty at Harvard Medical School, Boston.
Although the results by White and colleagues “cannot be interpreted as clinically directive,” the study offers a glimpse of the path forward in improving the experience of families with critically ill loved ones, Daniela Lamas, MD, wrote in an accompanying editorial (N Engl J Med. 2018; 378:2431-2).
The study didn’t meet its primary endpoint of reducing surrogates’ psychological symptoms at 6 months, but it did lead to an improved ICU experience, with better clinician communication. There was another finding that deserves a close look: In the intervention group, ICU length of stay was shorter and in-hospital mortality greater, although mortality among those who survived to discharge was similar at 6 months.
These findings suggest that the intervention did not lead to the premature death of patients who would have otherwise done well, but rather was associated with a shorter dying process for those who faced a dismal prognosis, according to Dr. Lamas.
“As we increasingly look beyond mortality as the primary outcome that matters, seeking to maximize quality of life and minimize suffering, this work represents an ‘end of the beginning’ by suggesting the next steps in moving closer to achieving these goals.”
Dr. Lamas is a pulmonary and critical care doctor at Brigham & Women’s Hospital and on the faculty at Harvard Medical School, Boston.
A nurse-led support intervention for the families of critically ill patients did little to ease families’ psychological symptoms, but it did improve their perception of staff communication and family-centered care in the intensive care unit.
The length of ICU stay was also significantly shorter and the in-unit death rate higher among patients whose families received the intervention – a finding that suggests difficult end-of-life choices may have been eased, reported Douglas B. White, MD, and his colleagues (N Engl J Med. 2018;378:2365-75).
“The intervention resulted in significant improvements in markers of the quality of decision making, including the patient- and family-centeredness of care and the quality of clinician-family communication. Taken together, these findings suggest that the intervention allowed surrogates to transition a patient’s treatment to comfort-focused care when doing so aligned with the patient’s values,” wrote Dr. White of the University of Pittsburgh. “A previous study that was conducted in the context of advanced illness suggested that treatment that accords with the patient’s preferences may lead to shorter survival among those who prioritize comfort over longevity.”
The trial randomized 1,420 patients and their family surrogates in five ICUs to usual care, or to the multicomponent family-support intervention. The primary outcome was change in the surrogates’ scores on the Hospital Anxiety Depression Scale (HADS) at 6 months. The secondary outcomes were changes in Impact of Event Scale (IES; a measure of posttraumatic stress) the Quality of Communication (QOC) scale, quality of clinician-family communication measured by the Patient Perception of Patient Centeredness (PPPC) scale and the mean length of ICU stay.
The intervention was delivered by nurses who received special training on communication and other skills needed to support the families of critically ill patients. Nurses met with families every day and arranged regular meetings with ICU clinicians. A quality improvement specialist incorporated the family support into daily work flow.
In a fully adjusted model, there was no significant between-group difference in the 6-month HADS scores (11.7 vs. 12 points). Likewise, there was no significant difference between the groups in the mean IES score at 6 months.
Family members in the active group did rate the quality of clinician-family communication as significantly better, and they also gave significantly higher ratings to the quality of patient- and family-centered care during the ICU stay.
The shorter length of stay was reflected in the time to death among patients who died during the stay (4.4 days in the intervention group vs. 6.8 days in the control group), although there was no significant difference in length of stay among patients who survived to discharge. Significantly more patients in the intervention group died in the ICU as well (36% vs. 28.5%); however, there was no significant difference in 6-month mortality (60.4% vs. 55.4%).
The study was supported by an Innovation Award from the University of Pittsburgh Medical Center Health System and by the Greenwell Foundation. Dr. White reported having no financial disclosures
A nurse-led support intervention for the families of critically ill patients did little to ease families’ psychological symptoms, but it did improve their perception of staff communication and family-centered care in the intensive care unit.
The length of ICU stay was also significantly shorter and the in-unit death rate higher among patients whose families received the intervention – a finding that suggests difficult end-of-life choices may have been eased, reported Douglas B. White, MD, and his colleagues (N Engl J Med. 2018;378:2365-75).
“The intervention resulted in significant improvements in markers of the quality of decision making, including the patient- and family-centeredness of care and the quality of clinician-family communication. Taken together, these findings suggest that the intervention allowed surrogates to transition a patient’s treatment to comfort-focused care when doing so aligned with the patient’s values,” wrote Dr. White of the University of Pittsburgh. “A previous study that was conducted in the context of advanced illness suggested that treatment that accords with the patient’s preferences may lead to shorter survival among those who prioritize comfort over longevity.”
The trial randomized 1,420 patients and their family surrogates in five ICUs to usual care, or to the multicomponent family-support intervention. The primary outcome was change in the surrogates’ scores on the Hospital Anxiety Depression Scale (HADS) at 6 months. The secondary outcomes were changes in Impact of Event Scale (IES; a measure of posttraumatic stress) the Quality of Communication (QOC) scale, quality of clinician-family communication measured by the Patient Perception of Patient Centeredness (PPPC) scale and the mean length of ICU stay.
The intervention was delivered by nurses who received special training on communication and other skills needed to support the families of critically ill patients. Nurses met with families every day and arranged regular meetings with ICU clinicians. A quality improvement specialist incorporated the family support into daily work flow.
In a fully adjusted model, there was no significant between-group difference in the 6-month HADS scores (11.7 vs. 12 points). Likewise, there was no significant difference between the groups in the mean IES score at 6 months.
Family members in the active group did rate the quality of clinician-family communication as significantly better, and they also gave significantly higher ratings to the quality of patient- and family-centered care during the ICU stay.
The shorter length of stay was reflected in the time to death among patients who died during the stay (4.4 days in the intervention group vs. 6.8 days in the control group), although there was no significant difference in length of stay among patients who survived to discharge. Significantly more patients in the intervention group died in the ICU as well (36% vs. 28.5%); however, there was no significant difference in 6-month mortality (60.4% vs. 55.4%).
The study was supported by an Innovation Award from the University of Pittsburgh Medical Center Health System and by the Greenwell Foundation. Dr. White reported having no financial disclosures
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A family communication intervention didn’t improve 6-month psychological symptoms among those with loved ones in intensive care units.
Major finding: There was no significant difference on the Hospital Anxiety and Depression Scale at 6 months (11.7 vs. 12 points).
Study details: The study randomized 1,420 ICU patients and surrogates to the intervention or to usual care.
Disclosures: The study was supported by an Innovation Award from the University of Pittsburgh Medical Center Health System and by the Greenwell Foundation. Dr. White had no financial disclosures.
Source: White et al. N Engl J Med. 2018;378:2365-75.
AGA Clinical Practice Update: Statins are safe, effective, and important for most patients with liver disease and dyslipidemia
The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.
Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.
“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”
Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.
The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
DILI
DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.
NAFLD
Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.
NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
Viral hepatitis
Hepatitis C virus
Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.
Hepatitis B virus
HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.
PBC
PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.
Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
Cirrhosis
Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.
Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.
There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
Posttransplant dyslipidemia
After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.
Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.
Neither Dr. Speliotes nor her coauthors had any financial disclosures.
SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.
The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.
Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.
“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”
Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.
The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
DILI
DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.
NAFLD
Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.
NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
Viral hepatitis
Hepatitis C virus
Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.
Hepatitis B virus
HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.
PBC
PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.
Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
Cirrhosis
Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.
Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.
There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
Posttransplant dyslipidemia
After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.
Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.
Neither Dr. Speliotes nor her coauthors had any financial disclosures.
SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.
The medications are only contraindicated in patients with decompensated cirrhosis and statin-induced liver injury, Elizabeth Speliotes, MD, PhD, MPH, and her colleagues wrote in an expert review published in Clinical Gastroenterology and Hepatology. In these patients, statin treatment can compound liver damage and should be avoided, wrote Dr. Speliotes and her coauthors.
Because the liver plays a central role in cholesterol production, many clinicians shy away from treating hyperlipidemia in patients with liver disease. But studies consistently show that lipid-lowering drugs improve dyslipidemia in these patients, which significantly improves both high- and low-density lipoproteins and thereby reduces the long-term risk of cardiovascular disease, the authors wrote.
“Furthermore, the liver plays a role in the metabolism of many drugs, including those that are used to treat dyslipidemia,” wrote Dr. Speliotes of the University of Michigan, Ann Arbor. “It is not surprising, therefore, that many practitioners are hesitant to prescribe medicines to treat dyslipidemia in the setting of liver disease.”
Cholesterol targets described in the 2013 American College of Cardiology/American Heart Association guidelines can safely be applied to patients with liver disease. “The guidelines recommend that adults with cardiovascular disease or LDL of 190 mg/dL or higher be treated with high-intensity statins with the goal of reducing LDL levels by 50%,” they said. Patients whose LDL is 189 mg/dL or lower will benefit from moderate-intensity statins, with a target of a 30%-50% decrease in LDL.
The authors described best practice advice for dyslipidemia treatment in six liver diseases: drug-induced liver injury (DILI), nonalcoholic fatty liver disease (NAFLD), viral hepatitis B and C (HBV and HCV), primary biliary cholangitis (PBC), cirrhosis, and posttransplant dyslipidemia.
DILI
DILI is characterized by elevations of threefold or more in serum alanine aminotransferase (ALT) or aspartate aminotransferase and at least a doubling of total serum bilirubin with no other identifiable cause of these aberrations except the suspect drug. Statins rarely cause a DILI (1 in 100,000 patients), but can cause transient, benign ALT elevations. Statins should be discontinued if ALT or aspartate aminotransferase levels exceed a tripling of the upper limit of normal with concomitant bilirubin elevations. They should not be prescribed to patients with acute liver failure or decompensated liver disease, but otherwise they are safe for most patients with liver disease.
NAFLD
Many patients with NAFLD also have dyslipidemia. All NAFLD patients have an increased risk of cardiovascular disease, although NAFLD and nonalcoholic steatohepatitis are not traditional cardiovascular risk factors. Nevertheless, statins and the accompanying improvement in dyslipidemia have been shown to decrease cardiovascular mortality in these patients. The IDEAL study, for example, showed that moderate statin treatment with 80 mg atorvastatin was associated with a 44% decreased risk in secondary cardiovascular events. Other studies show similar results.
NAFLD patients with elevated LDL may benefit from ezetimibe as primary or add-on therapy. However, none of the drugs used to treat dyslipidemia will improve NAFLD or nonalcoholic steatohepatitis histology.
Viral hepatitis
Hepatitis C virus
Patients with HCV infection often experience decreased serum LDL and total cholesterol. However, these are virally mediated and don’t confer cardiovascular protection. In fact, HCV infections are associated with an increased risk of myocardial infarction. If the patient spontaneously clears the virus, lipids may rebound, so levels should be regularly monitored even if the patient does not need statin therapy.
Hepatitis B virus
HBV also interacts with lipid metabolism and can lead to hyperlipidemia. The American College of Cardiology/American Heart Association guidelines for cardiovascular risk assessment and statin therapy apply to these patients. Statins are safe in patients with either HCV or HBV, who tolerate them well.
PBC
PBC is a chronic autoimmune inflammatory cholestatic disease that is associated with dyslipidemia. These patients exhibit increased serum triglyceride and HDL levels that vary according to PBC stage. About 10% have a significant risk of cardiovascular disease. PBC patients with compensated liver disease can safely tolerate statin treatment, but the drugs should not be given to PBC patients with decompensated liver disease.
Obeticholic acid (OCA) is sometimes used as second-line therapy for PBC; it affects genes that regulate bile acid synthesis, transport, and action. However, the POISE study showed that, while OCA improved PBC symptoms, it was associated with an increase in LDL and total cholesterol and a decrease in HDL. No follow-up studies have determined cardiovascular implications of that change, but OCA should be avoided in patients with active cardiovascular disease or with cardiovascular risk factors.
Cirrhosis
Recent work suggests that patients with cirrhosis may face a higher risk of coronary artery disease than was previously thought, although that risk varies widely according to the etiology of the cirrhosis.
Statins are safe and effective in patients with Child-Pugh class A cirrhosis; there are few data on their safety in patients with decompensated cirrhosis. Some guidance for these patients exists in the 2014 recommendations of the Liver Expert Panel, which advised against statin use in patients with Child-Pugh class B or C cirrhosis.
There’s some evidence that statins reduce portal pressure and may reduce the risk of decompensation in patients whose cirrhosis is caused by HCV or HBV infections, but they should not be used for this purpose.
Posttransplant dyslipidemia
After liver transplant, more than 60% of patients will develop dyslipidemia; these patients often have obesity or diabetes.
Statins are safe for patients with liver transplant. Concomitant use of calcineurin inhibitors and statins that are metabolized by cytochrome P450 may increase the risk of statin-associated myopathy. Pravastatin and fluvastatin are preferable, because they are metabolized by cytochrome P450 34A.
Neither Dr. Speliotes nor her coauthors had any financial disclosures.
SOURCE: Speliotes EK et al. Clin Gastroenterol Hepatol. 2018 Apr 21. doi: 10.1016/j.cgh.2018.04.023.
EXPERT ANALYSIS FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY