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Long-term opioid use substantial in elderly adults prior to total joint replacement
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.
Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.
“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.
This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.
Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.
Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.
Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.
Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.
Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.
SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Long-term opioid use is highly prevalent among older adults with osteoarthritis who underwent total joint replacement.
Major finding: Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama.
Study details: An observational cohort study including 358,121 Medicare enrollees with advanced osteoarthritis.
Disclosures: Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Coauthors provided disclosures related to a number of pharmaceutical companies.
Source: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.
Potential antidepressant overprescribing found in 24% of elderly cohort
Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.
In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). , 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.
Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).
Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.
“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”
The authors reported no conflicts of interest.
SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.
Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.
In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). , 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.
Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).
Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.
“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”
The authors reported no conflicts of interest.
SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.
Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.
In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). , 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.
Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).
Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.
“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”
The authors reported no conflicts of interest.
SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.
FROM PHARMACOLOGY RESEARCH & PERSPECTIVES
Ezetimibe found effective for primary prevention in elderly
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
CHICAGO – has been provided by the Japanese EWTOPIA 75 trial.
Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.
There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.
The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.
“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.
Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.
The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.
The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.
Ezetimibe was the lipid-lowering agent selected for EWTOPIA because it has an excellent safety record in older patients. There were no important differences between the two study arms in terms of adverse events, according to Dr. Ouchi.
Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.
She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.
“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.
“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.
Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.
“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.
As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.
Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
SOURCE: Ouchi Y. AHA Late Breaker 02.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point: LDL-lowering for primary cardiovascular prevention in elderly patients has been shown for the first time to impart significant net benefit.
Major finding: The incidence of atherosclerotic cardiovascular events was reduced by 34% in elderly patients on ezetimibe at 10 mg/day, compared with usual care.
Study details: The 5-year prospective randomized EWTOPIA 75 trial included 3,796 Japanese patients age 75 and older with elevated LDL and no history of CAD.
Disclosures: The presenter reported having no financial conflicts regarding the study, sponsored by the Japanese government.
Source: Ouchi Y. AHA Late Breaker 02.
Frailty may affect the expression of dementia
according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.
“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
More susceptible to dementia?
The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.
Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.
To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.
The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.
Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.
In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.
The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
Significant interaction between frailty and Alzheimer’s disease
After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.
One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.
Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.
The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.
SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.
The results of the study by Rockwood and colleagues confirm the strong links between frailty and Alzheimer’s disease and other dementias, said Francesco Panza, MD, PhD, of the University of Bari (Italy) Aldo Moro, and his colleagues in an accompanying editorial.
Frailty is primary or preclinical when it is not directly associated with a specific disease or when the patient has no substantial disability. Frailty is considered secondary or clinical when it is associated with known comorbidities (e.g., cardiovascular disease or depression). “This distinction is central in identifying frailty phenotypes with the potential to predict and prevent dementia, using novel models of risk that introduce modifiable factors,” wrote Dr. Panza and his colleagues.
“In light of current knowledge on the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty can be suggested,” they added. “For instance, individualized multidomain interventions can target physical, nutritional, cognitive, and psychological domains that might delay the progression to overt dementia and secondary occurrence of adverse health-related outcomes, such as disability, hospitalization, and mortality.”
Dr. Panza, Madia Lozupone, MD, PhD , and Giancarlo Logroscino, MD, PhD , are affiliated with the neurodegenerative disease unit in the department of basic medicine, neuroscience, and sense organs at the University of Bari (Italy) Aldo Moro. The above remarks come from an editorial that these authors wrote to accompany the study by Rockwood et al. The authors declared no competing interests.
The results of the study by Rockwood and colleagues confirm the strong links between frailty and Alzheimer’s disease and other dementias, said Francesco Panza, MD, PhD, of the University of Bari (Italy) Aldo Moro, and his colleagues in an accompanying editorial.
Frailty is primary or preclinical when it is not directly associated with a specific disease or when the patient has no substantial disability. Frailty is considered secondary or clinical when it is associated with known comorbidities (e.g., cardiovascular disease or depression). “This distinction is central in identifying frailty phenotypes with the potential to predict and prevent dementia, using novel models of risk that introduce modifiable factors,” wrote Dr. Panza and his colleagues.
“In light of current knowledge on the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty can be suggested,” they added. “For instance, individualized multidomain interventions can target physical, nutritional, cognitive, and psychological domains that might delay the progression to overt dementia and secondary occurrence of adverse health-related outcomes, such as disability, hospitalization, and mortality.”
Dr. Panza, Madia Lozupone, MD, PhD , and Giancarlo Logroscino, MD, PhD , are affiliated with the neurodegenerative disease unit in the department of basic medicine, neuroscience, and sense organs at the University of Bari (Italy) Aldo Moro. The above remarks come from an editorial that these authors wrote to accompany the study by Rockwood et al. The authors declared no competing interests.
The results of the study by Rockwood and colleagues confirm the strong links between frailty and Alzheimer’s disease and other dementias, said Francesco Panza, MD, PhD, of the University of Bari (Italy) Aldo Moro, and his colleagues in an accompanying editorial.
Frailty is primary or preclinical when it is not directly associated with a specific disease or when the patient has no substantial disability. Frailty is considered secondary or clinical when it is associated with known comorbidities (e.g., cardiovascular disease or depression). “This distinction is central in identifying frailty phenotypes with the potential to predict and prevent dementia, using novel models of risk that introduce modifiable factors,” wrote Dr. Panza and his colleagues.
“In light of current knowledge on the cognitive frailty phenotype, secondary preventive strategies for cognitive impairment and physical frailty can be suggested,” they added. “For instance, individualized multidomain interventions can target physical, nutritional, cognitive, and psychological domains that might delay the progression to overt dementia and secondary occurrence of adverse health-related outcomes, such as disability, hospitalization, and mortality.”
Dr. Panza, Madia Lozupone, MD, PhD , and Giancarlo Logroscino, MD, PhD , are affiliated with the neurodegenerative disease unit in the department of basic medicine, neuroscience, and sense organs at the University of Bari (Italy) Aldo Moro. The above remarks come from an editorial that these authors wrote to accompany the study by Rockwood et al. The authors declared no competing interests.
according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.
“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
More susceptible to dementia?
The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.
Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.
To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.
The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.
Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.
In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.
The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
Significant interaction between frailty and Alzheimer’s disease
After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.
One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.
Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.
The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.
SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.
according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.
“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
More susceptible to dementia?
The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.
Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.
To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.
The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.
Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.
In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.
The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
Significant interaction between frailty and Alzheimer’s disease
After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.
One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.
Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.
The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.
SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.
FROM LANCET NEUROLOGY
Key clinical point: Frailty modifies the association between Alzheimer’s disease pathology and Alzheimer dementia.
Major finding: Frailty index score (odds ratio, 1.76) is independently associated with dementia status.
Study details: A cross-sectional analysis of 456 deceased participants in the Rush Memory and Aging Project.
Disclosures: The study had no outside funding.
Source: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.
Deep sleep decreases, Alzheimer’s increases
Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
AAP guidance: How to ask about military service
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Researchers exploring ways to mitigate aging’s impact on diabetes
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
Antidepressants tied to greater hip fracture incidence in older adults
Older patients in a Swedish registry who took antidepressants had a greater incidence of hip fracture the year before beginning antidepressant therapy and the year after starting therapy, compared with individuals in a matched control group.
The use of antidepressants is associated with adverse events such as a higher risk of falls, wrote Jon Brännström, MD, and his colleagues in JAMA Psychiatry. Some evidence also suggests that antidepressants “might affect bone metabolism, thereby increasing the risk of hip fracture.”
To examine the relationship between antidepressants and hip fracture, Dr. Brännström and his colleagues performed a nationwide cohort study of 204,072 individuals in the Prescribed Drug Register of Sweden’s National Board of Health and Welfare. All of the individuals were aged at least 65 years (mean age, 80.1 years; 63.1% women) and filled a prescription for an antidepressant between July 2006 and December 2011. Selective serotonin reuptake inhibitors made up 62.6% of the antidepressants used.
Patients who filled an antidepressant prescription during that time period were matched with a control group of individuals by birth year and gender and were studied the year before and after beginning antidepressant therapy.
In the year after initiating antidepressant therapy, there was a 3.5% incidence rate for hip fractures, compared with 1.3% in the control group.
After adjusting the results using a conditional logistic regression model, the highest rate of hip fracture among antidepressant users occurred between 16 days and 30 days prior to filling the prescription (odds ratio, 5.76; 95% confidence interval, 4.73-7.01); this association persisted in further subgroup analyses based on age, reported Dr. Brännström, who is affiliated with the department of community medicine and rehabilitation and geriatric medicine at Umeå University (Sweden), and his colleagues.
They noted that, although the study included all Swedish individuals who filled prescriptions for antidepressants during the study period, there is an absence of primary care comorbidity data and indications for antidepressant use. In addition, the definition of high- and low-medication doses does not always match what is considered high and low therapeutically and the information that can be gleaned from merging data from several different registries was limited.
“These findings raise questions about associations between antidepressant use and hip fracture seen in previous observational studies,” Dr. Brännström and his colleagues wrote. “Further analysis of this association in treatment studies and examination of the incidence of hip fracture before and after the discontinuation of treatment is required and may shed further light on the possible residual risk associated with treatment.”
This study was funded by the Swedish Research Council. The authors reported no relevant conflicts of interest.
SOURCE: Brännström J et al. JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3679.
In many cases where an adverse event is linked to a medication, such as in the case of gastrointestinal bleeds and blood thinners, the adverse event is not linked to the medication. However, this is not the case with antidepressants and hip fracture, Andrea Iaboni, MD, DPhil, and Donovan T. Maust, MD, wrote in a related editorial (JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3632).
“Patients are routinely prescribed antidepressants following a fracture,” the authors wrote, noting that depression can occur for patients who do not have a history of depression and can last as long as 1 year after hip fracture. The reasons for depression after hip fracture are possibly caused by the consequences of the event or a comorbid condition, such as cerebrovascular disease burden, cognitive impairment, frailty, and impaired functional status. In addition, new antidepressant prescriptions are 10 times the normal rate for older adults in the months after a hip fracture.
Many older users of antidepressants have a hip fracture event in their past, which could be caused by an untreated case of depression and an elevated risk of elevated fall or fracture, as suggested by Brännström et al., while other reasons could include off-label indications such as insomnia, poor motivation during rehabilitation therapy, pain, or hyperactive delirium.
“If individuals with untreated depression are at risk of falls and fractures, it follows that there would be an elevated rate of fractures before antidepressant use,” the authors wrote. “However, as discussed earlier, it is also important to recognize that, during the postfracture period, rightly or wrongly, antidepressants are prescribed at a high rate.”
Clinicians who treat these patients should not stop all antidepressant prescribing to this population. Instead, “a pragmatic preventive approach is warranted, starting with selecting the antidepressant, a cautious initial dose and dose-escalation schedule, a review of potentially interacting therapies ... and referral to fall prevention programs for patients with other risk factors for falls,” they wrote.
“For most older adults, the toll of untreated depression will likely outweigh the potential risks associated with antidepressant use.”
Dr. Iabroni is with the Toronto Rehabilitation Institute and the University of Toronto. He reported receiving fees from serving as a scientific adviser for Winterlight Labs. Dr. Maust is with the department of psychiatry at the University of Michigan, Ann Arbor. He reported no relevant conflicts of interest.
In many cases where an adverse event is linked to a medication, such as in the case of gastrointestinal bleeds and blood thinners, the adverse event is not linked to the medication. However, this is not the case with antidepressants and hip fracture, Andrea Iaboni, MD, DPhil, and Donovan T. Maust, MD, wrote in a related editorial (JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3632).
“Patients are routinely prescribed antidepressants following a fracture,” the authors wrote, noting that depression can occur for patients who do not have a history of depression and can last as long as 1 year after hip fracture. The reasons for depression after hip fracture are possibly caused by the consequences of the event or a comorbid condition, such as cerebrovascular disease burden, cognitive impairment, frailty, and impaired functional status. In addition, new antidepressant prescriptions are 10 times the normal rate for older adults in the months after a hip fracture.
Many older users of antidepressants have a hip fracture event in their past, which could be caused by an untreated case of depression and an elevated risk of elevated fall or fracture, as suggested by Brännström et al., while other reasons could include off-label indications such as insomnia, poor motivation during rehabilitation therapy, pain, or hyperactive delirium.
“If individuals with untreated depression are at risk of falls and fractures, it follows that there would be an elevated rate of fractures before antidepressant use,” the authors wrote. “However, as discussed earlier, it is also important to recognize that, during the postfracture period, rightly or wrongly, antidepressants are prescribed at a high rate.”
Clinicians who treat these patients should not stop all antidepressant prescribing to this population. Instead, “a pragmatic preventive approach is warranted, starting with selecting the antidepressant, a cautious initial dose and dose-escalation schedule, a review of potentially interacting therapies ... and referral to fall prevention programs for patients with other risk factors for falls,” they wrote.
“For most older adults, the toll of untreated depression will likely outweigh the potential risks associated with antidepressant use.”
Dr. Iabroni is with the Toronto Rehabilitation Institute and the University of Toronto. He reported receiving fees from serving as a scientific adviser for Winterlight Labs. Dr. Maust is with the department of psychiatry at the University of Michigan, Ann Arbor. He reported no relevant conflicts of interest.
In many cases where an adverse event is linked to a medication, such as in the case of gastrointestinal bleeds and blood thinners, the adverse event is not linked to the medication. However, this is not the case with antidepressants and hip fracture, Andrea Iaboni, MD, DPhil, and Donovan T. Maust, MD, wrote in a related editorial (JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3632).
“Patients are routinely prescribed antidepressants following a fracture,” the authors wrote, noting that depression can occur for patients who do not have a history of depression and can last as long as 1 year after hip fracture. The reasons for depression after hip fracture are possibly caused by the consequences of the event or a comorbid condition, such as cerebrovascular disease burden, cognitive impairment, frailty, and impaired functional status. In addition, new antidepressant prescriptions are 10 times the normal rate for older adults in the months after a hip fracture.
Many older users of antidepressants have a hip fracture event in their past, which could be caused by an untreated case of depression and an elevated risk of elevated fall or fracture, as suggested by Brännström et al., while other reasons could include off-label indications such as insomnia, poor motivation during rehabilitation therapy, pain, or hyperactive delirium.
“If individuals with untreated depression are at risk of falls and fractures, it follows that there would be an elevated rate of fractures before antidepressant use,” the authors wrote. “However, as discussed earlier, it is also important to recognize that, during the postfracture period, rightly or wrongly, antidepressants are prescribed at a high rate.”
Clinicians who treat these patients should not stop all antidepressant prescribing to this population. Instead, “a pragmatic preventive approach is warranted, starting with selecting the antidepressant, a cautious initial dose and dose-escalation schedule, a review of potentially interacting therapies ... and referral to fall prevention programs for patients with other risk factors for falls,” they wrote.
“For most older adults, the toll of untreated depression will likely outweigh the potential risks associated with antidepressant use.”
Dr. Iabroni is with the Toronto Rehabilitation Institute and the University of Toronto. He reported receiving fees from serving as a scientific adviser for Winterlight Labs. Dr. Maust is with the department of psychiatry at the University of Michigan, Ann Arbor. He reported no relevant conflicts of interest.
Older patients in a Swedish registry who took antidepressants had a greater incidence of hip fracture the year before beginning antidepressant therapy and the year after starting therapy, compared with individuals in a matched control group.
The use of antidepressants is associated with adverse events such as a higher risk of falls, wrote Jon Brännström, MD, and his colleagues in JAMA Psychiatry. Some evidence also suggests that antidepressants “might affect bone metabolism, thereby increasing the risk of hip fracture.”
To examine the relationship between antidepressants and hip fracture, Dr. Brännström and his colleagues performed a nationwide cohort study of 204,072 individuals in the Prescribed Drug Register of Sweden’s National Board of Health and Welfare. All of the individuals were aged at least 65 years (mean age, 80.1 years; 63.1% women) and filled a prescription for an antidepressant between July 2006 and December 2011. Selective serotonin reuptake inhibitors made up 62.6% of the antidepressants used.
Patients who filled an antidepressant prescription during that time period were matched with a control group of individuals by birth year and gender and were studied the year before and after beginning antidepressant therapy.
In the year after initiating antidepressant therapy, there was a 3.5% incidence rate for hip fractures, compared with 1.3% in the control group.
After adjusting the results using a conditional logistic regression model, the highest rate of hip fracture among antidepressant users occurred between 16 days and 30 days prior to filling the prescription (odds ratio, 5.76; 95% confidence interval, 4.73-7.01); this association persisted in further subgroup analyses based on age, reported Dr. Brännström, who is affiliated with the department of community medicine and rehabilitation and geriatric medicine at Umeå University (Sweden), and his colleagues.
They noted that, although the study included all Swedish individuals who filled prescriptions for antidepressants during the study period, there is an absence of primary care comorbidity data and indications for antidepressant use. In addition, the definition of high- and low-medication doses does not always match what is considered high and low therapeutically and the information that can be gleaned from merging data from several different registries was limited.
“These findings raise questions about associations between antidepressant use and hip fracture seen in previous observational studies,” Dr. Brännström and his colleagues wrote. “Further analysis of this association in treatment studies and examination of the incidence of hip fracture before and after the discontinuation of treatment is required and may shed further light on the possible residual risk associated with treatment.”
This study was funded by the Swedish Research Council. The authors reported no relevant conflicts of interest.
SOURCE: Brännström J et al. JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3679.
Older patients in a Swedish registry who took antidepressants had a greater incidence of hip fracture the year before beginning antidepressant therapy and the year after starting therapy, compared with individuals in a matched control group.
The use of antidepressants is associated with adverse events such as a higher risk of falls, wrote Jon Brännström, MD, and his colleagues in JAMA Psychiatry. Some evidence also suggests that antidepressants “might affect bone metabolism, thereby increasing the risk of hip fracture.”
To examine the relationship between antidepressants and hip fracture, Dr. Brännström and his colleagues performed a nationwide cohort study of 204,072 individuals in the Prescribed Drug Register of Sweden’s National Board of Health and Welfare. All of the individuals were aged at least 65 years (mean age, 80.1 years; 63.1% women) and filled a prescription for an antidepressant between July 2006 and December 2011. Selective serotonin reuptake inhibitors made up 62.6% of the antidepressants used.
Patients who filled an antidepressant prescription during that time period were matched with a control group of individuals by birth year and gender and were studied the year before and after beginning antidepressant therapy.
In the year after initiating antidepressant therapy, there was a 3.5% incidence rate for hip fractures, compared with 1.3% in the control group.
After adjusting the results using a conditional logistic regression model, the highest rate of hip fracture among antidepressant users occurred between 16 days and 30 days prior to filling the prescription (odds ratio, 5.76; 95% confidence interval, 4.73-7.01); this association persisted in further subgroup analyses based on age, reported Dr. Brännström, who is affiliated with the department of community medicine and rehabilitation and geriatric medicine at Umeå University (Sweden), and his colleagues.
They noted that, although the study included all Swedish individuals who filled prescriptions for antidepressants during the study period, there is an absence of primary care comorbidity data and indications for antidepressant use. In addition, the definition of high- and low-medication doses does not always match what is considered high and low therapeutically and the information that can be gleaned from merging data from several different registries was limited.
“These findings raise questions about associations between antidepressant use and hip fracture seen in previous observational studies,” Dr. Brännström and his colleagues wrote. “Further analysis of this association in treatment studies and examination of the incidence of hip fracture before and after the discontinuation of treatment is required and may shed further light on the possible residual risk associated with treatment.”
This study was funded by the Swedish Research Council. The authors reported no relevant conflicts of interest.
SOURCE: Brännström J et al. JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3679.
FROM JAMA PSYCHIATRY
Key clinical point: An association was found between greater hip fracture incidence for older individuals taking antidepressants in the year before beginning therapy and the year after starting therapy.
Major finding: Individuals who took antidepressants had a greater incidence of hip fractures in the year before (2.8% vs. 1.1%) and the year after (3.5% vs. 1.3%) beginning antidepressants, compared with individuals in a matched control group.
Study details: A nationwide cohort study of 408,144 individuals in the Prescribed Drugs Register of Sweden’s National Board of Health and Welfare who were aged 65 years or older.
Disclosures: This study was funded by the Swedish Research Council. The authors reported no relevant conflicts of interest.
Source: Brännström J et al. JAMA Psychiatry. 2019 Jan 2. doi: 10.1001/jamapsychiatry.2018.3679.
Hypertension guidelines: Treat patients, not numbers
When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.1
In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.
HOW THE GOALS EVOLVED
JNC 7, 2003: 140/90 or 130/80
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),2 published in 2003, specified treatment goals of:
- < 140/90 mm Hg for most patients
- < 130/80 mm Hg for those with diabetes or chronic kidney disease.
JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).1–9
ACC/AHA/CDC 2014: 140/90
In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.3 As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).
JNC 8 2014: 140/90 or 150/90
Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.4 Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.
In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.
JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:
- < 140/90 mm Hg for patients under age 60
- < 150/90 mm Hg for patients age 60 and older.
Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.5 Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.
ASH/ISH 2014: 140/90 or 150/90
Also in 2014, the ASH and the International Society of Hypertension released their own report.6 Their goals:
- < 140/90 mm Hg for most patients
- < 150/90 mm Hg for patients age 80 and older.
AHA/ACC/ASH 2015: Goals in subgroups
In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations7:
- < 150/90 mm Hg for those age 80 and older
- < 140/90 mm Hg for those with coronary artery disease
- < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.
ADA 2016: Goals for patients with diabetes
In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes8:
- < 140/90 mm Hg for adults with diabetes
- < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
- 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.
ACP/AAFP 2017: Systolic 150 or 130
In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.9
ACC/AHA 2017: 130/80
The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.1
This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).
For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.
For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).
EVERYONE AGREES ON LIFESTYLE
Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.
Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.2
These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.10,11
In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.12
The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.1
HYPERTENSION BEGINS AT 130/80
The definition of hypertension changed in the 2017 ACC/AHA guidelines1: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.
Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,13 up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.
In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.14
SPRINT: INTENSIVE TREATMENT IS BENEFICIAL
The new ACC/AHA guidelines1 were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).15
This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.16 The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.
The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.
Two interventions were compared:
- Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
- Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.
The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.
Using these findings, Bress et al16 estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.
The downside is adverse effects. In SPRINT,15 the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:
- Hypotension 2.4% vs 1.4%, P = .001
- Syncope 2.3% vs 1.7%, P = .05
- Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
- Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
- Any treatment-related adverse event 4.7% vs 2.5%, P = .001.
Thus, Bress et al16 estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.
SPRINT caveats and limitations
SPRINT15 was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.
In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).
Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.
About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.
Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.
Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.
JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?
JNC 84 recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.17 Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.18
A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.19 It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.
OTHER TRIALS THAT INFLUENCED THE GUIDELINES
SHEP and HYVET (the Systolic Hypertension in the Elderly Program20 and the Hypertension in the Very Elderly Trial)21 supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.
FEVER (the Felodipine Event Reduction study)22 found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.
JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients23 and the Valsartan in Elderly Isolated Systolic Hypertension study)24 found that outcomes were similar with intensive vs standard treatment.
Ettehad et al25 performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.
BLOOD PRESSURE ISN’T EVERYTHING
Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.
HOPE (the Heart Outcomes Prevention Evaluation)26 investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.
Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:
- Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
- Cardiovascular death 6.1% vs 8.1%, RR 0.74, P < .001
- Stroke 3.4% vs 4.9%, RR = .68, P < .001
- The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).
Results were even better in the subset of patients who had diabetes.27 However, the decrease in blood pressure attributable to antihypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.26
HOPE 328–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:
- Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
- Cholesterol control with rosuvastatin (a statin)
- Blood pressure plus cholesterol control
- Placebo.
Therapy was started at a systolic blood pressure above 140 mm Hg.
Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)28 and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)29 but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).30
In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.30
These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.
Bundy et al31 performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.
The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.
WHAT ABOUT PATIENTS WITH COMORBIDITIES?
The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.
Diabetes
Emdin et al,32 in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.
ACCORD (the Action to Control Cardiovascular Risk in Diabetes)33 study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.
Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.1
The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.8 However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”8 Thus, it is not clear which blood pressure targets in patients with diabetes are the best.
Stroke
In patients with stroke, AHA/ACC guidelines1 recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.
In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.34 For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.1
Renal disease
The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.1 This recommendation is derived from the SPRINT trial,15 in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.
TREAT PATIENTS, NOT NUMBERS
Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.
For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.
Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.
OUR APPROACH
We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.
We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.
Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.
MOVING FORWARD
Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.
Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.
Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.
Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
- Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560–2572. doi:10.1001/jama.289.19.2560
- Go AS, Bauman MA, King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension 2014; 63(4):878–885. doi:10.1161/HYP.0000000000000003
- James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5):507–520. doi:10.1001/jama.2013.284427
- Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med 2014; 160(7):499–503. doi:10.7326/M13-2981
- Weber MA, Schiffrin EL, White WB, et al. Notice of duplicate publication [duplicate publication of Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens 2014; 16(1):14–26. doi:10.1111/jch.12237] J Hypertens 2014; 32(1):3–15. doi:10.1097/HJH.0000000000000065
- Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens 2015; 9(6):453–498. doi:10.1016/j.jash.2015.03.002
- de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care 2017; 40(9):1273–1284. doi:10.2337/dci17-0026
- Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2017; 166(6):430–437. doi:10.7326/M16-1785
- The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in over-weight people with high normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern Med 1997; 157(6):657–667. pmid:9080920
- He J, Whelton PK, Appel LJ, Charleston J, Klag MJ. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35(2):544–549. pmid:10679495
- Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344(1):3–10. doi:10.1056/NEJM200101043440101
- Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for US adults: National Health Interview Survey, 2012. National Center for Health Statistics. Vital Health Stat 10; 2014(260):1–161. pmid:24819891
- Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol 2018; 71(2):109–118. doi:10.1016/j.jacc.2017.10.073
- SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373(22):2103–2116. doi:10.1056/NEJMoa1511939
- Bress AP, Kramer H, Khatib R, et al. Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey). Circulation 2017; 135(17):1617–1628. doi:10.1161/CIRCULATIONAHA.116.025322
- Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315(24):2673–2682. doi:10.1001/jama.2016.7050
- Beddhu S, Rocco MV, Toto R, et al. Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial. Ann Intern Med 2017; 167(6):375–383. doi:10.7326/M16-2966
- Brunström M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis. JAMA Intern Med 2018; 178(1):28–36. doi:10.1001/jamainternmed.2017.6015
- Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265(24):3255–3264. pmid:2046107
- Bulpitt CJ, Beckett NS, Cooke J, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens 2003; 21(12):2409–2417. doi:10.1097/01.hjh.0000084782.15238.a2
- Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 23(12):2157–2172. pmid:16269957
- JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res 2008; 31(12):2115–2127. doi:10.1291/hypres.31.2115
- Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension 2010; 56(2):196–202. doi:10.1161/HYPERTENSIONAHA.109.146035
- Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022):957–967. doi:10.1016/S0140-6736(15)01225-8
- Sleight P. The HOPE study (Heart Outcomes Prevention Evaluation). J Renin Angiotensin Aldosterone Syst 2000; 1(1):18–20. doi:10.3317/jraas.2000.002
- Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355(9200):253–259. pmid:10675071
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2021–2031. doi:10.1056/NEJMoa1600176
- Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016; 374(21):2032–2043. doi:10.1056/NEJMoa1600177
- Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2009–2020. doi:10.1056/NEJMoa1600175
- Bundy JD, Li C, Stuchlik P, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol 2017; 2(7):775–781. doi:10.1001/jamacardio.2017.1421
- Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015; 313(6):603–615. doi:10.1001/jama.2014.18574
- ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362(17):1575–1585. doi:10.1056/NEJMoa1001286
- SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382(9891):507–515. doi:10.1016/S0140-6736(13)60852-1
When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.1
In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.
HOW THE GOALS EVOLVED
JNC 7, 2003: 140/90 or 130/80
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),2 published in 2003, specified treatment goals of:
- < 140/90 mm Hg for most patients
- < 130/80 mm Hg for those with diabetes or chronic kidney disease.
JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).1–9
ACC/AHA/CDC 2014: 140/90
In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.3 As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).
JNC 8 2014: 140/90 or 150/90
Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.4 Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.
In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.
JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:
- < 140/90 mm Hg for patients under age 60
- < 150/90 mm Hg for patients age 60 and older.
Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.5 Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.
ASH/ISH 2014: 140/90 or 150/90
Also in 2014, the ASH and the International Society of Hypertension released their own report.6 Their goals:
- < 140/90 mm Hg for most patients
- < 150/90 mm Hg for patients age 80 and older.
AHA/ACC/ASH 2015: Goals in subgroups
In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations7:
- < 150/90 mm Hg for those age 80 and older
- < 140/90 mm Hg for those with coronary artery disease
- < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.
ADA 2016: Goals for patients with diabetes
In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes8:
- < 140/90 mm Hg for adults with diabetes
- < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
- 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.
ACP/AAFP 2017: Systolic 150 or 130
In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.9
ACC/AHA 2017: 130/80
The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.1
This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).
For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.
For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).
EVERYONE AGREES ON LIFESTYLE
Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.
Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.2
These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.10,11
In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.12
The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.1
HYPERTENSION BEGINS AT 130/80
The definition of hypertension changed in the 2017 ACC/AHA guidelines1: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.
Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,13 up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.
In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.14
SPRINT: INTENSIVE TREATMENT IS BENEFICIAL
The new ACC/AHA guidelines1 were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).15
This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.16 The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.
The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.
Two interventions were compared:
- Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
- Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.
The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.
Using these findings, Bress et al16 estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.
The downside is adverse effects. In SPRINT,15 the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:
- Hypotension 2.4% vs 1.4%, P = .001
- Syncope 2.3% vs 1.7%, P = .05
- Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
- Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
- Any treatment-related adverse event 4.7% vs 2.5%, P = .001.
Thus, Bress et al16 estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.
SPRINT caveats and limitations
SPRINT15 was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.
In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).
Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.
About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.
Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.
Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.
JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?
JNC 84 recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.17 Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.18
A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.19 It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.
OTHER TRIALS THAT INFLUENCED THE GUIDELINES
SHEP and HYVET (the Systolic Hypertension in the Elderly Program20 and the Hypertension in the Very Elderly Trial)21 supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.
FEVER (the Felodipine Event Reduction study)22 found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.
JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients23 and the Valsartan in Elderly Isolated Systolic Hypertension study)24 found that outcomes were similar with intensive vs standard treatment.
Ettehad et al25 performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.
BLOOD PRESSURE ISN’T EVERYTHING
Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.
HOPE (the Heart Outcomes Prevention Evaluation)26 investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.
Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:
- Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
- Cardiovascular death 6.1% vs 8.1%, RR 0.74, P < .001
- Stroke 3.4% vs 4.9%, RR = .68, P < .001
- The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).
Results were even better in the subset of patients who had diabetes.27 However, the decrease in blood pressure attributable to antihypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.26
HOPE 328–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:
- Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
- Cholesterol control with rosuvastatin (a statin)
- Blood pressure plus cholesterol control
- Placebo.
Therapy was started at a systolic blood pressure above 140 mm Hg.
Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)28 and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)29 but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).30
In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.30
These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.
Bundy et al31 performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.
The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.
WHAT ABOUT PATIENTS WITH COMORBIDITIES?
The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.
Diabetes
Emdin et al,32 in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.
ACCORD (the Action to Control Cardiovascular Risk in Diabetes)33 study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.
Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.1
The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.8 However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”8 Thus, it is not clear which blood pressure targets in patients with diabetes are the best.
Stroke
In patients with stroke, AHA/ACC guidelines1 recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.
In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.34 For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.1
Renal disease
The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.1 This recommendation is derived from the SPRINT trial,15 in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.
TREAT PATIENTS, NOT NUMBERS
Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.
For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.
Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.
OUR APPROACH
We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.
We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.
Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.
MOVING FORWARD
Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.
Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.
Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.
Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.
When treating high blood pressure, how low should we try to go? Debate continues about optimal blood pressure goals after publication of guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) in 2017 that set or permitted a treatment goal of less than 130 mm Hg, depending on the population.1
In this article, we summarize the evolution of hypertension guidelines and the evidence behind them.
HOW THE GOALS EVOLVED
JNC 7, 2003: 140/90 or 130/80
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),2 published in 2003, specified treatment goals of:
- < 140/90 mm Hg for most patients
- < 130/80 mm Hg for those with diabetes or chronic kidney disease.
JNC 7 provided much-needed clarity and uniformity to managing hypertension. Since then, various scientific groups have published their own guidelines (Table 1).1–9
ACC/AHA/CDC 2014: 140/90
In 2014, the ACC, AHA, and US Centers for Disease Control and Prevention (CDC) published an evidence-based algorithm for hypertension management.3 As in JNC 7, they suggested a blood pressure goal of less than 140/90 mm Hg, lifestyle modification, and polytherapy, eg, a thiazide diuretic for stage 1 hypertension (< 160/100 mm Hg) and combination therapy with a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker for stage 2 hypertension (≥ 160/100 mm Hg).
JNC 8 2014: 140/90 or 150/90
Soon after, the much-anticipated report of the panel members appointed to the eighth JNC (JNC 8) was published.4 Previous JNC reports were written and published under the auspices of the National Heart, Lung, and Blood Institute, but while the JNC 8 report was being prepared, this government body announced it would no longer publish guidelines.
In contrast to JNC 7, the JNC 8 panel based its recommendations on a systematic review of randomized clinical trials. However, the process and methodology were controversial, especially as the panel excluded some important clinical trials from the analysis.
JNC 8 relaxed the targets in several subgroups, such as patients over age 60 and those with diabetes and chronic kidney disease, due to a lack of definitive evidence on the impact of blood pressure targets lower than 140/90 mm Hg in these groups. Thus, their goals were:
- < 140/90 mm Hg for patients under age 60
- < 150/90 mm Hg for patients age 60 and older.
Of note, a minority of the JNC 8 panel disagreed with the new targets and provided evidence for keeping the systolic blood pressure target below 140 mm Hg for patients 60 and older.5 Further, the JNC 8 report was not endorsed by several important societies, ie, the AHA, ACC, National Heart, Lung, and Blood Institute, and American Society of Hypertension (ASH). These issues compromised the acceptance and applicability of the guidelines.
ASH/ISH 2014: 140/90 or 150/90
Also in 2014, the ASH and the International Society of Hypertension released their own report.6 Their goals:
- < 140/90 mm Hg for most patients
- < 150/90 mm Hg for patients age 80 and older.
AHA/ACC/ASH 2015: Goals in subgroups
In 2015, the AHA, ACC, and ASH released a joint scientific statement outlining hypertension goals for specific patient populations7:
- < 150/90 mm Hg for those age 80 and older
- < 140/90 mm Hg for those with coronary artery disease
- < 130/80 mm Hg for those with comorbidities such as diabetes and cardiovascular disease.
ADA 2016: Goals for patients with diabetes
In 2016, the American Diabetes Association (ADA) set the following blood pressure goals for patients with diabetes8:
- < 140/90 mm Hg for adults with diabetes
- < 130/80 mm Hg for younger adults with diabetes and adults with a high risk of cardiovascular disease
- 120–160/80–105 mm Hg for pregnant patients with diabetes and preexisting hypertension who are treated with antihypertensive therapy.
ACP/AAFP 2017: Systolic 150 or 130
In 2017, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) recommended a relaxed systolic blood pressure target, ie, below 150 mm Hg, for adults over age 60, but a tighter goal of less than 140 mm Hg for the same age group if they have transient ischemic attack, stroke, or high cardiovascular risk.9
ACC/AHA 2017: 130/80
The 2017 ACC/AHA guidelines recommended a more aggressive goal of below 130/80 for all, including patients age 65 and older.1
This is a class I (strong) recommendation for patients with known cardiovascular disease or a 10-year risk of a cardiovascular event of 10% or higher, with a B-R level of evidence for the systolic goal (ie, moderate-quality, based on systematic review of randomized controlled trials) and a C-EO level of evidence for the diastolic goal (ie, based on expert opinion).
For patients who do not have cardiovascular disease and who are at lower risk of it, this is a class IIb (weak) recommendation, ie, it “may be reasonable,” with a B-NR level of evidence (moderate-quality, based on nonrandomized studies) for the systolic goal and C-EO (expert opinion) for the diastolic goal.
For many patients, this involves drug treatment. For those with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, the ACC/AHA guidelines say that drug treatment “is recommended” if their average blood pressure is 130/80 mm Hg or higher (class I recommendation, based on strong evidence for the systolic threshold and expert option for the diastolic). For those without cardiovascular disease and at lower risk, drug treatment is recommended if their average blood pressure is 140/90 mm Hg or higher (also class I, but based on limited data).
EVERYONE AGREES ON LIFESTYLE
Although the guidelines differ in their blood pressure targets, they consistently recommend lifestyle modifications.
Lifestyle modifications, first described in JNC 7, included weight loss, sodium restriction, and the DASH diet, which is rich in fruits, vegetables, low-fat dairy products, whole grains, poultry, and fish, and low in red meat, sweets, cholesterol, and total and saturated fat.2
These recommendations were based on results from 3 large randomized controlled trials in patients with and without hypertension.10–12 In patients with no history of hypertension, interventions to promote weight loss and sodium restriction significantly reduced blood pressure and the incidence of hypertension (the latter by as much as 77%) compared with usual care.10,11
In patients with and without hypertension, lowering sodium intake in conjunction with the DASH diet was associated with substantially larger reductions in systolic blood pressure.12
The recommendation to lower sodium intake has not changed in the guideline revisions. Meanwhile, other modifications have been added, such as incorporating both aerobic and resistance exercise and moderating alcohol intake. These recommendations have a class I level of evidence (ie, strongest level) in the 2017 ACC/AHA guidelines.1
HYPERTENSION BEGINS AT 130/80
The definition of hypertension changed in the 2017 ACC/AHA guidelines1: previously set at 140/90 mm Hg or higher, it is now 130/80 mm Hg or higher for all age groups. Adults with systolic blood pressure of 130 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg are now classified as having stage 1 hypertension.
Under the new definition, the number of US adults who have hypertension expanded to 45.6% of the general population,13 up from 31.9% under the JNC 7 definition. Thus, overall, 103.3 million US adults now have hypertension, compared with 72.2 million under the JNC 7 criteria.
In addition, the new guidelines expanded the population of adults for whom antihypertensive drug treatment is recommended to 36.2% (81.9 million). However, this represents only a 1.9% absolute increase over the JNC 7 recommendations (34.3%) and a 5.1% absolute increase over the JNC 8 recommendations.14
SPRINT: INTENSIVE TREATMENT IS BENEFICIAL
The new ACC/AHA guidelines1 were based on evidence from several trials, including the Systolic Blood Pressure Intervention Trial (SPRINT).15
This multicenter trial investigated the effect of intensive blood pressure treatment on cardiovascular disease risk.16 The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, and heart failure.
The trial enrolled 9,361 participants at least 50 years of age with systolic blood pressure 130 mm Hg or higher and at least 1 additional risk factor for cardiovascular disease. It excluded anyone with a history of diabetes mellitus, stroke, symptomatic heart failure, or end-stage renal disease.
Two interventions were compared:
- Intensive treatment, with a systolic blood pressure goal of less than 120 mm Hg: the protocol called for polytherapy, even for participants who were 75 or older if their blood pressure was 140 mm Hg or higher
- Standard treatment, with a systolic blood pressure goal of less than 140 mm Hg: it used polytherapy for patients whose systolic blood pressure was 160 mm Hg or higher.
The trial was intended to last 5 years but was stopped early at a median of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group: 1.65% per year vs 2.19%, a 25% relative risk reduction (P < .001) or a 0.54% absolute risk reduction. We calculate the number needed to treat (NNT) for 1 year to prevent 1 event as 185, and over the 3.26 years of the trial, the investigators calculated the NNT as 61. Similarly, the rate of death from any cause was also lower with intensive treatment, 1.03% per year vs 1.40% per year, a 27% relative risk reduction (P = .003) or a 0.37% absolute risk reduction, NNT 270.
Using these findings, Bress et al16 estimated that implementing intensive blood pressure goals could prevent 107,500 deaths annually.
The downside is adverse effects. In SPRINT,15 the intensive-treatment group experienced significantly higher rates of serious adverse effects than the standard-treatment group, ie:
- Hypotension 2.4% vs 1.4%, P = .001
- Syncope 2.3% vs 1.7%, P = .05
- Electrolyte abnormalities 3.1% vs 2.3%, P = .02)
- Acute kidney injury or kidney failure 4.1% vs 2.5%, P < .001
- Any treatment-related adverse event 4.7% vs 2.5%, P = .001.
Thus, Bress et al16 estimated that fully implementing the intensive-treatment goals could cause an additional 56,100 episodes of hypotension per year, 34,400 cases of syncope, 43,400 serious electrolyte disorders, and 88,700 cases of acute kidney injury. All told, about 3 million Americans could suffer a serious adverse effect under the intensive-treatment goals.
SPRINT caveats and limitations
SPRINT15 was stopped early, after 3.26 years instead of the planned 5 years. The true risk-benefit ratio may have been different if the trial had been extended longer.
In addition, SPRINT used automated office blood pressure measurements in which patients were seated alone and a device (Model 907, Omron Healthcare) took 3 blood pressure measurements at 1-minute intervals after 5 minutes of quiet rest. This was designed to reduce elevated blood pressure readings in the presence of a healthcare professional in a medical setting (ie, “white coat” hypertension).
Many physicians are still taking blood pressure manually, which tends to give higher readings. Therefore, if they aim for a lower goal, they may risk overtreating the patient.
About 50% of patients did not achieve the target systolic blood pressure (< 120 mm Hg) despite receiving an average of 2.8 antihypertensive medications in the intensive-treatment group and 1.8 in the standard-treatment group. The use of antihypertensive medications, however, was not a controlled variable in the trial, and practitioners chose the appropriate drugs for their patients.
Diastolic pressure, which can be markedly lower in older hypertensive patients, was largely ignored, although lower diastolic pressure may have contributed to higher syncope rates in response to alpha blockers and calcium blockers.
Moreover, the trial excluded those with significant comorbidities and those younger than 50 (the mean age was 67.9), which limits the generalizability of the results.
JNC 8 VS SPRINT GOALS: WHAT'S THE EFFECT ON OUTCOMES?
JNC 84 recommended a relaxed target of less than 140/90 mm Hg for adults younger than 60, including those with chronic kidney disease or diabetes, and less than 150/90 mm Hg for adults 60 and older. The SPRINT findings upended those recommendations, showing that intensive treatment in adults age 75 or older significantly improved the composite cardiovascular disease outcome (2.59 vs 3.85 events per year; P < .001) and all-cause mortality (1.78 vs 2.63 events per year; P < .05) compared with standard treatment.17 Also, a subset review of SPRINT trial data found no difference in benefit based on chronic kidney disease status.18
A meta-analysis of 74 clinical trials (N = 306,273) offers a compromise between the SPRINT findings and the JNC 8 recommendations.19 It found that the beneficial effect of blood pressure treatment depended on the patient’s baseline systolic blood pressure. In those with a baseline systolic pressure of 160 mm Hg or higher, treatment reduced cardiovascular mortality by about 15% (relative risk [RR] 0.85; 95% confidence interval [CI] 0.77–0.95). In patients with systolic pressure below 140 mm Hg, treatment effects were neutral (RR 1.03, 95% CI 0.87–1.20) and not associated with any benefit as primary prevention, although data suggest it may reduce the risk of adverse outcomes in patients with coronary heart disease.
OTHER TRIALS THAT INFLUENCED THE GUIDELINES
SHEP and HYVET (the Systolic Hypertension in the Elderly Program20 and the Hypertension in the Very Elderly Trial)21 supported intensive blood pressure treatment for older patients by reporting a reduction in fatal and nonfatal stroke risks for those with a systolic blood pressure above 160 mm Hg.
FEVER (the Felodipine Event Reduction study)22 found that treatment with a calcium channel blocker in even a low dose can significantly decrease cardiovascular events, cardiovascular disease, and heart failure compared with no treatment.
JATOS and VALISH (the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients23 and the Valsartan in Elderly Isolated Systolic Hypertension study)24 found that outcomes were similar with intensive vs standard treatment.
Ettehad et al25 performed a meta-analysis of 123 studies with more than 600,000 participants that provided strong evidence supporting blood pressure treatment goals below 130/90 mm Hg, in line with the SPRINT trial results.
BLOOD PRESSURE ISN’T EVERYTHING
Other trials remind us that although blood pressure is important, it is not the only factor affecting cardiovascular risk.
HOPE (the Heart Outcomes Prevention Evaluation)26 investigated the use of ramipril (an ACE inhibitor) in preventing myocardial infarction, stroke, or cardiovascular death in patients at high risk of cardiovascular events. The study included 9,297 participants over age 55 (mean age 66) with a baseline blood pressure 139/79 mm Hg. Follow-up was 4.5 years.
Ramipril was better than placebo, with significantly fewer patients experiencing adverse end points in the ramipril group compared with the placebo group:
- Myocardial infarction 9.9% vs 12.3%, RR 0.80, P < .001
- Cardiovascular death 6.1% vs 8.1%, RR 0.74, P < .001
- Stroke 3.4% vs 4.9%, RR = .68, P < .001
- The composite end point 14.0% vs 17.8%, RR 0.78, P < .001).
Results were even better in the subset of patients who had diabetes.27 However, the decrease in blood pressure attributable to antihypertensive therapy with ramipril was minimal (3–4 mm Hg systolic and 1–2 mm Hg diastolic). This slight change should not have been enough to produce significant differences in clinical outcomes, a major limitation of this trial. The investigators speculated that the positive results may be due to a class effect of ACE inhibitors.26
HOPE 328–30 explored the effect of blood pressure- and cholesterol-controlling drugs on the same primary end points but in patients at intermediate risk of major cardiovascular events. Investigators randomized the 12,705 patients to 4 treatment groups:
- Blood pressure control with candesartan (an ARB) plus hydrochlorothiazide (a thiazide diuretic)
- Cholesterol control with rosuvastatin (a statin)
- Blood pressure plus cholesterol control
- Placebo.
Therapy was started at a systolic blood pressure above 140 mm Hg.
Compared with placebo, the rate of composite events was significantly reduced in the rosuvastatin group (3.7% vs 4.8%, HR 0.76, P = .002)28 and the candesartan-hydrochlorothiazide-rosuvastatin group (3.6% vs 5.0%, HR 0.71; P = .005)29 but not in the candesartan-hydrochlorothiazide group (4.1% vs 4.4%; HR 0.93; P = .40).30
In addition, a subgroup analysis comparing active treatment vs placebo found a significant reduction in major cardiovascular events for treated patients whose baseline systolic blood pressure was in the upper third (> 143.5 mm Hg, mean 154.1 mm Hg), while treated patients in the lower middle and lower thirds had no significant reduction.30
These results suggest that intensive treatment to achieve a systolic blood pressure below 140 mm Hg in patients at intermediate risk may not be helpful. Nevertheless, there seems to be agreement that intensive treatment generally leads to a reduction in cardiovascular events. The results also show the benefit of lowering cholesterol.
Bundy et al31 performed a meta-analysis that provides support for intensive antihypertensive treatment. Reviewing 42 clinical trials in more than 144,000 patients, they found that treating to reach a target systolic blood pressure of 120 to 124 mm Hg can reduce cardiovascular events and all-cause mortality.
The trade-off is a minimal increase in the risk of adverse events. Also, the risk-benefit ratio of intensive treatment seems to vary in different patient subgroups.
WHAT ABOUT PATIENTS WITH COMORBIDITIES?
The debate over intensive vs standard treatment in blood pressure management extends beyond hypertension and includes important comorbidities such as diabetes, stroke, and renal disease. Patients with a history of stroke or end-stage renal disease have only a minimal mention in the AHA/ACC guidelines.
Diabetes
Emdin et al,32 in a meta-analysis of 40 trials that included more than 100,000 patients with diabetes, concluded that a 10-mm Hg lowering of systolic blood pressure significantly reduces the rates of all-cause mortality, cardiovascular disease, coronary heart disease, stroke, albuminuria, and retinopathy. Stratifying the results according to the systolic blood pressure achieved (≥ 130 or < 130 mm Hg), the relative risks of mortality, coronary heart disease, cardiovascular disease, heart failure, and albuminuria were actually lower in the higher stratum than in the lower.
ACCORD (the Action to Control Cardiovascular Risk in Diabetes)33 study provides contrary results. It examined intensive and standard blood pressure control targets in patients with type 2 diabetes at high risk of cardiovascular events, using primary outcome measures similar to those in SPRINT. It found no significant difference in fatal and nonfatal cardiovascular events between the intensive and standard blood pressure target arms.
Despite those results, the ACC/AHA guidelines still advocate for more intensive treatment (goal < 130/80 mm Hg) in all patients, including those with diabetes.1
The ADA position statement (September 2017) recommended a target below 140/90 mm Hg in patients with diabetes and hypertension.8 However, they also noted that lower systolic and diastolic blood pressure targets, such as below 130/80 mm Hg, may be appropriate for patients at high risk of cardiovascular disease “if they can be achieved without undue treatment burden.”8 Thus, it is not clear which blood pressure targets in patients with diabetes are the best.
Stroke
In patients with stroke, AHA/ACC guidelines1 recommend treatment if the blood pressure is 140/90 mm Hg or higher because antihypertensive therapy has been associated with a decrease in the recurrence of transient ischemic attack and stroke. The ideal target blood pressure is not known, but a goal of less than 130/80 mm Hg may be reasonable.
In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, a retrospective open-label trial, a target blood pressure below 130/80 mm Hg in patients with a history of lacunar stroke was associated with a lower risk of intracranial hemorrhage, but the difference was not statistically significant.34 For this reason, the ACC/AHA guidelines consider it reasonable to aim for a systolic blood pressure below 130 mm Hg in these patients.1
Renal disease
The ACC/AHA guidelines do not address how to manage hypertension in patients with end-stage renal disease, but for patients with chronic kidney disease they recommend a blood pressure target below 130/80 mm Hg.1 This recommendation is derived from the SPRINT trial,15 in which patients with stage 3 or 4 chronic kidney disease accounted for 28% of the study population. In that subgroup, intensive blood pressure control seemed to provide the same benefits for reduction in cardiovascular death and all-cause mortality.
TREAT PATIENTS, NOT NUMBERS
Blood pressure targets should be applied in the appropriate clinical context and on a patient-by-patient basis. In clinical practice, one size does not always fit all, as special cases exist.
For example, blood pressure can oscillate widely in patients with autonomic nerve disorders, making it difficult to strive for a specific target, especially an intensive one. Thus, it may be necessary to allow higher systolic blood pressure in these patients. Similarly, patients with diabetes or chronic kidney disease may be at higher risk of kidney injury with more intensive blood pressure management.
Treating numbers rather than patients may result in unbalanced patient care. The optimal approach to blood pressure management relies on a comprehensive risk factor assessment and shared decision-making with the patient before setting specific blood pressure targets.
OUR APPROACH
We aim for a blood pressure goal below 130/80 mm Hg for all patients with cardiovascular disease, according to the AHA/ACC guidelines. We aim for that same target in patients without cardiovascular disease but who have an elevated estimated cardiovascular risk (> 10%) over the next 10 years.
We recognize, however, that the benefits of aggressive blood pressure reduction may not be as clear in all patients, such as those with diabetes. We also recognize that some patient subgroups are at high risk of adverse events, including those with low diastolic pressure, chronic kidney disease, a history of falls, and older age. In those patients, we are extremely judicious when titrating antihypertensive medications. We often make smaller titrations, at longer intervals, and with more frequent laboratory testing and in-office follow-up.
Our process of managing hypertension through intensive blood pressure control to achieve lower systolic blood pressure targets requires a concerted effort among healthcare providers at all levels. It especially requires more involvement and investment from primary care providers to individualize treatment in their patients. This process has helped us to reach our treatment goals while limiting adverse effects of lower blood pressure targets.
MOVING FORWARD
Hypertension is a major risk factor for cardiovascular disease, and intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease. Thus, a general consensus on the definition of hypertension and treatment goals is essential to reduce the risk of cardiovascular events in this large patient population.
Intensive blood pressure treatment has shown efficacy, but it has a small accompanying risk of adverse events, which varies in patient subgroups and affects the benefit-risk ratio of this therapy. For example, the cardiovascular benefit of intensive treatment is less clear in diabetic patients, and the risk of adverse events may be higher in older patients with chronic kidney disease.
Moving forward, more research is needed into the effects of intensive and standard treatment on patients of all ages, those with common comorbid conditions, and those with other important factors such as diastolic hypertension.
Finally, the various medical societies should collaborate on hypertension guideline development. This would require considerable planning and coordination but would ultimately be useful in creating a generalizable approach to hypertension management.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
- Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560–2572. doi:10.1001/jama.289.19.2560
- Go AS, Bauman MA, King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension 2014; 63(4):878–885. doi:10.1161/HYP.0000000000000003
- James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5):507–520. doi:10.1001/jama.2013.284427
- Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med 2014; 160(7):499–503. doi:10.7326/M13-2981
- Weber MA, Schiffrin EL, White WB, et al. Notice of duplicate publication [duplicate publication of Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens 2014; 16(1):14–26. doi:10.1111/jch.12237] J Hypertens 2014; 32(1):3–15. doi:10.1097/HJH.0000000000000065
- Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens 2015; 9(6):453–498. doi:10.1016/j.jash.2015.03.002
- de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care 2017; 40(9):1273–1284. doi:10.2337/dci17-0026
- Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2017; 166(6):430–437. doi:10.7326/M16-1785
- The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in over-weight people with high normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern Med 1997; 157(6):657–667. pmid:9080920
- He J, Whelton PK, Appel LJ, Charleston J, Klag MJ. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35(2):544–549. pmid:10679495
- Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344(1):3–10. doi:10.1056/NEJM200101043440101
- Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for US adults: National Health Interview Survey, 2012. National Center for Health Statistics. Vital Health Stat 10; 2014(260):1–161. pmid:24819891
- Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol 2018; 71(2):109–118. doi:10.1016/j.jacc.2017.10.073
- SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373(22):2103–2116. doi:10.1056/NEJMoa1511939
- Bress AP, Kramer H, Khatib R, et al. Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey). Circulation 2017; 135(17):1617–1628. doi:10.1161/CIRCULATIONAHA.116.025322
- Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315(24):2673–2682. doi:10.1001/jama.2016.7050
- Beddhu S, Rocco MV, Toto R, et al. Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial. Ann Intern Med 2017; 167(6):375–383. doi:10.7326/M16-2966
- Brunström M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis. JAMA Intern Med 2018; 178(1):28–36. doi:10.1001/jamainternmed.2017.6015
- Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265(24):3255–3264. pmid:2046107
- Bulpitt CJ, Beckett NS, Cooke J, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens 2003; 21(12):2409–2417. doi:10.1097/01.hjh.0000084782.15238.a2
- Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 23(12):2157–2172. pmid:16269957
- JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res 2008; 31(12):2115–2127. doi:10.1291/hypres.31.2115
- Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension 2010; 56(2):196–202. doi:10.1161/HYPERTENSIONAHA.109.146035
- Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022):957–967. doi:10.1016/S0140-6736(15)01225-8
- Sleight P. The HOPE study (Heart Outcomes Prevention Evaluation). J Renin Angiotensin Aldosterone Syst 2000; 1(1):18–20. doi:10.3317/jraas.2000.002
- Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355(9200):253–259. pmid:10675071
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2021–2031. doi:10.1056/NEJMoa1600176
- Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016; 374(21):2032–2043. doi:10.1056/NEJMoa1600177
- Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2009–2020. doi:10.1056/NEJMoa1600175
- Bundy JD, Li C, Stuchlik P, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol 2017; 2(7):775–781. doi:10.1001/jamacardio.2017.1421
- Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015; 313(6):603–615. doi:10.1001/jama.2014.18574
- ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362(17):1575–1585. doi:10.1056/NEJMoa1001286
- SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382(9891):507–515. doi:10.1016/S0140-6736(13)60852-1
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
- Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289(19):2560–2572. doi:10.1001/jama.289.19.2560
- Go AS, Bauman MA, King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension 2014; 63(4):878–885. doi:10.1161/HYP.0000000000000003
- James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311(5):507–520. doi:10.1001/jama.2013.284427
- Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med 2014; 160(7):499–503. doi:10.7326/M13-2981
- Weber MA, Schiffrin EL, White WB, et al. Notice of duplicate publication [duplicate publication of Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens 2014; 16(1):14–26. doi:10.1111/jch.12237] J Hypertens 2014; 32(1):3–15. doi:10.1097/HJH.0000000000000065
- Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens 2015; 9(6):453–498. doi:10.1016/j.jash.2015.03.002
- de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care 2017; 40(9):1273–1284. doi:10.2337/dci17-0026
- Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2017; 166(6):430–437. doi:10.7326/M16-1785
- The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in over-weight people with high normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern Med 1997; 157(6):657–667. pmid:9080920
- He J, Whelton PK, Appel LJ, Charleston J, Klag MJ. Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35(2):544–549. pmid:10679495
- Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001; 344(1):3–10. doi:10.1056/NEJM200101043440101
- Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for US adults: National Health Interview Survey, 2012. National Center for Health Statistics. Vital Health Stat 10; 2014(260):1–161. pmid:24819891
- Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. J Am Coll Cardiol 2018; 71(2):109–118. doi:10.1016/j.jacc.2017.10.073
- SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373(22):2103–2116. doi:10.1056/NEJMoa1511939
- Bress AP, Kramer H, Khatib R, et al. Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey). Circulation 2017; 135(17):1617–1628. doi:10.1161/CIRCULATIONAHA.116.025322
- Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315(24):2673–2682. doi:10.1001/jama.2016.7050
- Beddhu S, Rocco MV, Toto R, et al. Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial. Ann Intern Med 2017; 167(6):375–383. doi:10.7326/M16-2966
- Brunström M, Carlberg B. Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: a systematic review and meta-analysis. JAMA Intern Med 2018; 178(1):28–36. doi:10.1001/jamainternmed.2017.6015
- Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265(24):3255–3264. pmid:2046107
- Bulpitt CJ, Beckett NS, Cooke J, et al. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens 2003; 21(12):2409–2417. doi:10.1097/01.hjh.0000084782.15238.a2
- Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens 2005; 23(12):2157–2172. pmid:16269957
- JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res 2008; 31(12):2115–2127. doi:10.1291/hypres.31.2115
- Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension 2010; 56(2):196–202. doi:10.1161/HYPERTENSIONAHA.109.146035
- Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387(10022):957–967. doi:10.1016/S0140-6736(15)01225-8
- Sleight P. The HOPE study (Heart Outcomes Prevention Evaluation). J Renin Angiotensin Aldosterone Syst 2000; 1(1):18–20. doi:10.3317/jraas.2000.002
- Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355(9200):253–259. pmid:10675071
- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2021–2031. doi:10.1056/NEJMoa1600176
- Yusuf S, Lonn E, Pais P, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016; 374(21):2032–2043. doi:10.1056/NEJMoa1600177
- Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374(21):2009–2020. doi:10.1056/NEJMoa1600175
- Bundy JD, Li C, Stuchlik P, et al. Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis. JAMA Cardiol 2017; 2(7):775–781. doi:10.1001/jamacardio.2017.1421
- Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 2015; 313(6):603–615. doi:10.1001/jama.2014.18574
- ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362(17):1575–1585. doi:10.1056/NEJMoa1001286
- SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382(9891):507–515. doi:10.1016/S0140-6736(13)60852-1
KEY POINTS
- The 2017 ACC/AHA guidelines lowered the definition of hypertension to 130/80 mm Hg or higher, thereby in-creasing the number of US adults with hypertension from 31.9% to 45.6%.
- For patients with known cardiovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, drug treatment “is recommended” if the average blood pressure is 130/80 mm Hg or higher. For those without cardiovascular disease and at lower risk, drug treatment is recommended if the aver-age blood pressure is 140/90 mm Hg or higher.
- A treatment goal of less than 130/80 mm Hg “is recommended” for patients with hypertension and known car-diovascular disease or a 10-year risk of an atherosclerotic cardiovascular disease event of 10% or higher, and “may be reasonable” for those without additional markers of increased cardiovascular risk.
- Intensive blood pressure control has the potential to significantly reduce rates of morbidity and death associated with cardiovascular disease, at the price of causing more adverse effects.
Acute-onset quadriplegia with hyperreflexia
A 79-year-old man presented with sudden-onset bilateral weakness in the lower and upper extremities that had started 6 hours earlier. He reported no vision disturbances or urinary incontinence. He was afebrile, with a blood pressure of 148/94 mm Hg, heart rate 98 bpm, and oxygen saturation of 95% on room air.
Physical examination revealed quadriplegia with hyperreflexia, sustained ankle clonus, and bilateral Babinski reflex, as well as spontaneous adductor and extensor spasms of the lower extremities.
Funduscopy was negative for optic neuritis. Results of a complete blood cell count and renal and liver function testing were within normal limits.
The patient was admitted to the intensive care unit. Methylprednisolone 1 g was given intravenously once daily for 5 days, with plasma exchange every other day for 5 sessions. A workup for neoplastic, autoimmune, and infectious disease was negative, as was testing for serum aquaporin-4 antibody (ie, neuromyelitis optica immunoglobulin G antibody).
Over the course of 7 days, the patient’s motor strength improved, and he was able to walk without assistance. Steroid therapy was tapered, and he was prescribed rituximab to prevent recurrence.
LONGITUDINALLY EXTENSIVE TRANSVERSE MYELITIS
A subtype of transverse myelitis, LETM is defined by partial or complete spinal cord dysfunction due to a lesion extending 3 or more vertebrae as confirmed on MRI. The clinical presentation can include paraparesis, sensory disturbances, and gait, bladder, bowel, or sexual dysfunction.1 Identifying the cause requires an extensive workup, as the differential diagnosis includes a wide range of conditions2:
- Autoimmune disorders such as Behçet disease, systemic lupus erythematosus, and Sjögren syndrome
- Infectious disorders such as syphilis, tuberculosis, and viral and parasitic infections
- Demyelinating disorders such as multiple sclerosis and neuromyelitis optica
- Neoplastic conditions such as intramedullary metastasis and lymphoma
- Paraneoplastic syndromes.
In our patient, the evaluation did not identify a specific underlying condition, and testing for serum aquaporin-4 antibody was negative. Therefore, the LETM was ruled an isolated idiopathic episode.
Idiopathic seronegative LETM has been associated with fewer recurrences than seropositive LETM.3 Management consists of high-dose intravenous steroids and plasma exchange. Rituximab can be used to prevent recurrence.4
- Trebst C, Raab P, Voss EV, et al. Longitudinal extensive transverse myelitis—it’s not all neuromyelitis optica. Nat Rev Neurol 2011; 7(12):688–698. doi:10.1038/nrneurol.2011.176
- Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K. Differential diagnosis of neuromyelitis optica spectrum disorders. Ther Adv Neurol Disord 2017; 10(7):265–289. doi:10.1177/1756285617709723
- Kitley J, Leite MI, Küker W, et al. Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol 2013; 70(11):1375–1381. doi:10.1001/jamaneurol.2013.3890
- Tobin WO, Weinshenker BG, Lucchinetti CF. Longitudinally extensive transverse myelitis. Curr Opin Neurol 2014; 27(3):279–289. doi:10.1097/WCO.0000000000000093
A 79-year-old man presented with sudden-onset bilateral weakness in the lower and upper extremities that had started 6 hours earlier. He reported no vision disturbances or urinary incontinence. He was afebrile, with a blood pressure of 148/94 mm Hg, heart rate 98 bpm, and oxygen saturation of 95% on room air.
Physical examination revealed quadriplegia with hyperreflexia, sustained ankle clonus, and bilateral Babinski reflex, as well as spontaneous adductor and extensor spasms of the lower extremities.
Funduscopy was negative for optic neuritis. Results of a complete blood cell count and renal and liver function testing were within normal limits.
The patient was admitted to the intensive care unit. Methylprednisolone 1 g was given intravenously once daily for 5 days, with plasma exchange every other day for 5 sessions. A workup for neoplastic, autoimmune, and infectious disease was negative, as was testing for serum aquaporin-4 antibody (ie, neuromyelitis optica immunoglobulin G antibody).
Over the course of 7 days, the patient’s motor strength improved, and he was able to walk without assistance. Steroid therapy was tapered, and he was prescribed rituximab to prevent recurrence.
LONGITUDINALLY EXTENSIVE TRANSVERSE MYELITIS
A subtype of transverse myelitis, LETM is defined by partial or complete spinal cord dysfunction due to a lesion extending 3 or more vertebrae as confirmed on MRI. The clinical presentation can include paraparesis, sensory disturbances, and gait, bladder, bowel, or sexual dysfunction.1 Identifying the cause requires an extensive workup, as the differential diagnosis includes a wide range of conditions2:
- Autoimmune disorders such as Behçet disease, systemic lupus erythematosus, and Sjögren syndrome
- Infectious disorders such as syphilis, tuberculosis, and viral and parasitic infections
- Demyelinating disorders such as multiple sclerosis and neuromyelitis optica
- Neoplastic conditions such as intramedullary metastasis and lymphoma
- Paraneoplastic syndromes.
In our patient, the evaluation did not identify a specific underlying condition, and testing for serum aquaporin-4 antibody was negative. Therefore, the LETM was ruled an isolated idiopathic episode.
Idiopathic seronegative LETM has been associated with fewer recurrences than seropositive LETM.3 Management consists of high-dose intravenous steroids and plasma exchange. Rituximab can be used to prevent recurrence.4
A 79-year-old man presented with sudden-onset bilateral weakness in the lower and upper extremities that had started 6 hours earlier. He reported no vision disturbances or urinary incontinence. He was afebrile, with a blood pressure of 148/94 mm Hg, heart rate 98 bpm, and oxygen saturation of 95% on room air.
Physical examination revealed quadriplegia with hyperreflexia, sustained ankle clonus, and bilateral Babinski reflex, as well as spontaneous adductor and extensor spasms of the lower extremities.
Funduscopy was negative for optic neuritis. Results of a complete blood cell count and renal and liver function testing were within normal limits.
The patient was admitted to the intensive care unit. Methylprednisolone 1 g was given intravenously once daily for 5 days, with plasma exchange every other day for 5 sessions. A workup for neoplastic, autoimmune, and infectious disease was negative, as was testing for serum aquaporin-4 antibody (ie, neuromyelitis optica immunoglobulin G antibody).
Over the course of 7 days, the patient’s motor strength improved, and he was able to walk without assistance. Steroid therapy was tapered, and he was prescribed rituximab to prevent recurrence.
LONGITUDINALLY EXTENSIVE TRANSVERSE MYELITIS
A subtype of transverse myelitis, LETM is defined by partial or complete spinal cord dysfunction due to a lesion extending 3 or more vertebrae as confirmed on MRI. The clinical presentation can include paraparesis, sensory disturbances, and gait, bladder, bowel, or sexual dysfunction.1 Identifying the cause requires an extensive workup, as the differential diagnosis includes a wide range of conditions2:
- Autoimmune disorders such as Behçet disease, systemic lupus erythematosus, and Sjögren syndrome
- Infectious disorders such as syphilis, tuberculosis, and viral and parasitic infections
- Demyelinating disorders such as multiple sclerosis and neuromyelitis optica
- Neoplastic conditions such as intramedullary metastasis and lymphoma
- Paraneoplastic syndromes.
In our patient, the evaluation did not identify a specific underlying condition, and testing for serum aquaporin-4 antibody was negative. Therefore, the LETM was ruled an isolated idiopathic episode.
Idiopathic seronegative LETM has been associated with fewer recurrences than seropositive LETM.3 Management consists of high-dose intravenous steroids and plasma exchange. Rituximab can be used to prevent recurrence.4
- Trebst C, Raab P, Voss EV, et al. Longitudinal extensive transverse myelitis—it’s not all neuromyelitis optica. Nat Rev Neurol 2011; 7(12):688–698. doi:10.1038/nrneurol.2011.176
- Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K. Differential diagnosis of neuromyelitis optica spectrum disorders. Ther Adv Neurol Disord 2017; 10(7):265–289. doi:10.1177/1756285617709723
- Kitley J, Leite MI, Küker W, et al. Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol 2013; 70(11):1375–1381. doi:10.1001/jamaneurol.2013.3890
- Tobin WO, Weinshenker BG, Lucchinetti CF. Longitudinally extensive transverse myelitis. Curr Opin Neurol 2014; 27(3):279–289. doi:10.1097/WCO.0000000000000093
- Trebst C, Raab P, Voss EV, et al. Longitudinal extensive transverse myelitis—it’s not all neuromyelitis optica. Nat Rev Neurol 2011; 7(12):688–698. doi:10.1038/nrneurol.2011.176
- Kim SM, Kim SJ, Lee HJ, Kuroda H, Palace J, Fujihara K. Differential diagnosis of neuromyelitis optica spectrum disorders. Ther Adv Neurol Disord 2017; 10(7):265–289. doi:10.1177/1756285617709723
- Kitley J, Leite MI, Küker W, et al. Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol 2013; 70(11):1375–1381. doi:10.1001/jamaneurol.2013.3890
- Tobin WO, Weinshenker BG, Lucchinetti CF. Longitudinally extensive transverse myelitis. Curr Opin Neurol 2014; 27(3):279–289. doi:10.1097/WCO.0000000000000093
