Geriatrics

Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. 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.

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Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. 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
 

Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. 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
 

Children in military families face unique challenges that other children do not face. 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
 

Children in military families face unique challenges that other children do not face. 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
 

Children in military families face unique challenges that other children do not face. 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
 

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.

Doug Brunk/MDedge News

“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. Studies have shown that beta cell function declines with age regardless of diabetes status. This is characterized by abnormal pulsatile insulin response, decreased beta-cell responsiveness to glucose, increased proinsulin-to-insulin ratio, and decreased insulin production and secretion.”

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 A_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c over time had the lowest HbA_1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA_1c 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.

dbrunk@mdedge.com

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.

Doug Brunk/MDedge News

“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. Studies have shown that beta cell function declines with age regardless of diabetes status. This is characterized by abnormal pulsatile insulin response, decreased beta-cell responsiveness to glucose, increased proinsulin-to-insulin ratio, and decreased insulin production and secretion.”

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 A_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c over time had the lowest HbA_1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA_1c 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.

dbrunk@mdedge.com

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.

Doug Brunk/MDedge News

“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. Studies have shown that beta cell function declines with age regardless of diabetes status. This is characterized by abnormal pulsatile insulin response, decreased beta-cell responsiveness to glucose, increased proinsulin-to-insulin ratio, and decreased insulin production and secretion.”

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 A_1c 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 HbA_1c 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 HbA_1c 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 HbA_1c over time had the lowest HbA_1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA_1c 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.

dbrunk@mdedge.com

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 before initiating antidepressant therapy, the rate of hip fractures was more than twice (2.8% vs. 1.1%) that of the control group. 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 before initiating antidepressant therapy, the rate of hip fractures was more than twice (2.8% vs. 1.1%) that of the control group. 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 before initiating antidepressant therapy, the rate of hip fractures was more than twice (2.8% vs. 1.1%) that of the control group. 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.

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 3^28–30 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 3^28–30 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 3^28–30 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.

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

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

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

 

 

Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

Drug Brand Name

Curcumin • Theracurmin

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

 

 

Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

Drug Brand Name

Curcumin • Theracurmin

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

 

 

Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

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Curcumin • Theracurmin

A group of internists is suing the American Board of Internal Medicine over its maintenance of certification. Also today, drug test results should not dictate treatment, duodenoscopes contain more bacteria than expected, and weight-loss medications may have a role following bariatric surgery.

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A group of internists is suing the American Board of Internal Medicine over its maintenance of certification. Also today, drug test results should not dictate treatment, duodenoscopes contain more bacteria than expected, and weight-loss medications may have a role following bariatric surgery.

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A group of internists is suing the American Board of Internal Medicine over its maintenance of certification. Also today, drug test results should not dictate treatment, duodenoscopes contain more bacteria than expected, and weight-loss medications may have a role following bariatric surgery.

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There will be 53 million older adults in the US by 2020.¹ Increasing age often brings medical comorbidities and prescriptions for multiple medications. An increasing number of prescribed medications combined with age-related changes in the ability to metabolize drugs makes older adults highly vulnerable to adverse drug events (ADEs).² In addition, older adults often have difficulty self-managing their medications and adhering to prescribed regimens.³ As a result, ADEs can lead to poor health outcomes, including hospitalizations, in older adults.

Medication errors and ADEs are particularly common during transitions from hospital to home and can lead to unnecessary readmissions,a major cause of wasteful health care spending in the US.^4,5 More than $25 billion are estimated to be spent annually on hospital readmissions, with Medicare picking up the bill for $17 billion of the total.^6,7 Researchers have found that the majority of ADEs following hospital discharge are either entirely preventable or at least ameliorable (ie, the negative impact or harm resulting from the ADE could have been reduced).⁸

To address these issues, we undertook a clinical demonstration project that implemented a new transitional care program to improve the quality of care for older veterans transitioning from the Audie L. Murphy Veterans Memorial Hospital of the South Texas Veterans Health Care System (STVHCS) in San Antonio to home. The Geriatrics Medication Education at Discharge project (GMED) falls under the auspices of the San Antonio Geriatrics Research Education and Clinical Center (GRECC). Clinical demonstration projects are mandated for US Department of Veterans Affairs (VA) GRECCs to create and promote innovative models of care for older veterans. Dissemination of successful clinical demonstration projects to other VA sites is strongly encouraged. The GMED program was modeled after the Boston GRECC Pharmacological Intervention in Late Life (PILL) program.⁹ The PILL program, which focuses on serving older veterans with cognitive impairment, demonstrated that a postdischarge pharmacist telephone visit for medication reconciliation leads to a reduction in readmission within 60 days of discharge.⁹ The goals of the GMED program were to reduce polypharmacy, inappropriate prescribing and 30-day readmissions.

Methods

The project was conducted when a full-time clinical pharmacy specialist (CPS) was available (May-September 2013 and April 2014-March 2015). This project was approved as nonresearch/quality improvement by the University of Texas Health Science Center Institutional Review Board, which serves the STVHCS. Consent was not required.

Eligibility

Patients were identified via a daily hospital database query of all adults aged ≥ 65 years admitted to the hospital through Inpatient Medicine, Neurology, or Cardiology services within the prior 24 hours. Patients meeting any of the following criteria based on review of the Computerized Patient Record System (CPRS) by the team geriatrician and CPS were considered eligible: (1) aged ≥ 70 years prescribed ≥ 12 outpatient medications; (2) aged ≥ 65 years with a medical history of dementia; (3) aged ≥ 65 years prescribed outpatient medications meeting Beers criteria¹⁰; (4) age ≥ 65 years with ≥ 2 hospital admissions (including the current, index admission) within the past calendar year; or (5) aged ≥ 65 years with ≥ 3 emergency department visits within the past calendar year. For the first polypharmacy criterion, patients aged ≥ 70 years were selected instead of aged ≥ 65 years so as not to exceed the capacity of 1 CPS. Twelve or more medications were used as a cutoff for polypharmacy based on prior quality improvement information gathered from our VA geriatrics clinic examining the average number of medications taken by older veterans in the outpatient setting.

Related: Reducing COPD Readmission Rates: Using a COPD Care Service During Care Transitions

Patients were excluded if they were expected to be discharged to any facility where the patient and/or the caregiver were not primarily responsible for medication administration after discharge. Patients who met eligibility criteria but were not seen by the transitional program pharmacist (due to staff capacity) were included in this analysis as a convenience comparison group of patients who received usual care. Patients were not randomized. All communication occurred in English, but this project did not exclude patients with limited English proficiency.

A program support assistant conducted the daily query of the hospital database. The pharmacist conducted the chart review to determine eligibility and delivered the intervention. Eligible patients were selected at random for the intervention with the intention of providing the intervention to as many veterans as possible.

The GMED Intervention

The GMED program included 2 phases, which were both conducted by a CPS with oversight from a senior CPS with geriatric pharmacology expertise and an internist/geriatrician. 

The first phase of the transitional care program included an individual, face-to-face meeting between the CPS and the patient during the hospitalization. If a veteran was not present in the room at the time of an attempted visit, the pharmacist made 2 additional attempts (3 total) to include the patient in the transitional care program during the hospitalization. 

The second component of the transitional care program included a telephone visit within 2 to 3 days of discharge, conducted by the same CPS who performed the face-to-face visit. The purpose of the telephone visit was to perform medication reconciliation, identify and rectify medication errors, provide further patient education, and assist in facilitating appropriate follow-up by the patient’s primary care provider (PCP), if required. At a minimum, veterans were asked a series of questions pertaining to their concerns about medication regimens, receipt of newly prescribed medications at discharge, additional education regarding medications after the CPS encounter during hospitalization, and whether the veteran required assistance with the medication regimen in the home setting. Follow-up questions were asked as needed to clarify and identify potential medication problems. All information from this telephone encounter was communicated to the PCP through CPRS documentation and by telephone as needed.

Related: Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) Polypharmacy Clinic

Data Collection

A standardized questionnaire was used prospectively for patients in the transitional care program group to assess patient education, primary residence, presence of a caregiver, fall history, medication adherence, and cognitive status (using Mini-Cog).¹³ Additional information (patient age, number of outpatient medications prior to and following the admission, presence of Beers criteria outpatient medications prior to and following the admission, new outpatient prescriptions, and changes to existing prescriptions as a result of the hospitalization) was gathered prospectively from patient interviews or from chart review.

For patients included in the comparison group, a retrospective administrative chart review was conducted to collect information such as age, sex, ethnic group, admission within 1 year prior to index admission, frailty, and Charlson Comorbidity Index (CCI) score, a method of categorizing comorbidities of patients based on the diagnosis codes found in administrative data.¹⁴ Each comorbidity category has an associated weight (from 1 to 6), based on the adjusted risk of mortality or resource use, and the sum of all the weights results in a single comorbidity score for a patient (0 indicates no comorbidities; higher scores predict greater risk of mortality or increased resource use).

We used the index developed from 17 disease categories. The range for CCI was 0 to 25. Frailty was defined as the presence of any of the following frailty-related diagnoses: anemia; fall, head injury, other injury; coagulopathy; electrolyte disturbance; or gait disorder. These diagnoses are either primary frailty characteristics within the frailty phenotype or have been shown in prior studies to be associated with the frailty phenotype.^15-18 While more widely accepted frailty definitions exist,these other definitions require direct examination of the patient and could not be used in this project because we did not directly interact with the comparison group.^16,19 The frailty definition used has been previously identified as a predictor of health care utilization and 30-day readmission in a veteran population.²⁰ Whether or not the CPS detected a postdischarge medication error was recorded. All CPS recommendations were documented.

An index admission was defined as a hospital admission that occurred during the project period. Thirty-day readmission was defined as a hospital admission that occurred within 30 days of the discharge date of an index admission. Each index admission was considered individually for readmission (yes vs no) even if it occurred in the same patient over the project period. A 30-day readmission was not considered an index admission. An admission that occurred after a 30-day readmission was considered a subsequent index admission. Patients who died in the hospital were not included in this analysis, as they would not have participated in the entire intervention.

Statistical Analysis

We compared characteristics between patients who received GMED and patients who never received GMED (comparison group). Generalized estimating equations (GEE) were used to determine whether the rate of 30-day readmission (yes vs no) in the transitional care program group differed from that of the comparison group. In our GEE analysis, we assumed a binomial distribution and the logit link to model the log-odds of readmission as a linear function of transitional care program status (yes vs no) and other covariates, including age, frailty, hospital admission within 1 year prior to the index admission, and CCI score as covariates. Thirty-day readmission status associated with each index admission was coded as 1 for a readmission within 30 days of the discharge date of the index admission, or 0 for no readmission within 30 days.

Transitional care program status was determined whether or not the individual received the transitional care program for each index admission. This analysis allowed us to model repeated measures of index admissions as a function of the project period and whether the patient was seen by the GMED CPS during the index admission. The patient identifier was used as a cluster variable in the GEE analysis. Inverse propensity scores of receiving GMED at the index admission were adjusted as weights in the GEE analysis to minimize confounding and, hence, to strengthen the causal interpretation of the effect of the transitional care program. If there was ≥ 1 index admission, the GMED status (yes vs no) at the initial index admission was used as the dependent variable to calculate propensity scores. The propensity scores of transitional care program status were derived from the logistic regression analysis that modeled the log-odds of receiving the transitional care program at the index admission as a linear function of age, CCI, frailty, and prior hospitalization during the 1-year period prior to the index admission.

Related: Development and Implementation of a Geriatric Walking Clinic

Results

The GMED CPS saw 435 patients during the project period; 47 (10.8%) died prior to 30 days and were excluded, leaving 388 patients who received the transitional care program included in this evaluation. 

Data from the CPS-patient interviews and chart reviews were available for 378 of the 388 patients (Table 2). Patients were primarily male, non-Hispanic white, with a high school education. More than half (65%) the patients were admitted for a new diagnosis or clinical condition. 

The 30-day readmission rate was 15.6% for the transitional care program group and 21.9% for the comparison group. Three hundred seventy-one patients received the transitional care program only once, 16 patients received the transitional care program twice (ie, they had 2 index admissions during the study period and received the intervention both times), and 1 patient received the transitional care program 3 times.

In an unadjusted GEE model, the odds ratio (OR) for readmission in the transitional care program group was 0.74 (95% CI, 0.54-1.0, P = .06) compared with the usual care group (Table 3). 

Thirty-five percent of patients had ≥ 1 CPS-recommended change in their treatment at the time of the inpatient admission (Table 4). 

Discussion

We developed a transitional care program for hospitalized older veterans to improve the transition from hospital to home. After adjusting for clinical factors, GMED was associated with 26% lower odds of readmission within 30 days of discharge compared with that of the control group. The GMED CPS made changes to the medical regimen both during the inpatient admission as well as after discharge to correct medication errors and educate patients.

In addition, GMED led to a reduction in the number of prescribed medications, which impacts inappropriate polypharmacy—a significant problem in older adults, which contributes to ADEs.²¹ Our intervention was patient centered, as all decisions and education regarding medication management were tailored to each patient, taking into account medical and psychosocial factors.

Studies of similar programs have shown that a pharmacist-based program can improve outcomes in patients transitioning from hospital to home. A meta-analysis of 19 studies that evaluated the effectiveness of pharmacy-led medication reconciliation interventions at the time of a care transition showed that compared with usual care a pharmacist intervention led to reduced medication discrepancies.²² In this meta-analysis, medication discrepancies of higher clinical impact were more easily identified through pharmacy-led interventions than with usual care, suggesting improved safety. Although not all studies have shown a clear reduction in readmission rates or other health care utilization, the addition of clinical pharmacist services in the care of inpatients has generally resulted in improved care with no evidence of harm.²³

Based on these findings and collaboration with another GRECC, we designed our program to focus on older adults with polypharmacy, cognitive impairment, high-risk medication usage, and/or a history of high health care use.⁹ Our findings add to the growing body of evidence that a CPS-led transitional care program results in reduced polypharmacy and reduced unnecessary hospital readmissions. Further, our findings have demonstrated the effectiveness of this type of program in a practical, clinical setting with veteran patients.

At the time of project inception, we believed that the majority of our interventions would occur postdischarge. We were somewhat surprised that a major component of GMED was suggested interventions by our pharmacist at the time of admission. We believe that because the CPS made suggestions during admission, we prevented postdischarge ADEs. A frequent intervention corrected the medication reconciliation on file at admission. This finding also was seen in another study by Gleason and colleagues, which examined medication errors at admission for 651 adult medicine inpatients.²⁴ This study found that more than one-third of patients had medication reconciliation errors. Further, older age (≥ 65 years) was associated with increased odds of medication errors in this study.

Of note, a survey of hospital-based pharmacists indicated medication reconciliation is the most important role of the pharmacist in improving care transitions.²⁵ The pharmacists stated that detection of errors at the time of admission is very important. The pharmacists further reported that additional education and counseling for patients with poor understanding of their medications was also important. Our findings support these findings and the use of a pharmacist as part of the medical team to improve medication reconciliation and education.

Limitations

A limitation of GMED is that we monitored only admissions to our hospital; therefore, we did not account for any hospitalizations that may have occurred outside the STVHCS. Another limitation is that this was not a randomized controlled trial, and we used a convenience sample of patients who met our criteria for eligibility but were not seen due to time constraints. This introduces potential bias such that patients admitted and discharged on nights or weekends when the CPS was not available were not included in the transitional care program group, and these patients may fundamentally differ from those admitted and discharged Monday through Friday.

However, Khanna and colleagues found that night or weekend admission was not associated with 30-day readmission or other worse outcomes (such as length of stay, 30-day emergency department visit, or intensive care unit transfer) in 857 general medicine admissions at a tertiary care hospital.²⁶ Every effort was made to include as many eligible patients as possible in the transitional program group, and we were able to demonstrate that the patients in the 2 groups were similar. Frailty and prior hospital admission were more prevalent, although not significantly so, in the transitional program group, suggesting that any selection bias would have actually attenuated—not enhanced—the observed effect of the transitional program. Although the transitional program group patients were slightly younger by 0.3 years, they were similar in frailty status and CCI score.

Conclusion

The GMED program was associated with reduced 30-day hospital readmission, discontinuation of unnecessary medications, and corrected medication errors and discrepancies. We propose that a CPS-based transitional care program can improve the quality of care for older patients being discharged to home.

Acknowledgments

Supported by funding from the Veterans Health Administration T21 Non-Institutional Long-Term Care Initiative and VA Office of Rural Health and the San Antonio Geriatrics Research, Education, and Clinical Center. The sponsor did not have any role in the design, methods, data collection, or analysis, and preparation.

Author Contributions

R. Rottman-Sagebiel developed the transitional program concept and design and executed the program implementation, interpretation of data, and preparation of the manuscript. S. Pastewait, N. Cupples, A. Conde, M. Moris, and E. Gonzalez assisted with program design and implementation. S. Cope assisted with interpretation of data and preparation of the manuscript. H. Braden assisted with interpretation of data. D. MacCarthy assisted with data management and statistical analysis. C. Wang and S. Espinoza developed the program concept and design, performed statistical analysis and interpretation of data, and helped prepare the manuscript.

Advances in Geriatrics

Advances in Geriatrics features articles focused on quality improvement/quality assurance initiatives, pilot studies, best practices, research, patient education, and patient-centered care written by health care providers associated with Veteran Health Administration Geriatric Research Education and Clinical Centers. Interested authors can submit articles at editorialmanager.com/fedprac or send a brief 2 to 3 sentence abstract to fedprac@mdedge.com for feedback and publication recommendations.

There will be 53 million older adults in the US by 2020.¹ Increasing age often brings medical comorbidities and prescriptions for multiple medications. An increasing number of prescribed medications combined with age-related changes in the ability to metabolize drugs makes older adults highly vulnerable to adverse drug events (ADEs).² In addition, older adults often have difficulty self-managing their medications and adhering to prescribed regimens.³ As a result, ADEs can lead to poor health outcomes, including hospitalizations, in older adults.

Medication errors and ADEs are particularly common during transitions from hospital to home and can lead to unnecessary readmissions,a major cause of wasteful health care spending in the US.^4,5 More than $25 billion are estimated to be spent annually on hospital readmissions, with Medicare picking up the bill for $17 billion of the total.^6,7 Researchers have found that the majority of ADEs following hospital discharge are either entirely preventable or at least ameliorable (ie, the negative impact or harm resulting from the ADE could have been reduced).⁸

To address these issues, we undertook a clinical demonstration project that implemented a new transitional care program to improve the quality of care for older veterans transitioning from the Audie L. Murphy Veterans Memorial Hospital of the South Texas Veterans Health Care System (STVHCS) in San Antonio to home. The Geriatrics Medication Education at Discharge project (GMED) falls under the auspices of the San Antonio Geriatrics Research Education and Clinical Center (GRECC). Clinical demonstration projects are mandated for US Department of Veterans Affairs (VA) GRECCs to create and promote innovative models of care for older veterans. Dissemination of successful clinical demonstration projects to other VA sites is strongly encouraged. The GMED program was modeled after the Boston GRECC Pharmacological Intervention in Late Life (PILL) program.⁹ The PILL program, which focuses on serving older veterans with cognitive impairment, demonstrated that a postdischarge pharmacist telephone visit for medication reconciliation leads to a reduction in readmission within 60 days of discharge.⁹ The goals of the GMED program were to reduce polypharmacy, inappropriate prescribing and 30-day readmissions.

Methods

The project was conducted when a full-time clinical pharmacy specialist (CPS) was available (May-September 2013 and April 2014-March 2015). This project was approved as nonresearch/quality improvement by the University of Texas Health Science Center Institutional Review Board, which serves the STVHCS. Consent was not required.

Eligibility

Patients were identified via a daily hospital database query of all adults aged ≥ 65 years admitted to the hospital through Inpatient Medicine, Neurology, or Cardiology services within the prior 24 hours. Patients meeting any of the following criteria based on review of the Computerized Patient Record System (CPRS) by the team geriatrician and CPS were considered eligible: (1) aged ≥ 70 years prescribed ≥ 12 outpatient medications; (2) aged ≥ 65 years with a medical history of dementia; (3) aged ≥ 65 years prescribed outpatient medications meeting Beers criteria¹⁰; (4) age ≥ 65 years with ≥ 2 hospital admissions (including the current, index admission) within the past calendar year; or (5) aged ≥ 65 years with ≥ 3 emergency department visits within the past calendar year. For the first polypharmacy criterion, patients aged ≥ 70 years were selected instead of aged ≥ 65 years so as not to exceed the capacity of 1 CPS. Twelve or more medications were used as a cutoff for polypharmacy based on prior quality improvement information gathered from our VA geriatrics clinic examining the average number of medications taken by older veterans in the outpatient setting.

Related: Reducing COPD Readmission Rates: Using a COPD Care Service During Care Transitions

Patients were excluded if they were expected to be discharged to any facility where the patient and/or the caregiver were not primarily responsible for medication administration after discharge. Patients who met eligibility criteria but were not seen by the transitional program pharmacist (due to staff capacity) were included in this analysis as a convenience comparison group of patients who received usual care. Patients were not randomized. All communication occurred in English, but this project did not exclude patients with limited English proficiency.

A program support assistant conducted the daily query of the hospital database. The pharmacist conducted the chart review to determine eligibility and delivered the intervention. Eligible patients were selected at random for the intervention with the intention of providing the intervention to as many veterans as possible.

The GMED Intervention

The GMED program included 2 phases, which were both conducted by a CPS with oversight from a senior CPS with geriatric pharmacology expertise and an internist/geriatrician. 

The first phase of the transitional care program included an individual, face-to-face meeting between the CPS and the patient during the hospitalization. If a veteran was not present in the room at the time of an attempted visit, the pharmacist made 2 additional attempts (3 total) to include the patient in the transitional care program during the hospitalization. 

The second component of the transitional care program included a telephone visit within 2 to 3 days of discharge, conducted by the same CPS who performed the face-to-face visit. The purpose of the telephone visit was to perform medication reconciliation, identify and rectify medication errors, provide further patient education, and assist in facilitating appropriate follow-up by the patient’s primary care provider (PCP), if required. At a minimum, veterans were asked a series of questions pertaining to their concerns about medication regimens, receipt of newly prescribed medications at discharge, additional education regarding medications after the CPS encounter during hospitalization, and whether the veteran required assistance with the medication regimen in the home setting. Follow-up questions were asked as needed to clarify and identify potential medication problems. All information from this telephone encounter was communicated to the PCP through CPRS documentation and by telephone as needed.

Related: Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) Polypharmacy Clinic

Data Collection

A standardized questionnaire was used prospectively for patients in the transitional care program group to assess patient education, primary residence, presence of a caregiver, fall history, medication adherence, and cognitive status (using Mini-Cog).¹³ Additional information (patient age, number of outpatient medications prior to and following the admission, presence of Beers criteria outpatient medications prior to and following the admission, new outpatient prescriptions, and changes to existing prescriptions as a result of the hospitalization) was gathered prospectively from patient interviews or from chart review.

For patients included in the comparison group, a retrospective administrative chart review was conducted to collect information such as age, sex, ethnic group, admission within 1 year prior to index admission, frailty, and Charlson Comorbidity Index (CCI) score, a method of categorizing comorbidities of patients based on the diagnosis codes found in administrative data.¹⁴ Each comorbidity category has an associated weight (from 1 to 6), based on the adjusted risk of mortality or resource use, and the sum of all the weights results in a single comorbidity score for a patient (0 indicates no comorbidities; higher scores predict greater risk of mortality or increased resource use).

We used the index developed from 17 disease categories. The range for CCI was 0 to 25. Frailty was defined as the presence of any of the following frailty-related diagnoses: anemia; fall, head injury, other injury; coagulopathy; electrolyte disturbance; or gait disorder. These diagnoses are either primary frailty characteristics within the frailty phenotype or have been shown in prior studies to be associated with the frailty phenotype.^15-18 While more widely accepted frailty definitions exist,these other definitions require direct examination of the patient and could not be used in this project because we did not directly interact with the comparison group.^16,19 The frailty definition used has been previously identified as a predictor of health care utilization and 30-day readmission in a veteran population.²⁰ Whether or not the CPS detected a postdischarge medication error was recorded. All CPS recommendations were documented.

An index admission was defined as a hospital admission that occurred during the project period. Thirty-day readmission was defined as a hospital admission that occurred within 30 days of the discharge date of an index admission. Each index admission was considered individually for readmission (yes vs no) even if it occurred in the same patient over the project period. A 30-day readmission was not considered an index admission. An admission that occurred after a 30-day readmission was considered a subsequent index admission. Patients who died in the hospital were not included in this analysis, as they would not have participated in the entire intervention.

Statistical Analysis

We compared characteristics between patients who received GMED and patients who never received GMED (comparison group). Generalized estimating equations (GEE) were used to determine whether the rate of 30-day readmission (yes vs no) in the transitional care program group differed from that of the comparison group. In our GEE analysis, we assumed a binomial distribution and the logit link to model the log-odds of readmission as a linear function of transitional care program status (yes vs no) and other covariates, including age, frailty, hospital admission within 1 year prior to the index admission, and CCI score as covariates. Thirty-day readmission status associated with each index admission was coded as 1 for a readmission within 30 days of the discharge date of the index admission, or 0 for no readmission within 30 days.

Transitional care program status was determined whether or not the individual received the transitional care program for each index admission. This analysis allowed us to model repeated measures of index admissions as a function of the project period and whether the patient was seen by the GMED CPS during the index admission. The patient identifier was used as a cluster variable in the GEE analysis. Inverse propensity scores of receiving GMED at the index admission were adjusted as weights in the GEE analysis to minimize confounding and, hence, to strengthen the causal interpretation of the effect of the transitional care program. If there was ≥ 1 index admission, the GMED status (yes vs no) at the initial index admission was used as the dependent variable to calculate propensity scores. The propensity scores of transitional care program status were derived from the logistic regression analysis that modeled the log-odds of receiving the transitional care program at the index admission as a linear function of age, CCI, frailty, and prior hospitalization during the 1-year period prior to the index admission.

Related: Development and Implementation of a Geriatric Walking Clinic

Results

The GMED CPS saw 435 patients during the project period; 47 (10.8%) died prior to 30 days and were excluded, leaving 388 patients who received the transitional care program included in this evaluation. 

Data from the CPS-patient interviews and chart reviews were available for 378 of the 388 patients (Table 2). Patients were primarily male, non-Hispanic white, with a high school education. More than half (65%) the patients were admitted for a new diagnosis or clinical condition. 

The 30-day readmission rate was 15.6% for the transitional care program group and 21.9% for the comparison group. Three hundred seventy-one patients received the transitional care program only once, 16 patients received the transitional care program twice (ie, they had 2 index admissions during the study period and received the intervention both times), and 1 patient received the transitional care program 3 times.

In an unadjusted GEE model, the odds ratio (OR) for readmission in the transitional care program group was 0.74 (95% CI, 0.54-1.0, P = .06) compared with the usual care group (Table 3). 

Thirty-five percent of patients had ≥ 1 CPS-recommended change in their treatment at the time of the inpatient admission (Table 4). 

Discussion

We developed a transitional care program for hospitalized older veterans to improve the transition from hospital to home. After adjusting for clinical factors, GMED was associated with 26% lower odds of readmission within 30 days of discharge compared with that of the control group. The GMED CPS made changes to the medical regimen both during the inpatient admission as well as after discharge to correct medication errors and educate patients.

In addition, GMED led to a reduction in the number of prescribed medications, which impacts inappropriate polypharmacy—a significant problem in older adults, which contributes to ADEs.²¹ Our intervention was patient centered, as all decisions and education regarding medication management were tailored to each patient, taking into account medical and psychosocial factors.

Studies of similar programs have shown that a pharmacist-based program can improve outcomes in patients transitioning from hospital to home. A meta-analysis of 19 studies that evaluated the effectiveness of pharmacy-led medication reconciliation interventions at the time of a care transition showed that compared with usual care a pharmacist intervention led to reduced medication discrepancies.²² In this meta-analysis, medication discrepancies of higher clinical impact were more easily identified through pharmacy-led interventions than with usual care, suggesting improved safety. Although not all studies have shown a clear reduction in readmission rates or other health care utilization, the addition of clinical pharmacist services in the care of inpatients has generally resulted in improved care with no evidence of harm.²³

Based on these findings and collaboration with another GRECC, we designed our program to focus on older adults with polypharmacy, cognitive impairment, high-risk medication usage, and/or a history of high health care use.⁹ Our findings add to the growing body of evidence that a CPS-led transitional care program results in reduced polypharmacy and reduced unnecessary hospital readmissions. Further, our findings have demonstrated the effectiveness of this type of program in a practical, clinical setting with veteran patients.

At the time of project inception, we believed that the majority of our interventions would occur postdischarge. We were somewhat surprised that a major component of GMED was suggested interventions by our pharmacist at the time of admission. We believe that because the CPS made suggestions during admission, we prevented postdischarge ADEs. A frequent intervention corrected the medication reconciliation on file at admission. This finding also was seen in another study by Gleason and colleagues, which examined medication errors at admission for 651 adult medicine inpatients.²⁴ This study found that more than one-third of patients had medication reconciliation errors. Further, older age (≥ 65 years) was associated with increased odds of medication errors in this study.

Of note, a survey of hospital-based pharmacists indicated medication reconciliation is the most important role of the pharmacist in improving care transitions.²⁵ The pharmacists stated that detection of errors at the time of admission is very important. The pharmacists further reported that additional education and counseling for patients with poor understanding of their medications was also important. Our findings support these findings and the use of a pharmacist as part of the medical team to improve medication reconciliation and education.

Limitations

A limitation of GMED is that we monitored only admissions to our hospital; therefore, we did not account for any hospitalizations that may have occurred outside the STVHCS. Another limitation is that this was not a randomized controlled trial, and we used a convenience sample of patients who met our criteria for eligibility but were not seen due to time constraints. This introduces potential bias such that patients admitted and discharged on nights or weekends when the CPS was not available were not included in the transitional care program group, and these patients may fundamentally differ from those admitted and discharged Monday through Friday.

However, Khanna and colleagues found that night or weekend admission was not associated with 30-day readmission or other worse outcomes (such as length of stay, 30-day emergency department visit, or intensive care unit transfer) in 857 general medicine admissions at a tertiary care hospital.²⁶ Every effort was made to include as many eligible patients as possible in the transitional program group, and we were able to demonstrate that the patients in the 2 groups were similar. Frailty and prior hospital admission were more prevalent, although not significantly so, in the transitional program group, suggesting that any selection bias would have actually attenuated—not enhanced—the observed effect of the transitional program. Although the transitional program group patients were slightly younger by 0.3 years, they were similar in frailty status and CCI score.

Conclusion

The GMED program was associated with reduced 30-day hospital readmission, discontinuation of unnecessary medications, and corrected medication errors and discrepancies. We propose that a CPS-based transitional care program can improve the quality of care for older patients being discharged to home.

Acknowledgments

Supported by funding from the Veterans Health Administration T21 Non-Institutional Long-Term Care Initiative and VA Office of Rural Health and the San Antonio Geriatrics Research, Education, and Clinical Center. The sponsor did not have any role in the design, methods, data collection, or analysis, and preparation.

Author Contributions

R. Rottman-Sagebiel developed the transitional program concept and design and executed the program implementation, interpretation of data, and preparation of the manuscript. S. Pastewait, N. Cupples, A. Conde, M. Moris, and E. Gonzalez assisted with program design and implementation. S. Cope assisted with interpretation of data and preparation of the manuscript. H. Braden assisted with interpretation of data. D. MacCarthy assisted with data management and statistical analysis. C. Wang and S. Espinoza developed the program concept and design, performed statistical analysis and interpretation of data, and helped prepare the manuscript.

Advances in Geriatrics

Advances in Geriatrics features articles focused on quality improvement/quality assurance initiatives, pilot studies, best practices, research, patient education, and patient-centered care written by health care providers associated with Veteran Health Administration Geriatric Research Education and Clinical Centers. Interested authors can submit articles at editorialmanager.com/fedprac or send a brief 2 to 3 sentence abstract to fedprac@mdedge.com for feedback and publication recommendations.

There will be 53 million older adults in the US by 2020.¹ Increasing age often brings medical comorbidities and prescriptions for multiple medications. An increasing number of prescribed medications combined with age-related changes in the ability to metabolize drugs makes older adults highly vulnerable to adverse drug events (ADEs).² In addition, older adults often have difficulty self-managing their medications and adhering to prescribed regimens.³ As a result, ADEs can lead to poor health outcomes, including hospitalizations, in older adults.

Medication errors and ADEs are particularly common during transitions from hospital to home and can lead to unnecessary readmissions,a major cause of wasteful health care spending in the US.^4,5 More than $25 billion are estimated to be spent annually on hospital readmissions, with Medicare picking up the bill for $17 billion of the total.^6,7 Researchers have found that the majority of ADEs following hospital discharge are either entirely preventable or at least ameliorable (ie, the negative impact or harm resulting from the ADE could have been reduced).⁸

To address these issues, we undertook a clinical demonstration project that implemented a new transitional care program to improve the quality of care for older veterans transitioning from the Audie L. Murphy Veterans Memorial Hospital of the South Texas Veterans Health Care System (STVHCS) in San Antonio to home. The Geriatrics Medication Education at Discharge project (GMED) falls under the auspices of the San Antonio Geriatrics Research Education and Clinical Center (GRECC). Clinical demonstration projects are mandated for US Department of Veterans Affairs (VA) GRECCs to create and promote innovative models of care for older veterans. Dissemination of successful clinical demonstration projects to other VA sites is strongly encouraged. The GMED program was modeled after the Boston GRECC Pharmacological Intervention in Late Life (PILL) program.⁹ The PILL program, which focuses on serving older veterans with cognitive impairment, demonstrated that a postdischarge pharmacist telephone visit for medication reconciliation leads to a reduction in readmission within 60 days of discharge.⁹ The goals of the GMED program were to reduce polypharmacy, inappropriate prescribing and 30-day readmissions.

Methods

The project was conducted when a full-time clinical pharmacy specialist (CPS) was available (May-September 2013 and April 2014-March 2015). This project was approved as nonresearch/quality improvement by the University of Texas Health Science Center Institutional Review Board, which serves the STVHCS. Consent was not required.

Eligibility

Patients were identified via a daily hospital database query of all adults aged ≥ 65 years admitted to the hospital through Inpatient Medicine, Neurology, or Cardiology services within the prior 24 hours. Patients meeting any of the following criteria based on review of the Computerized Patient Record System (CPRS) by the team geriatrician and CPS were considered eligible: (1) aged ≥ 70 years prescribed ≥ 12 outpatient medications; (2) aged ≥ 65 years with a medical history of dementia; (3) aged ≥ 65 years prescribed outpatient medications meeting Beers criteria¹⁰; (4) age ≥ 65 years with ≥ 2 hospital admissions (including the current, index admission) within the past calendar year; or (5) aged ≥ 65 years with ≥ 3 emergency department visits within the past calendar year. For the first polypharmacy criterion, patients aged ≥ 70 years were selected instead of aged ≥ 65 years so as not to exceed the capacity of 1 CPS. Twelve or more medications were used as a cutoff for polypharmacy based on prior quality improvement information gathered from our VA geriatrics clinic examining the average number of medications taken by older veterans in the outpatient setting.

Related: Reducing COPD Readmission Rates: Using a COPD Care Service During Care Transitions

Patients were excluded if they were expected to be discharged to any facility where the patient and/or the caregiver were not primarily responsible for medication administration after discharge. Patients who met eligibility criteria but were not seen by the transitional program pharmacist (due to staff capacity) were included in this analysis as a convenience comparison group of patients who received usual care. Patients were not randomized. All communication occurred in English, but this project did not exclude patients with limited English proficiency.

A program support assistant conducted the daily query of the hospital database. The pharmacist conducted the chart review to determine eligibility and delivered the intervention. Eligible patients were selected at random for the intervention with the intention of providing the intervention to as many veterans as possible.

The GMED Intervention

The GMED program included 2 phases, which were both conducted by a CPS with oversight from a senior CPS with geriatric pharmacology expertise and an internist/geriatrician. 

The first phase of the transitional care program included an individual, face-to-face meeting between the CPS and the patient during the hospitalization. If a veteran was not present in the room at the time of an attempted visit, the pharmacist made 2 additional attempts (3 total) to include the patient in the transitional care program during the hospitalization. 

The second component of the transitional care program included a telephone visit within 2 to 3 days of discharge, conducted by the same CPS who performed the face-to-face visit. The purpose of the telephone visit was to perform medication reconciliation, identify and rectify medication errors, provide further patient education, and assist in facilitating appropriate follow-up by the patient’s primary care provider (PCP), if required. At a minimum, veterans were asked a series of questions pertaining to their concerns about medication regimens, receipt of newly prescribed medications at discharge, additional education regarding medications after the CPS encounter during hospitalization, and whether the veteran required assistance with the medication regimen in the home setting. Follow-up questions were asked as needed to clarify and identify potential medication problems. All information from this telephone encounter was communicated to the PCP through CPRS documentation and by telephone as needed.

Related: Initiative to Minimize Pharmaceutical Risk in Older Veterans (IMPROVE) Polypharmacy Clinic

Data Collection

A standardized questionnaire was used prospectively for patients in the transitional care program group to assess patient education, primary residence, presence of a caregiver, fall history, medication adherence, and cognitive status (using Mini-Cog).¹³ Additional information (patient age, number of outpatient medications prior to and following the admission, presence of Beers criteria outpatient medications prior to and following the admission, new outpatient prescriptions, and changes to existing prescriptions as a result of the hospitalization) was gathered prospectively from patient interviews or from chart review.

For patients included in the comparison group, a retrospective administrative chart review was conducted to collect information such as age, sex, ethnic group, admission within 1 year prior to index admission, frailty, and Charlson Comorbidity Index (CCI) score, a method of categorizing comorbidities of patients based on the diagnosis codes found in administrative data.¹⁴ Each comorbidity category has an associated weight (from 1 to 6), based on the adjusted risk of mortality or resource use, and the sum of all the weights results in a single comorbidity score for a patient (0 indicates no comorbidities; higher scores predict greater risk of mortality or increased resource use).

We used the index developed from 17 disease categories. The range for CCI was 0 to 25. Frailty was defined as the presence of any of the following frailty-related diagnoses: anemia; fall, head injury, other injury; coagulopathy; electrolyte disturbance; or gait disorder. These diagnoses are either primary frailty characteristics within the frailty phenotype or have been shown in prior studies to be associated with the frailty phenotype.^15-18 While more widely accepted frailty definitions exist,these other definitions require direct examination of the patient and could not be used in this project because we did not directly interact with the comparison group.^16,19 The frailty definition used has been previously identified as a predictor of health care utilization and 30-day readmission in a veteran population.²⁰ Whether or not the CPS detected a postdischarge medication error was recorded. All CPS recommendations were documented.

An index admission was defined as a hospital admission that occurred during the project period. Thirty-day readmission was defined as a hospital admission that occurred within 30 days of the discharge date of an index admission. Each index admission was considered individually for readmission (yes vs no) even if it occurred in the same patient over the project period. A 30-day readmission was not considered an index admission. An admission that occurred after a 30-day readmission was considered a subsequent index admission. Patients who died in the hospital were not included in this analysis, as they would not have participated in the entire intervention.

Statistical Analysis

We compared characteristics between patients who received GMED and patients who never received GMED (comparison group). Generalized estimating equations (GEE) were used to determine whether the rate of 30-day readmission (yes vs no) in the transitional care program group differed from that of the comparison group. In our GEE analysis, we assumed a binomial distribution and the logit link to model the log-odds of readmission as a linear function of transitional care program status (yes vs no) and other covariates, including age, frailty, hospital admission within 1 year prior to the index admission, and CCI score as covariates. Thirty-day readmission status associated with each index admission was coded as 1 for a readmission within 30 days of the discharge date of the index admission, or 0 for no readmission within 30 days.

Transitional care program status was determined whether or not the individual received the transitional care program for each index admission. This analysis allowed us to model repeated measures of index admissions as a function of the project period and whether the patient was seen by the GMED CPS during the index admission. The patient identifier was used as a cluster variable in the GEE analysis. Inverse propensity scores of receiving GMED at the index admission were adjusted as weights in the GEE analysis to minimize confounding and, hence, to strengthen the causal interpretation of the effect of the transitional care program. If there was ≥ 1 index admission, the GMED status (yes vs no) at the initial index admission was used as the dependent variable to calculate propensity scores. The propensity scores of transitional care program status were derived from the logistic regression analysis that modeled the log-odds of receiving the transitional care program at the index admission as a linear function of age, CCI, frailty, and prior hospitalization during the 1-year period prior to the index admission.

Related: Development and Implementation of a Geriatric Walking Clinic

Results

The GMED CPS saw 435 patients during the project period; 47 (10.8%) died prior to 30 days and were excluded, leaving 388 patients who received the transitional care program included in this evaluation. 

Data from the CPS-patient interviews and chart reviews were available for 378 of the 388 patients (Table 2). Patients were primarily male, non-Hispanic white, with a high school education. More than half (65%) the patients were admitted for a new diagnosis or clinical condition. 

The 30-day readmission rate was 15.6% for the transitional care program group and 21.9% for the comparison group. Three hundred seventy-one patients received the transitional care program only once, 16 patients received the transitional care program twice (ie, they had 2 index admissions during the study period and received the intervention both times), and 1 patient received the transitional care program 3 times.

In an unadjusted GEE model, the odds ratio (OR) for readmission in the transitional care program group was 0.74 (95% CI, 0.54-1.0, P = .06) compared with the usual care group (Table 3). 

Thirty-five percent of patients had ≥ 1 CPS-recommended change in their treatment at the time of the inpatient admission (Table 4). 

Discussion

We developed a transitional care program for hospitalized older veterans to improve the transition from hospital to home. After adjusting for clinical factors, GMED was associated with 26% lower odds of readmission within 30 days of discharge compared with that of the control group. The GMED CPS made changes to the medical regimen both during the inpatient admission as well as after discharge to correct medication errors and educate patients.

In addition, GMED led to a reduction in the number of prescribed medications, which impacts inappropriate polypharmacy—a significant problem in older adults, which contributes to ADEs.²¹ Our intervention was patient centered, as all decisions and education regarding medication management were tailored to each patient, taking into account medical and psychosocial factors.

Studies of similar programs have shown that a pharmacist-based program can improve outcomes in patients transitioning from hospital to home. A meta-analysis of 19 studies that evaluated the effectiveness of pharmacy-led medication reconciliation interventions at the time of a care transition showed that compared with usual care a pharmacist intervention led to reduced medication discrepancies.²² In this meta-analysis, medication discrepancies of higher clinical impact were more easily identified through pharmacy-led interventions than with usual care, suggesting improved safety. Although not all studies have shown a clear reduction in readmission rates or other health care utilization, the addition of clinical pharmacist services in the care of inpatients has generally resulted in improved care with no evidence of harm.²³

Based on these findings and collaboration with another GRECC, we designed our program to focus on older adults with polypharmacy, cognitive impairment, high-risk medication usage, and/or a history of high health care use.⁹ Our findings add to the growing body of evidence that a CPS-led transitional care program results in reduced polypharmacy and reduced unnecessary hospital readmissions. Further, our findings have demonstrated the effectiveness of this type of program in a practical, clinical setting with veteran patients.

At the time of project inception, we believed that the majority of our interventions would occur postdischarge. We were somewhat surprised that a major component of GMED was suggested interventions by our pharmacist at the time of admission. We believe that because the CPS made suggestions during admission, we prevented postdischarge ADEs. A frequent intervention corrected the medication reconciliation on file at admission. This finding also was seen in another study by Gleason and colleagues, which examined medication errors at admission for 651 adult medicine inpatients.²⁴ This study found that more than one-third of patients had medication reconciliation errors. Further, older age (≥ 65 years) was associated with increased odds of medication errors in this study.

Of note, a survey of hospital-based pharmacists indicated medication reconciliation is the most important role of the pharmacist in improving care transitions.²⁵ The pharmacists stated that detection of errors at the time of admission is very important. The pharmacists further reported that additional education and counseling for patients with poor understanding of their medications was also important. Our findings support these findings and the use of a pharmacist as part of the medical team to improve medication reconciliation and education.

Limitations

A limitation of GMED is that we monitored only admissions to our hospital; therefore, we did not account for any hospitalizations that may have occurred outside the STVHCS. Another limitation is that this was not a randomized controlled trial, and we used a convenience sample of patients who met our criteria for eligibility but were not seen due to time constraints. This introduces potential bias such that patients admitted and discharged on nights or weekends when the CPS was not available were not included in the transitional care program group, and these patients may fundamentally differ from those admitted and discharged Monday through Friday.

However, Khanna and colleagues found that night or weekend admission was not associated with 30-day readmission or other worse outcomes (such as length of stay, 30-day emergency department visit, or intensive care unit transfer) in 857 general medicine admissions at a tertiary care hospital.²⁶ Every effort was made to include as many eligible patients as possible in the transitional program group, and we were able to demonstrate that the patients in the 2 groups were similar. Frailty and prior hospital admission were more prevalent, although not significantly so, in the transitional program group, suggesting that any selection bias would have actually attenuated—not enhanced—the observed effect of the transitional program. Although the transitional program group patients were slightly younger by 0.3 years, they were similar in frailty status and CCI score.

Conclusion

The GMED program was associated with reduced 30-day hospital readmission, discontinuation of unnecessary medications, and corrected medication errors and discrepancies. We propose that a CPS-based transitional care program can improve the quality of care for older patients being discharged to home.

Acknowledgments

Supported by funding from the Veterans Health Administration T21 Non-Institutional Long-Term Care Initiative and VA Office of Rural Health and the San Antonio Geriatrics Research, Education, and Clinical Center. The sponsor did not have any role in the design, methods, data collection, or analysis, and preparation.

Author Contributions

R. Rottman-Sagebiel developed the transitional program concept and design and executed the program implementation, interpretation of data, and preparation of the manuscript. S. Pastewait, N. Cupples, A. Conde, M. Moris, and E. Gonzalez assisted with program design and implementation. S. Cope assisted with interpretation of data and preparation of the manuscript. H. Braden assisted with interpretation of data. D. MacCarthy assisted with data management and statistical analysis. C. Wang and S. Espinoza developed the program concept and design, performed statistical analysis and interpretation of data, and helped prepare the manuscript.

Advances in Geriatrics

Advances in Geriatrics features articles focused on quality improvement/quality assurance initiatives, pilot studies, best practices, research, patient education, and patient-centered care written by health care providers associated with Veteran Health Administration Geriatric Research Education and Clinical Centers. Interested authors can submit articles at editorialmanager.com/fedprac or send a brief 2 to 3 sentence abstract to fedprac@mdedge.com for feedback and publication recommendations.