LOS ANGELES—Current guidelines can help physicians prevent stroke in patients with diabetes, according to a lecture delivered at the International Stroke Conference 2018. The prevalence of diabetes is expected to approximately double by 2050, and 16% of patients with diabetes die from stroke, said Philip B. Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids. Patients with diabetes and ischemic stroke tend to have hypertension, thus controlling blood pressure in these patients could improve public health.

The ACC/AHA 2017 Hypertension Guideline

The 2017 hypertension guideline published by the American College of Cardiology (ACC) and the American Heart Association (AHA) recommends antihypertensive therapy for patients with diabetes and blood pressure of 130/80 mm Hg or higher. The treatment goal is blood pressure lower than 130/80 mm Hg. First-line treatment options include thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium-channel blockers. For patients with albuminuria, physicians may consider treatment with an ACE inhibitor or an ARB.

The ADA Position Statement

The American Diabetes Association (ADA) published an updated position statement on diabetes and hypertension in Diabetes Care in September 2017. One of its important recommendations is that orthostatic measurement of blood pressure be performed during the initial evaluation of hypertension and periodically at follow-up, said Dr. Gorelick. “Many of us are not doing that, I suspect,” he added.

Unlike the ACC and AHA, the ADA recommends a blood pressure target of less than 140/90 mm Hg and adds that lower blood pressure targets may be indicated for patients at high risk of cardiovascular disease. For patients with blood pressure greater than 120/80 mm Hg, the ADA recommends lifestyle management such as weight loss, the Dietary Approaches to Stop Hypertension diet, increased consumption of fruits and vegetables, moderate alcohol consumption, and increased physical activity.

Furthermore, the ADA recommends timely titration of pharmacologic therapy plus lifestyle management for patients with diabetes and blood pressure of 140/90 mm Hg or greater. For patients with blood pressure of 160/100 mm Hg or greater, the statement recommends prompt initiation and timely titration of two drugs or a single-pill combination, plus lifestyle intervention. Appropriate therapies include ACE inhibitors, ARBs, thiazide-like diuretics, and calcium-channel blockers, according to the statement. An ACE inhibitor or ARB is recommended for patients with a high ratio of urine albumin to creatinine.

AHA/ASA 2014 Guidelines

The ADA’s recommendations are similar to those of the guidelines for primary stroke prevention that the AHA and the American Stroke Association (ASA) issued in 2014. The latter guidance recommends control of blood pressure to a target of less than 140/90 mm Hg for patients with type 1 or type 2 diabetes. The associations recommend statin therapy to lower the risk of a first stroke and suggest that aspirin be considered for primary stroke prevention in patients with diabetes and a high 10-year risk of cardiovascular disease. Finally, the AHA and ASA recommend that physicians use the ADA’s guidance for glycemic control and management of cardiovascular risk factors.

Evidence That Informed Guidelines

The abovementioned guidelines incorporate evidence from various trials that examined the effect of antihypertensive treatment on stroke risk in patients with and without diabetes. One such trial is the Secondary Prevention of Small Subcortical Strokes study, the results of which were published by Benavente et al in 2013. They found that treatment to a target systolic blood pressure of less than 130 mm Hg reduced the risk of recurrent stroke by about 20%, compared with a target of between 130 mm Hg and 149 mm Hg, but the difference was not statistically significant. Treatment to the lower blood pressure target did, however, significantly reduce the risk of intracranial hemorrhage by about two-thirds.

In the ACCORD trial, which was published in 2010, investigators randomized participants with type 2 diabetes to intensive therapy (ie, a target systolic blood pressure of less than 120 mm Hg) or standard therapy (ie, a target systolic blood pressure of less than 140 mm Hg). Although intensive therapy did not reduce the composite risk of fatal and nonfatal major cardiovascular events, compared with standard therapy, it did reduce the risk of stroke.

—Erik Greb

Suggested Reading

ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.

de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(9):1273-1284.

Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-3832.

SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-515.

Whelton PK, Carey RM. The 2017 American College of Cardiology/American Heart Association clinical practice guideline for high blood pressure in adults. JAMA Cardiol. 2018 Feb 21 [Epub ahead of print].

LOS ANGELES—Current guidelines can help physicians prevent stroke in patients with diabetes, according to a lecture delivered at the International Stroke Conference 2018. The prevalence of diabetes is expected to approximately double by 2050, and 16% of patients with diabetes die from stroke, said Philip B. Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids. Patients with diabetes and ischemic stroke tend to have hypertension, thus controlling blood pressure in these patients could improve public health.

The ACC/AHA 2017 Hypertension Guideline

The 2017 hypertension guideline published by the American College of Cardiology (ACC) and the American Heart Association (AHA) recommends antihypertensive therapy for patients with diabetes and blood pressure of 130/80 mm Hg or higher. The treatment goal is blood pressure lower than 130/80 mm Hg. First-line treatment options include thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium-channel blockers. For patients with albuminuria, physicians may consider treatment with an ACE inhibitor or an ARB.

The ADA Position Statement

The American Diabetes Association (ADA) published an updated position statement on diabetes and hypertension in Diabetes Care in September 2017. One of its important recommendations is that orthostatic measurement of blood pressure be performed during the initial evaluation of hypertension and periodically at follow-up, said Dr. Gorelick. “Many of us are not doing that, I suspect,” he added.

Unlike the ACC and AHA, the ADA recommends a blood pressure target of less than 140/90 mm Hg and adds that lower blood pressure targets may be indicated for patients at high risk of cardiovascular disease. For patients with blood pressure greater than 120/80 mm Hg, the ADA recommends lifestyle management such as weight loss, the Dietary Approaches to Stop Hypertension diet, increased consumption of fruits and vegetables, moderate alcohol consumption, and increased physical activity.

Furthermore, the ADA recommends timely titration of pharmacologic therapy plus lifestyle management for patients with diabetes and blood pressure of 140/90 mm Hg or greater. For patients with blood pressure of 160/100 mm Hg or greater, the statement recommends prompt initiation and timely titration of two drugs or a single-pill combination, plus lifestyle intervention. Appropriate therapies include ACE inhibitors, ARBs, thiazide-like diuretics, and calcium-channel blockers, according to the statement. An ACE inhibitor or ARB is recommended for patients with a high ratio of urine albumin to creatinine.

AHA/ASA 2014 Guidelines

The ADA’s recommendations are similar to those of the guidelines for primary stroke prevention that the AHA and the American Stroke Association (ASA) issued in 2014. The latter guidance recommends control of blood pressure to a target of less than 140/90 mm Hg for patients with type 1 or type 2 diabetes. The associations recommend statin therapy to lower the risk of a first stroke and suggest that aspirin be considered for primary stroke prevention in patients with diabetes and a high 10-year risk of cardiovascular disease. Finally, the AHA and ASA recommend that physicians use the ADA’s guidance for glycemic control and management of cardiovascular risk factors.

Evidence That Informed Guidelines

The abovementioned guidelines incorporate evidence from various trials that examined the effect of antihypertensive treatment on stroke risk in patients with and without diabetes. One such trial is the Secondary Prevention of Small Subcortical Strokes study, the results of which were published by Benavente et al in 2013. They found that treatment to a target systolic blood pressure of less than 130 mm Hg reduced the risk of recurrent stroke by about 20%, compared with a target of between 130 mm Hg and 149 mm Hg, but the difference was not statistically significant. Treatment to the lower blood pressure target did, however, significantly reduce the risk of intracranial hemorrhage by about two-thirds.

In the ACCORD trial, which was published in 2010, investigators randomized participants with type 2 diabetes to intensive therapy (ie, a target systolic blood pressure of less than 120 mm Hg) or standard therapy (ie, a target systolic blood pressure of less than 140 mm Hg). Although intensive therapy did not reduce the composite risk of fatal and nonfatal major cardiovascular events, compared with standard therapy, it did reduce the risk of stroke.

—Erik Greb

Suggested Reading

ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.

de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(9):1273-1284.

Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-3832.

SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-515.

Whelton PK, Carey RM. The 2017 American College of Cardiology/American Heart Association clinical practice guideline for high blood pressure in adults. JAMA Cardiol. 2018 Feb 21 [Epub ahead of print].

LOS ANGELES—Current guidelines can help physicians prevent stroke in patients with diabetes, according to a lecture delivered at the International Stroke Conference 2018. The prevalence of diabetes is expected to approximately double by 2050, and 16% of patients with diabetes die from stroke, said Philip B. Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids. Patients with diabetes and ischemic stroke tend to have hypertension, thus controlling blood pressure in these patients could improve public health.

The ACC/AHA 2017 Hypertension Guideline

The 2017 hypertension guideline published by the American College of Cardiology (ACC) and the American Heart Association (AHA) recommends antihypertensive therapy for patients with diabetes and blood pressure of 130/80 mm Hg or higher. The treatment goal is blood pressure lower than 130/80 mm Hg. First-line treatment options include thiazide-like diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium-channel blockers. For patients with albuminuria, physicians may consider treatment with an ACE inhibitor or an ARB.

The ADA Position Statement

The American Diabetes Association (ADA) published an updated position statement on diabetes and hypertension in Diabetes Care in September 2017. One of its important recommendations is that orthostatic measurement of blood pressure be performed during the initial evaluation of hypertension and periodically at follow-up, said Dr. Gorelick. “Many of us are not doing that, I suspect,” he added.

Unlike the ACC and AHA, the ADA recommends a blood pressure target of less than 140/90 mm Hg and adds that lower blood pressure targets may be indicated for patients at high risk of cardiovascular disease. For patients with blood pressure greater than 120/80 mm Hg, the ADA recommends lifestyle management such as weight loss, the Dietary Approaches to Stop Hypertension diet, increased consumption of fruits and vegetables, moderate alcohol consumption, and increased physical activity.

Furthermore, the ADA recommends timely titration of pharmacologic therapy plus lifestyle management for patients with diabetes and blood pressure of 140/90 mm Hg or greater. For patients with blood pressure of 160/100 mm Hg or greater, the statement recommends prompt initiation and timely titration of two drugs or a single-pill combination, plus lifestyle intervention. Appropriate therapies include ACE inhibitors, ARBs, thiazide-like diuretics, and calcium-channel blockers, according to the statement. An ACE inhibitor or ARB is recommended for patients with a high ratio of urine albumin to creatinine.

AHA/ASA 2014 Guidelines

The ADA’s recommendations are similar to those of the guidelines for primary stroke prevention that the AHA and the American Stroke Association (ASA) issued in 2014. The latter guidance recommends control of blood pressure to a target of less than 140/90 mm Hg for patients with type 1 or type 2 diabetes. The associations recommend statin therapy to lower the risk of a first stroke and suggest that aspirin be considered for primary stroke prevention in patients with diabetes and a high 10-year risk of cardiovascular disease. Finally, the AHA and ASA recommend that physicians use the ADA’s guidance for glycemic control and management of cardiovascular risk factors.

Evidence That Informed Guidelines

The abovementioned guidelines incorporate evidence from various trials that examined the effect of antihypertensive treatment on stroke risk in patients with and without diabetes. One such trial is the Secondary Prevention of Small Subcortical Strokes study, the results of which were published by Benavente et al in 2013. They found that treatment to a target systolic blood pressure of less than 130 mm Hg reduced the risk of recurrent stroke by about 20%, compared with a target of between 130 mm Hg and 149 mm Hg, but the difference was not statistically significant. Treatment to the lower blood pressure target did, however, significantly reduce the risk of intracranial hemorrhage by about two-thirds.

In the ACCORD trial, which was published in 2010, investigators randomized participants with type 2 diabetes to intensive therapy (ie, a target systolic blood pressure of less than 120 mm Hg) or standard therapy (ie, a target systolic blood pressure of less than 140 mm Hg). Although intensive therapy did not reduce the composite risk of fatal and nonfatal major cardiovascular events, compared with standard therapy, it did reduce the risk of stroke.

—Erik Greb

Suggested Reading

ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.

de Boer IH, Bangalore S, Benetos A, et al. Diabetes and hypertension: A position statement by the American Diabetes Association. Diabetes Care. 2017;40(9):1273-1284.

Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-3832.

SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-515.

Whelton PK, Carey RM. The 2017 American College of Cardiology/American Heart Association clinical practice guideline for high blood pressure in adults. JAMA Cardiol. 2018 Feb 21 [Epub ahead of print].

LOS ANGELES—Modifying cardiovascular risk factors in midlife may help to prevent or delay cognitive impairment, according to an overview presented at the International Stroke Conference 2018. This conclusion comes from a presidential advisory published by the American Heart Association (AHA) and the American Stroke Association (ASA) that also defines optimal brain health.

“By prevention or control of cardiovascular and behavioral health risks, in addition to prevention of heart attack and stroke, we may be able to prolong cognitive vitality and prevent cognitive decline or dementia as we age,” said Philip Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids, and an author of the advisory. “Further study through clinical trials is necessary to support the contention that we can prevent cognitive decline and dementia. However, observational epidemiological studies support the premise.”

Decades of Evidence

Decades of research preceded the AHA/ASA effort to draft a presidential advisory. In a 1999 literature review, Dr. Gorelick and colleagues found that modifying cardiovascular risk factors in midlife might delay or prevent vascular causes of cognitive impairment or Alzheimer’s disease.

Casserly and Topol in 2004 found that Alzheimer’s disease and atherosclerosis shared common risk factors. Many of the factors, such as hypercholesterolemia, hypertension, hyperhomocysteinemia, diabetes, metabolic syndrome, and smoking, relate to cardiovascular risks.

In the 2006 Honolulu–Asia Aging Study, Willcox et al found that avoidance of overweight status, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with survival and cognitive health. “The Honolulu–Asia Aging Study was one of the first epidemiological studies to show that healthy lifestyle and a beneficial cardiovascular risk profile in midlife were linked to good cognitive and functional outcomes later in life,” said Dr. Gorelick. 

In 2017, Allen et al found that a favorable cardiovascular risk profile at younger ages extended survival by nearly four years and postponed the onset of all-cause morbidity by four and a half years.

A Definition of Optimal Brain Health

The AHA and ASA convened an expert panel to provide an initial definition of optimal brain health in adults and offer guidance on how to maintain brain health. The panel also investigated the impact of cognitive impairment on public health. A review of the relevant literature formed the basis of the panel’s advisory.

The group based its definition of optimal brain health on the AHA’s list of “Life’s Simple Seven.” These seven factors include nonsmoking status, physical activity, healthy diet consistent with current guidelines, BMI lower than 25 kg/m², untreated blood pressure lower than 120/80 mm Hg, untreated total cholesterol level lower than 200 mg/dL, and fasting blood glucose level lower than 100 mg/dL. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study previously had indicated that the more of these factors a patient achieves, the more likely his or her cognition will be preserved.

“This work in defining optimal brain health in adults serves to provide the AHA/ASA with a foundation for a new strategic direction going forward in cardiovascular health promotion and disease prevention,” said Dr. Gorelick and colleagues.

Recommendations for Preserving Cognitive Health

The presidential advisory recommends that individuals follow AHA/ASA guidelines on stroke and cardiovascular disease to maintain cognitive health. The authors also endorsed recommendations from the Institute of Medicine, which include social and intellectual engagement, adequate sleep and treatment for sleep disorders, steps to avoid cognitive changes due to delirium if hospitalized, and regularly discussing and reviewing health conditions and medications that might influence cognitive health with a health care professional.

“Maintaining optimal brain health requires actions by individuals, health care practitioners, public health organizations, policy makers, and the private sector,” said Dr. Gorelick and colleagues.

Current Research and Recommendations

The AHA/ASA presidential advisory was published in October 2017, and new research on cognitive and brain health has since emerged. In December 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care recommended active treatment of hypertension in middle-aged and older adults. They also concluded that one-third of all cases of dementia could be delayed or prevented through interventions such as childhood education, exercise, maintenance of social engagement, reduction of smoking, and management of hearing loss, depression, diabetes mellitus, and obesity.

In January, a series of systematic analyses funded by the Agency for Healthcare Research and Quality found insufficient evidence to support pharmacologic treatments or over-the-counter supplements for cognitive protection in individuals with normal cognition or mild cognitive impairment. The analyses also found insufficient evidence to support short-term, single-component physical activity interventions to promote cognitive function and prevent cognitive decline or dementia in older adults. Evidence also did not support cognitive training to prevent or delay cognitive decline or dementia.

—Erica Tricarico

Suggested Reading

Allen NB, Zhao L, Liu L, et al. Favorable cardiovascular health, compression of morbidity, and healthcare costs: Forty-year follow-up of the CHA Study (Chicago Heart Association Detection Project in Industry). Circulation. 2017;135(18):1693-1701.

Butler M, McCreedy E, Nelson VA, et al. Does cognitive training prevent cognitive decline?: a systematic review. Ann Intern Med. 2018;168(1):63-68.

Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363(9415):1139-1146.

Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann Intern Med. 2018;168(1):39-51.

Gorelick PB, Erkinjuntti T, Hofman A, et al. Prevention of vascular dementia. Alzheimer Dis Assoc Disord. 1999;13 Suppl 3:S131-9.

Gorelick PB, Furie KL, Iadecola C, et al. Defining optimal brain health in adults: A presidential advisory from the American Heart Association/American Stroke Association. Stroke. 2017;48(10):e284-e303.

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734.

Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.

Thacker EL, Gillett SR, Wadley VG, et al. The American Heart Association Life’s Simple 7 and incident cognitive impairment: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. J Am Heart Assoc. 2014;3(3):e000635.

Willcox BJ, He Q, Chen R, et al. Midlife risk factors and healthy survival in men. JAMA. 2006;296(19):2343-2350.

LOS ANGELES—Modifying cardiovascular risk factors in midlife may help to prevent or delay cognitive impairment, according to an overview presented at the International Stroke Conference 2018. This conclusion comes from a presidential advisory published by the American Heart Association (AHA) and the American Stroke Association (ASA) that also defines optimal brain health.

“By prevention or control of cardiovascular and behavioral health risks, in addition to prevention of heart attack and stroke, we may be able to prolong cognitive vitality and prevent cognitive decline or dementia as we age,” said Philip Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids, and an author of the advisory. “Further study through clinical trials is necessary to support the contention that we can prevent cognitive decline and dementia. However, observational epidemiological studies support the premise.”

Decades of Evidence

Decades of research preceded the AHA/ASA effort to draft a presidential advisory. In a 1999 literature review, Dr. Gorelick and colleagues found that modifying cardiovascular risk factors in midlife might delay or prevent vascular causes of cognitive impairment or Alzheimer’s disease.

Casserly and Topol in 2004 found that Alzheimer’s disease and atherosclerosis shared common risk factors. Many of the factors, such as hypercholesterolemia, hypertension, hyperhomocysteinemia, diabetes, metabolic syndrome, and smoking, relate to cardiovascular risks.

In the 2006 Honolulu–Asia Aging Study, Willcox et al found that avoidance of overweight status, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with survival and cognitive health. “The Honolulu–Asia Aging Study was one of the first epidemiological studies to show that healthy lifestyle and a beneficial cardiovascular risk profile in midlife were linked to good cognitive and functional outcomes later in life,” said Dr. Gorelick. 

In 2017, Allen et al found that a favorable cardiovascular risk profile at younger ages extended survival by nearly four years and postponed the onset of all-cause morbidity by four and a half years.

A Definition of Optimal Brain Health

The AHA and ASA convened an expert panel to provide an initial definition of optimal brain health in adults and offer guidance on how to maintain brain health. The panel also investigated the impact of cognitive impairment on public health. A review of the relevant literature formed the basis of the panel’s advisory.

The group based its definition of optimal brain health on the AHA’s list of “Life’s Simple Seven.” These seven factors include nonsmoking status, physical activity, healthy diet consistent with current guidelines, BMI lower than 25 kg/m², untreated blood pressure lower than 120/80 mm Hg, untreated total cholesterol level lower than 200 mg/dL, and fasting blood glucose level lower than 100 mg/dL. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study previously had indicated that the more of these factors a patient achieves, the more likely his or her cognition will be preserved.

“This work in defining optimal brain health in adults serves to provide the AHA/ASA with a foundation for a new strategic direction going forward in cardiovascular health promotion and disease prevention,” said Dr. Gorelick and colleagues.

Recommendations for Preserving Cognitive Health

The presidential advisory recommends that individuals follow AHA/ASA guidelines on stroke and cardiovascular disease to maintain cognitive health. The authors also endorsed recommendations from the Institute of Medicine, which include social and intellectual engagement, adequate sleep and treatment for sleep disorders, steps to avoid cognitive changes due to delirium if hospitalized, and regularly discussing and reviewing health conditions and medications that might influence cognitive health with a health care professional.

“Maintaining optimal brain health requires actions by individuals, health care practitioners, public health organizations, policy makers, and the private sector,” said Dr. Gorelick and colleagues.

Current Research and Recommendations

The AHA/ASA presidential advisory was published in October 2017, and new research on cognitive and brain health has since emerged. In December 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care recommended active treatment of hypertension in middle-aged and older adults. They also concluded that one-third of all cases of dementia could be delayed or prevented through interventions such as childhood education, exercise, maintenance of social engagement, reduction of smoking, and management of hearing loss, depression, diabetes mellitus, and obesity.

In January, a series of systematic analyses funded by the Agency for Healthcare Research and Quality found insufficient evidence to support pharmacologic treatments or over-the-counter supplements for cognitive protection in individuals with normal cognition or mild cognitive impairment. The analyses also found insufficient evidence to support short-term, single-component physical activity interventions to promote cognitive function and prevent cognitive decline or dementia in older adults. Evidence also did not support cognitive training to prevent or delay cognitive decline or dementia.

—Erica Tricarico

Suggested Reading

Allen NB, Zhao L, Liu L, et al. Favorable cardiovascular health, compression of morbidity, and healthcare costs: Forty-year follow-up of the CHA Study (Chicago Heart Association Detection Project in Industry). Circulation. 2017;135(18):1693-1701.

Butler M, McCreedy E, Nelson VA, et al. Does cognitive training prevent cognitive decline?: a systematic review. Ann Intern Med. 2018;168(1):63-68.

Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363(9415):1139-1146.

Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann Intern Med. 2018;168(1):39-51.

Gorelick PB, Erkinjuntti T, Hofman A, et al. Prevention of vascular dementia. Alzheimer Dis Assoc Disord. 1999;13 Suppl 3:S131-9.

Gorelick PB, Furie KL, Iadecola C, et al. Defining optimal brain health in adults: A presidential advisory from the American Heart Association/American Stroke Association. Stroke. 2017;48(10):e284-e303.

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734.

Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.

Thacker EL, Gillett SR, Wadley VG, et al. The American Heart Association Life’s Simple 7 and incident cognitive impairment: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. J Am Heart Assoc. 2014;3(3):e000635.

Willcox BJ, He Q, Chen R, et al. Midlife risk factors and healthy survival in men. JAMA. 2006;296(19):2343-2350.

LOS ANGELES—Modifying cardiovascular risk factors in midlife may help to prevent or delay cognitive impairment, according to an overview presented at the International Stroke Conference 2018. This conclusion comes from a presidential advisory published by the American Heart Association (AHA) and the American Stroke Association (ASA) that also defines optimal brain health.

“By prevention or control of cardiovascular and behavioral health risks, in addition to prevention of heart attack and stroke, we may be able to prolong cognitive vitality and prevent cognitive decline or dementia as we age,” said Philip Gorelick, MD, MPH, Professor of Translational Science and Molecular Medicine at Michigan State University College of Human Medicine in Grand Rapids, and an author of the advisory. “Further study through clinical trials is necessary to support the contention that we can prevent cognitive decline and dementia. However, observational epidemiological studies support the premise.”

Decades of Evidence

Decades of research preceded the AHA/ASA effort to draft a presidential advisory. In a 1999 literature review, Dr. Gorelick and colleagues found that modifying cardiovascular risk factors in midlife might delay or prevent vascular causes of cognitive impairment or Alzheimer’s disease.

Casserly and Topol in 2004 found that Alzheimer’s disease and atherosclerosis shared common risk factors. Many of the factors, such as hypercholesterolemia, hypertension, hyperhomocysteinemia, diabetes, metabolic syndrome, and smoking, relate to cardiovascular risks.

In the 2006 Honolulu–Asia Aging Study, Willcox et al found that avoidance of overweight status, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with survival and cognitive health. “The Honolulu–Asia Aging Study was one of the first epidemiological studies to show that healthy lifestyle and a beneficial cardiovascular risk profile in midlife were linked to good cognitive and functional outcomes later in life,” said Dr. Gorelick. 

In 2017, Allen et al found that a favorable cardiovascular risk profile at younger ages extended survival by nearly four years and postponed the onset of all-cause morbidity by four and a half years.

A Definition of Optimal Brain Health

The AHA and ASA convened an expert panel to provide an initial definition of optimal brain health in adults and offer guidance on how to maintain brain health. The panel also investigated the impact of cognitive impairment on public health. A review of the relevant literature formed the basis of the panel’s advisory.

The group based its definition of optimal brain health on the AHA’s list of “Life’s Simple Seven.” These seven factors include nonsmoking status, physical activity, healthy diet consistent with current guidelines, BMI lower than 25 kg/m², untreated blood pressure lower than 120/80 mm Hg, untreated total cholesterol level lower than 200 mg/dL, and fasting blood glucose level lower than 100 mg/dL. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study previously had indicated that the more of these factors a patient achieves, the more likely his or her cognition will be preserved.

“This work in defining optimal brain health in adults serves to provide the AHA/ASA with a foundation for a new strategic direction going forward in cardiovascular health promotion and disease prevention,” said Dr. Gorelick and colleagues.

Recommendations for Preserving Cognitive Health

The presidential advisory recommends that individuals follow AHA/ASA guidelines on stroke and cardiovascular disease to maintain cognitive health. The authors also endorsed recommendations from the Institute of Medicine, which include social and intellectual engagement, adequate sleep and treatment for sleep disorders, steps to avoid cognitive changes due to delirium if hospitalized, and regularly discussing and reviewing health conditions and medications that might influence cognitive health with a health care professional.

“Maintaining optimal brain health requires actions by individuals, health care practitioners, public health organizations, policy makers, and the private sector,” said Dr. Gorelick and colleagues.

Current Research and Recommendations

The AHA/ASA presidential advisory was published in October 2017, and new research on cognitive and brain health has since emerged. In December 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care recommended active treatment of hypertension in middle-aged and older adults. They also concluded that one-third of all cases of dementia could be delayed or prevented through interventions such as childhood education, exercise, maintenance of social engagement, reduction of smoking, and management of hearing loss, depression, diabetes mellitus, and obesity.

In January, a series of systematic analyses funded by the Agency for Healthcare Research and Quality found insufficient evidence to support pharmacologic treatments or over-the-counter supplements for cognitive protection in individuals with normal cognition or mild cognitive impairment. The analyses also found insufficient evidence to support short-term, single-component physical activity interventions to promote cognitive function and prevent cognitive decline or dementia in older adults. Evidence also did not support cognitive training to prevent or delay cognitive decline or dementia.

—Erica Tricarico

Suggested Reading

Allen NB, Zhao L, Liu L, et al. Favorable cardiovascular health, compression of morbidity, and healthcare costs: Forty-year follow-up of the CHA Study (Chicago Heart Association Detection Project in Industry). Circulation. 2017;135(18):1693-1701.

Butler M, McCreedy E, Nelson VA, et al. Does cognitive training prevent cognitive decline?: a systematic review. Ann Intern Med. 2018;168(1):63-68.

Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363(9415):1139-1146.

Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: A systematic review. Ann Intern Med. 2018;168(1):39-51.

Gorelick PB, Erkinjuntti T, Hofman A, et al. Prevention of vascular dementia. Alzheimer Dis Assoc Disord. 1999;13 Suppl 3:S131-9.

Gorelick PB, Furie KL, Iadecola C, et al. Defining optimal brain health in adults: A presidential advisory from the American Heart Association/American Stroke Association. Stroke. 2017;48(10):e284-e303.

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734.

Lloyd-Jones DM, Hong Y, Labarthe D, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121(4):586-613.

Thacker EL, Gillett SR, Wadley VG, et al. The American Heart Association Life’s Simple 7 and incident cognitive impairment: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. J Am Heart Assoc. 2014;3(3):e000635.

Willcox BJ, He Q, Chen R, et al. Midlife risk factors and healthy survival in men. JAMA. 2006;296(19):2343-2350.

Microneedling treatment produced statistically significant improvements in pigmentation-associated acne scars in a study of patients with dark skin, and did not contribute to more pigmentation, the study authors reported.

Most patients were pleased with the results. “Microneedling is an effective and safe treatment for acne scars associated with pigmentation in dark-skinned patients, without adding any risk of causing worsening of pigmentation,” the study’s lead author, Firas Al Qarqaz, MD said in an interview.

The study was published online in the Journal of Cosmetic Dermatology.

Dr. Al Qarqaz, of the department of dermatology, Jordan University of Science and Technology, Irbid, Jordan, pointed out that patients with darker skin and acne scars pose a unique challenge because some current treatments “can improve the scars but carry a risk of worsening the pigmentation and making skin/scars darker, which can be as troublesome to patients as their original scars.” Indeed, a review of microneedling as a treatment for dermatologic conditions in patients with darker skin noted that conventional resurfacing procedures can be limited in this patient population, because of concerns of adverse effects, including dyspigmentation (J Am Acad Dermatol. 2016 Feb;74[2]:348-55).

The situation is especially complex because “the current assessment methods for evaluating acne scars are not addressing clearly the important aspect of pigmentation that is associated with such scars, especially in darker skin, which can make objective assessment for improvement lacking,” Dr. Al Qarqaz noted.

He and a coauthor conducted the new study to determine whether microneedling can safely and effectively improve both acne scars and related hyperpigmentation in patients with darker skin. The study of 39 patients with postacne scarring comprised 31 women and 8 men aged 18-43 years (mean age, 27); their skin colors ranged from Fitzpatrick skin types type III to V. Most (27) were type IV.

The patients were treated with an electronic microneedling device and were evaluated at 2 weeks, and at least 4 weeks after their initial assessment (range, 4-14 weeks) for the final evaluation. The researchers found statistically significant improvement in two measures: The Postacne Hyperpigmentation Index improved from a mean score of 13 at baseline to a mean of 10 post procedure (P = .0035), and the Goodman-Baron acne scarring scale improved from a mean of 18 at baseline to a mean of 12 post procedure (P = .008).

Side effects were mild and temporary. “This treatment seems to be safe apart from short-lived erythema and occasional small hematoma following procedure,” the researchers concluded.

Nearly 80% of patients said they were satisfied with the procedure; the rest were not satisfied with the results (no reasons were cited). “Additional studies focusing on postacne scarring with hyperpigmentation are needed,” in addition to “assessment tools designed for this particular patient group,” the authors noted. They added that more treatments may be needed in some patients for hyperpigmentation.

Jordan University of Science and Technology funded the study. The study authors reported no relevant disclosures.

SOURCE: Al-Qarqaz F et al. J Cosmet Dermatol. 2018 Mar 15. (doi: 10.1111/jocd.12520.)

Microneedling treatment produced statistically significant improvements in pigmentation-associated acne scars in a study of patients with dark skin, and did not contribute to more pigmentation, the study authors reported.

Most patients were pleased with the results. “Microneedling is an effective and safe treatment for acne scars associated with pigmentation in dark-skinned patients, without adding any risk of causing worsening of pigmentation,” the study’s lead author, Firas Al Qarqaz, MD said in an interview.

The study was published online in the Journal of Cosmetic Dermatology.

Dr. Al Qarqaz, of the department of dermatology, Jordan University of Science and Technology, Irbid, Jordan, pointed out that patients with darker skin and acne scars pose a unique challenge because some current treatments “can improve the scars but carry a risk of worsening the pigmentation and making skin/scars darker, which can be as troublesome to patients as their original scars.” Indeed, a review of microneedling as a treatment for dermatologic conditions in patients with darker skin noted that conventional resurfacing procedures can be limited in this patient population, because of concerns of adverse effects, including dyspigmentation (J Am Acad Dermatol. 2016 Feb;74[2]:348-55).

The situation is especially complex because “the current assessment methods for evaluating acne scars are not addressing clearly the important aspect of pigmentation that is associated with such scars, especially in darker skin, which can make objective assessment for improvement lacking,” Dr. Al Qarqaz noted.

He and a coauthor conducted the new study to determine whether microneedling can safely and effectively improve both acne scars and related hyperpigmentation in patients with darker skin. The study of 39 patients with postacne scarring comprised 31 women and 8 men aged 18-43 years (mean age, 27); their skin colors ranged from Fitzpatrick skin types type III to V. Most (27) were type IV.

The patients were treated with an electronic microneedling device and were evaluated at 2 weeks, and at least 4 weeks after their initial assessment (range, 4-14 weeks) for the final evaluation. The researchers found statistically significant improvement in two measures: The Postacne Hyperpigmentation Index improved from a mean score of 13 at baseline to a mean of 10 post procedure (P = .0035), and the Goodman-Baron acne scarring scale improved from a mean of 18 at baseline to a mean of 12 post procedure (P = .008).

Side effects were mild and temporary. “This treatment seems to be safe apart from short-lived erythema and occasional small hematoma following procedure,” the researchers concluded.

Nearly 80% of patients said they were satisfied with the procedure; the rest were not satisfied with the results (no reasons were cited). “Additional studies focusing on postacne scarring with hyperpigmentation are needed,” in addition to “assessment tools designed for this particular patient group,” the authors noted. They added that more treatments may be needed in some patients for hyperpigmentation.

Jordan University of Science and Technology funded the study. The study authors reported no relevant disclosures.

SOURCE: Al-Qarqaz F et al. J Cosmet Dermatol. 2018 Mar 15. (doi: 10.1111/jocd.12520.)

Microneedling treatment produced statistically significant improvements in pigmentation-associated acne scars in a study of patients with dark skin, and did not contribute to more pigmentation, the study authors reported.

Most patients were pleased with the results. “Microneedling is an effective and safe treatment for acne scars associated with pigmentation in dark-skinned patients, without adding any risk of causing worsening of pigmentation,” the study’s lead author, Firas Al Qarqaz, MD said in an interview.

The study was published online in the Journal of Cosmetic Dermatology.

Dr. Al Qarqaz, of the department of dermatology, Jordan University of Science and Technology, Irbid, Jordan, pointed out that patients with darker skin and acne scars pose a unique challenge because some current treatments “can improve the scars but carry a risk of worsening the pigmentation and making skin/scars darker, which can be as troublesome to patients as their original scars.” Indeed, a review of microneedling as a treatment for dermatologic conditions in patients with darker skin noted that conventional resurfacing procedures can be limited in this patient population, because of concerns of adverse effects, including dyspigmentation (J Am Acad Dermatol. 2016 Feb;74[2]:348-55).

The situation is especially complex because “the current assessment methods for evaluating acne scars are not addressing clearly the important aspect of pigmentation that is associated with such scars, especially in darker skin, which can make objective assessment for improvement lacking,” Dr. Al Qarqaz noted.

He and a coauthor conducted the new study to determine whether microneedling can safely and effectively improve both acne scars and related hyperpigmentation in patients with darker skin. The study of 39 patients with postacne scarring comprised 31 women and 8 men aged 18-43 years (mean age, 27); their skin colors ranged from Fitzpatrick skin types type III to V. Most (27) were type IV.

The patients were treated with an electronic microneedling device and were evaluated at 2 weeks, and at least 4 weeks after their initial assessment (range, 4-14 weeks) for the final evaluation. The researchers found statistically significant improvement in two measures: The Postacne Hyperpigmentation Index improved from a mean score of 13 at baseline to a mean of 10 post procedure (P = .0035), and the Goodman-Baron acne scarring scale improved from a mean of 18 at baseline to a mean of 12 post procedure (P = .008).

Side effects were mild and temporary. “This treatment seems to be safe apart from short-lived erythema and occasional small hematoma following procedure,” the researchers concluded.

Nearly 80% of patients said they were satisfied with the procedure; the rest were not satisfied with the results (no reasons were cited). “Additional studies focusing on postacne scarring with hyperpigmentation are needed,” in addition to “assessment tools designed for this particular patient group,” the authors noted. They added that more treatments may be needed in some patients for hyperpigmentation.

Jordan University of Science and Technology funded the study. The study authors reported no relevant disclosures.

SOURCE: Al-Qarqaz F et al. J Cosmet Dermatol. 2018 Mar 15. (doi: 10.1111/jocd.12520.)

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

April has been designated “Rosacea Awareness Month” by the National Rosacea Society (NRS), with the aim of educating the public about the disease.

“During April and throughout the year, people who suspect they may have rosacea can contact the NRS for more information,” according to a press release issued April 2 by the NRS.

National Rosacea Society

National Rosacea Society

[email protected]

April has been designated “Rosacea Awareness Month” by the National Rosacea Society (NRS), with the aim of educating the public about the disease.

“During April and throughout the year, people who suspect they may have rosacea can contact the NRS for more information,” according to a press release issued April 2 by the NRS.

National Rosacea Society

National Rosacea Society

[email protected]

April has been designated “Rosacea Awareness Month” by the National Rosacea Society (NRS), with the aim of educating the public about the disease.

“During April and throughout the year, people who suspect they may have rosacea can contact the NRS for more information,” according to a press release issued April 2 by the NRS.

National Rosacea Society

National Rosacea Society

[email protected]

The US has seen a rise in the number of prescriptions of opioids to treat chronic pain; however, the rise has been associated with increased rates of addiction and deaths related to opioid abuse and heroin use. Chronic pain is associated with the use of prescription opioids in veterans, which sometimes complicates the concurrent treatment of mental health disorders.^1-3 Also, opioid use issues, including suicide, have affected veterans at higher numbers than it has in the nonveteran population.^4,5

Unfortunately, the prevailing Western medical model with its focus on treating disease has not proven to be adequate in solving the problem. Hence, the Department of Veterans Affairs (VA) is in the process of a paradigm shift to a whole person model that prioritizes health and well-being, as defined by the individual, while proactively addressing risk factors before illness develops.

The new model includes an emphasis on complementary and integrative health (CIH) therapies to promote optimal health, healing, and well-being.⁶ Yoga, massage, acupuncture, meditation, and guided imagery are some examples of VA-approved CIH therapies favored by veterans and their health care providers (HCPs) to treat and/or divert the subject’s attention from physical pain or mental anguish.^7,8

In response to opioid overuse, Congress passed the Comprehensive Addiction and Recovery Act of 2016 (CARA).⁹ Title IX of CARA mandates the VA to work with the Department of Defense (DoD) to limit the amount of time a patient is prescribed an opioid.

Replacing opioids with other ways to control chronic pain may be helpful in addressing the real distress experienced by persons with these diagnoses. Hence, the CARA suggests augmenting opioid therapy with other pain management therapies and modalities, including CIH. Instead of focusing on the treatment of a specific illness after it develops, CIH therapies aim to promote wellness in the whole person. However, good intentions are not enough. Due to existing institutional culture and prioritization of resources, the adoption of CIH therapies across the VA has been inconsistent.¹⁰

The CARA furnishes the VA with an opportunity to serve as a leader in the innovative use of CIH therapies. Previous research conducted by the VA has shown that veterans and their HCPs would like increased availability of CIH through the VA.^7,10,11 Research also suggests CIH for specific conditions in veterans, such as posttraumatic stress disorder or postoperative pain.^12,13 For its part, the VA has declared the provision of personalized, proactive, patient-driven health care for veterans as its top strategic priority.

To achieve the organizational transformation associated with providing this type of care, the VA established the Office of Patient Centered Care and Cultural Transformation (OPCC&CT), which created the Integrative Health Coordinating Center (IHCC).⁶ The main functions of the IHCC are to identify and remove barriers to providing CIH within VA and to serve as a resource for practice and education for veterans as well as HCPs.

Several VA facilities already have demonstrated what can be done with the support and encouragement of the OPCC&CT plus an enormous amount of dedicated effort from local HCPs and highly supportive service chiefs. Examples include the Perry Point VA Residential Wellness Center in Maryland and the Integrative Medicine and Wellness Center in the Central Arkansas VA Healthcare System in Little Rock. Perry Point has a focus on veterans with substance abuse diagnoses and uses multiple therapies, including acupuncture, yoga, guided meditation, osteopathic manipulation, music, and creative arts. The Little Rock center focuses on skills building, self-care, and accountability with modalities such as yoga, acupuncture, mindfulness, and chiropractic.

The CARA mandates the continuance and expansion of similar pilot projects that assess the feasibility and advisability of CIH programs to complement the provision of pain management and related health care services, including mental health care services to veterans. Thus, the VA Secretary was directed to select at least 15 geographically diverse locations for the pilot projects. The VA has committed to conducting 18 full-scale demonstration projects in 2018—1 project in each VISN (Veterans Integrated Service Network). Section 933 of the CARA, prioritizes medical centers where the “prescription rate of opioids conflicts with or is otherwise inconsistent with the standards of appropriate and safe care.”⁹

Several issues must be addressed to make the provision of CIH in the VA a success.¹⁴ They include but are not limited to the following:

1. Clarification that CIH services for veterans are included in the Medical Benefits Package, which requires that care meets generally accepted standards of medical practice.
2. Vetting of CIH therapies to determine which ones should be recommended for inclusion in the Medical Benefits Package. Factors to consider include clinical evidence, community standards, practice guidelines, licensing and credentialing requirements, potential for harm, and veteran demand.
3. Changes to VA business processes to provide the infrastructure for CIH delivery.
4. Competition with existing VA programs for resources.
5. Education of HCPs and administrators about CIH through the development of CIH instruction manuals, curriculum, and faculty.

Although the VA faces the daunting task of reducing opioid use while continuing to treat chronic physical and mental pain, CIH therapies seem to offer a viable adjunctive therapy. It will be incumbent on the VA to explore through ongoing research all that CIH therapies may have to offer; veterans deserve no less. If the VA can demonstrate the effectiveness of CIH in treating the challenges faced by veterans, the results will serve as a useful example for treating chronic pain in the nonveteran population as well.

The US has seen a rise in the number of prescriptions of opioids to treat chronic pain; however, the rise has been associated with increased rates of addiction and deaths related to opioid abuse and heroin use. Chronic pain is associated with the use of prescription opioids in veterans, which sometimes complicates the concurrent treatment of mental health disorders.^1-3 Also, opioid use issues, including suicide, have affected veterans at higher numbers than it has in the nonveteran population.^4,5

Unfortunately, the prevailing Western medical model with its focus on treating disease has not proven to be adequate in solving the problem. Hence, the Department of Veterans Affairs (VA) is in the process of a paradigm shift to a whole person model that prioritizes health and well-being, as defined by the individual, while proactively addressing risk factors before illness develops.

The new model includes an emphasis on complementary and integrative health (CIH) therapies to promote optimal health, healing, and well-being.⁶ Yoga, massage, acupuncture, meditation, and guided imagery are some examples of VA-approved CIH therapies favored by veterans and their health care providers (HCPs) to treat and/or divert the subject’s attention from physical pain or mental anguish.^7,8

In response to opioid overuse, Congress passed the Comprehensive Addiction and Recovery Act of 2016 (CARA).⁹ Title IX of CARA mandates the VA to work with the Department of Defense (DoD) to limit the amount of time a patient is prescribed an opioid.

Replacing opioids with other ways to control chronic pain may be helpful in addressing the real distress experienced by persons with these diagnoses. Hence, the CARA suggests augmenting opioid therapy with other pain management therapies and modalities, including CIH. Instead of focusing on the treatment of a specific illness after it develops, CIH therapies aim to promote wellness in the whole person. However, good intentions are not enough. Due to existing institutional culture and prioritization of resources, the adoption of CIH therapies across the VA has been inconsistent.¹⁰

The CARA furnishes the VA with an opportunity to serve as a leader in the innovative use of CIH therapies. Previous research conducted by the VA has shown that veterans and their HCPs would like increased availability of CIH through the VA.^7,10,11 Research also suggests CIH for specific conditions in veterans, such as posttraumatic stress disorder or postoperative pain.^12,13 For its part, the VA has declared the provision of personalized, proactive, patient-driven health care for veterans as its top strategic priority.

To achieve the organizational transformation associated with providing this type of care, the VA established the Office of Patient Centered Care and Cultural Transformation (OPCC&CT), which created the Integrative Health Coordinating Center (IHCC).⁶ The main functions of the IHCC are to identify and remove barriers to providing CIH within VA and to serve as a resource for practice and education for veterans as well as HCPs.

Several VA facilities already have demonstrated what can be done with the support and encouragement of the OPCC&CT plus an enormous amount of dedicated effort from local HCPs and highly supportive service chiefs. Examples include the Perry Point VA Residential Wellness Center in Maryland and the Integrative Medicine and Wellness Center in the Central Arkansas VA Healthcare System in Little Rock. Perry Point has a focus on veterans with substance abuse diagnoses and uses multiple therapies, including acupuncture, yoga, guided meditation, osteopathic manipulation, music, and creative arts. The Little Rock center focuses on skills building, self-care, and accountability with modalities such as yoga, acupuncture, mindfulness, and chiropractic.

The CARA mandates the continuance and expansion of similar pilot projects that assess the feasibility and advisability of CIH programs to complement the provision of pain management and related health care services, including mental health care services to veterans. Thus, the VA Secretary was directed to select at least 15 geographically diverse locations for the pilot projects. The VA has committed to conducting 18 full-scale demonstration projects in 2018—1 project in each VISN (Veterans Integrated Service Network). Section 933 of the CARA, prioritizes medical centers where the “prescription rate of opioids conflicts with or is otherwise inconsistent with the standards of appropriate and safe care.”⁹

Several issues must be addressed to make the provision of CIH in the VA a success.¹⁴ They include but are not limited to the following:

1. Clarification that CIH services for veterans are included in the Medical Benefits Package, which requires that care meets generally accepted standards of medical practice.
2. Vetting of CIH therapies to determine which ones should be recommended for inclusion in the Medical Benefits Package. Factors to consider include clinical evidence, community standards, practice guidelines, licensing and credentialing requirements, potential for harm, and veteran demand.
3. Changes to VA business processes to provide the infrastructure for CIH delivery.
4. Competition with existing VA programs for resources.
5. Education of HCPs and administrators about CIH through the development of CIH instruction manuals, curriculum, and faculty.

Although the VA faces the daunting task of reducing opioid use while continuing to treat chronic physical and mental pain, CIH therapies seem to offer a viable adjunctive therapy. It will be incumbent on the VA to explore through ongoing research all that CIH therapies may have to offer; veterans deserve no less. If the VA can demonstrate the effectiveness of CIH in treating the challenges faced by veterans, the results will serve as a useful example for treating chronic pain in the nonveteran population as well.

The US has seen a rise in the number of prescriptions of opioids to treat chronic pain; however, the rise has been associated with increased rates of addiction and deaths related to opioid abuse and heroin use. Chronic pain is associated with the use of prescription opioids in veterans, which sometimes complicates the concurrent treatment of mental health disorders.^1-3 Also, opioid use issues, including suicide, have affected veterans at higher numbers than it has in the nonveteran population.^4,5

Unfortunately, the prevailing Western medical model with its focus on treating disease has not proven to be adequate in solving the problem. Hence, the Department of Veterans Affairs (VA) is in the process of a paradigm shift to a whole person model that prioritizes health and well-being, as defined by the individual, while proactively addressing risk factors before illness develops.

The new model includes an emphasis on complementary and integrative health (CIH) therapies to promote optimal health, healing, and well-being.⁶ Yoga, massage, acupuncture, meditation, and guided imagery are some examples of VA-approved CIH therapies favored by veterans and their health care providers (HCPs) to treat and/or divert the subject’s attention from physical pain or mental anguish.^7,8

In response to opioid overuse, Congress passed the Comprehensive Addiction and Recovery Act of 2016 (CARA).⁹ Title IX of CARA mandates the VA to work with the Department of Defense (DoD) to limit the amount of time a patient is prescribed an opioid.

Replacing opioids with other ways to control chronic pain may be helpful in addressing the real distress experienced by persons with these diagnoses. Hence, the CARA suggests augmenting opioid therapy with other pain management therapies and modalities, including CIH. Instead of focusing on the treatment of a specific illness after it develops, CIH therapies aim to promote wellness in the whole person. However, good intentions are not enough. Due to existing institutional culture and prioritization of resources, the adoption of CIH therapies across the VA has been inconsistent.¹⁰

The CARA furnishes the VA with an opportunity to serve as a leader in the innovative use of CIH therapies. Previous research conducted by the VA has shown that veterans and their HCPs would like increased availability of CIH through the VA.^7,10,11 Research also suggests CIH for specific conditions in veterans, such as posttraumatic stress disorder or postoperative pain.^12,13 For its part, the VA has declared the provision of personalized, proactive, patient-driven health care for veterans as its top strategic priority.

To achieve the organizational transformation associated with providing this type of care, the VA established the Office of Patient Centered Care and Cultural Transformation (OPCC&CT), which created the Integrative Health Coordinating Center (IHCC).⁶ The main functions of the IHCC are to identify and remove barriers to providing CIH within VA and to serve as a resource for practice and education for veterans as well as HCPs.

Several VA facilities already have demonstrated what can be done with the support and encouragement of the OPCC&CT plus an enormous amount of dedicated effort from local HCPs and highly supportive service chiefs. Examples include the Perry Point VA Residential Wellness Center in Maryland and the Integrative Medicine and Wellness Center in the Central Arkansas VA Healthcare System in Little Rock. Perry Point has a focus on veterans with substance abuse diagnoses and uses multiple therapies, including acupuncture, yoga, guided meditation, osteopathic manipulation, music, and creative arts. The Little Rock center focuses on skills building, self-care, and accountability with modalities such as yoga, acupuncture, mindfulness, and chiropractic.

The CARA mandates the continuance and expansion of similar pilot projects that assess the feasibility and advisability of CIH programs to complement the provision of pain management and related health care services, including mental health care services to veterans. Thus, the VA Secretary was directed to select at least 15 geographically diverse locations for the pilot projects. The VA has committed to conducting 18 full-scale demonstration projects in 2018—1 project in each VISN (Veterans Integrated Service Network). Section 933 of the CARA, prioritizes medical centers where the “prescription rate of opioids conflicts with or is otherwise inconsistent with the standards of appropriate and safe care.”⁹

Several issues must be addressed to make the provision of CIH in the VA a success.¹⁴ They include but are not limited to the following:

1. Clarification that CIH services for veterans are included in the Medical Benefits Package, which requires that care meets generally accepted standards of medical practice.
2. Vetting of CIH therapies to determine which ones should be recommended for inclusion in the Medical Benefits Package. Factors to consider include clinical evidence, community standards, practice guidelines, licensing and credentialing requirements, potential for harm, and veteran demand.
3. Changes to VA business processes to provide the infrastructure for CIH delivery.
4. Competition with existing VA programs for resources.
5. Education of HCPs and administrators about CIH through the development of CIH instruction manuals, curriculum, and faculty.

Although the VA faces the daunting task of reducing opioid use while continuing to treat chronic physical and mental pain, CIH therapies seem to offer a viable adjunctive therapy. It will be incumbent on the VA to explore through ongoing research all that CIH therapies may have to offer; veterans deserve no less. If the VA can demonstrate the effectiveness of CIH in treating the challenges faced by veterans, the results will serve as a useful example for treating chronic pain in the nonveteran population as well.

How gastric bypass tames diabetes. New efforts aim to get addiction specialists on the job. Preconception hypertension poses pregnancy risks. And don’t leave transgender patients out of breast cancer surveillance.

Listen to the MDedge Daily News podcast for all the details on today’s top news.
 

How gastric bypass tames diabetes. New efforts aim to get addiction specialists on the job. Preconception hypertension poses pregnancy risks. And don’t leave transgender patients out of breast cancer surveillance.

Listen to the MDedge Daily News podcast for all the details on today’s top news.
 

How gastric bypass tames diabetes. New efforts aim to get addiction specialists on the job. Preconception hypertension poses pregnancy risks. And don’t leave transgender patients out of breast cancer surveillance.

Listen to the MDedge Daily News podcast for all the details on today’s top news.
 

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Increased risk of suicide among veterans with posttraumatic stress disorder (PTSD) is well established. Posttraumatic stress disorder and related consequences are associated with higher rates of suicidal ideation and suicidal self-directed violence (S-SDV).¹ Based on a systematic review, several explanations for this relationship have been hypothesized.¹ Particular emphasis has been placed on trauma type (eg, premilitary childhood abuse, combat exposure), frequency of trauma exposure (ie, a single traumatic episode vs multiple traumatic experiences), specific PTSD symptoms (eg, avoidance, sleep disturbance, alteration in mood and cognitions, risky behaviors), and other psychosocial consequences associated with PTSD (eg, low social support, psychiatric comorbidity, substance use). However, there is limited understanding regarding how to conceptualize and assess risk for suicide when treating veterans who have PTSD.

PTSD and the Interpersonal-Psychological Theory of Suicide

Although PTSD is associated with risk for S-SDV among veterans, a diagnosis-specific approach to conceptualizing risk of suicide (ie, an explanation specific to PTSD) might not be enough because most individuals with a psychiatric diagnosis do not engage in S-SDV.² Rather, theories that are able to conceptualize suicide risk across many different psychiatric diagnoses are likely to improve mental health providers’ ability to understand risk of suicide. Although many theories attempt to understand suicide risk, the Interpersonal-Psychological Theory of Suicide (IPTS) has robust empirical support.³

The IPTS proposes that suicidal ideation is driven by perceptions of stable and unchanging thwarted belongingness (TB), defined as an unmet psychological need to socially belong, and perceived burdensomeness (PB), defined as the perception that one is a burden on others.⁴ However, PB and TB are not considered sufficient for S-SDV to occur unless an individual also has acquired the capability for suicide. Capability for suicide is thought to happen when an individual loses the fear of dying by suicide and develops tolerance to physical pain, which is proposed to occur through habituation or repeated exposure to painful stimuli.³

Several studies have examined the IPTS in a number of clinical populations, including veterans and active-duty service members; yet limited research has applied the IPTS to veterans with PTSD.³ However, a recent article proposed that a number of PTSD-related factors increase risk of suicide through the lens of the IPTS.⁵ In particular, repeated exposure to painful and provocative events—especially those characterized by violence and aggression—might increase acquired capability for suicide by causing habituation to physical pain and discomfort and reducing fear of injury and death. This concept is especially concerning because of the frequent occurrence of both military- (eg, combat, military sexual trauma) and nonmilitary-related (eg, childhood abuse, intimate partner violence) stressful and traumatic events among veterans, especially individuals with PTSD.

Moreover, the acquired capability for suicide correlates highly with anxious, intrusive, and hyperarousal symptoms of PTSD.^5-7 Over time, these PTSD symptoms are thought to increase habituation to the physically painful and frightening aspects of S-SDV, resulting in increased pain tolerance and fearlessness about death.³

In addition, PTSD-related cognitive-affective states (ie, thoughts and emotions), such as guilt, shame, and self-deprecation, might drive beliefs of PB and TB.^5,8 Repeated exposure to such trauma-related thoughts and emotions could further reinforce beliefs of self-hate or inadequacy (PB).² Trauma-related beliefs that the world or others are unsafe also might reduce the likelihood of seeking social support, thereby increasing TB.² The PTSD symptoms of avoidance and self-blame also are likely to reinforce beliefs of PB and TB.²

Assessing Suicide Risk in the Context of PTSD

The IPTS framework is one that can be used by mental health providers to conceptualize risk of suicide across populations and psychiatric diagnoses, including veterans with PTSD. However, integrating additional risk assessment and management techniques is essential to guide appropriate risk stratification and treatment.

One such method of suicide risk assessment and management is therapeutic risk management (TRM).⁹ Therapeutic risk management involves a stratification process by which temporal aspects (ie, acute and chronic) and severity (ie, low, moderate, and high) of suicide risk are assessed using a combination of clinical interview and psychometrically sound self-report measures, such as the Beck Scale for Suicide Ideation, Beck Hopelessness Scale, and Reasons for Living Inventory. Appropriate clinical interventions that correspond to acute and chronic suicide risk stratification are then implemented (eg, safety planning, lethal means counseling, increasing frequency of care, hospitalization if warranted).

Therapeutic risk management emphasizes the necessity of assessing current and past suicidal ideation, intent, plan, and access to means. Moreover, additional considerations might be indicated when assessing and conceptualizing suicide risk among veterans with PTSD. Assessing lifetime trauma history, including traumas that occurred before, during, and after military service, is important for understanding whether traumatic experiences influence acute and chronic risks of suicide. As previously described, careful attention to stressful and traumatic experiences with violent and aggressive characteristics is recommended because research suggests that these experiences are associated with increased capability for suicide.⁵ Awareness of the diversity of traumatic experiences and the importance of contextual factors surrounding such experiences also are essential. For example, the nature of violence and proximity to violence (eg, directly involved in a firefight vs hearing a mortar explosion in the distance) are key components of military-related combat trauma that might differentially influence risk of suicide.¹⁰

Similarly, although military sexual trauma can include repeated threatening sexual harassment or sexual assault, research suggests that military sexual assault is particularly important for understanding suicidal ideation, and experiences of military sexual harassment are less important.¹¹ Therefore, a careful and nuanced understanding of how contextual aspects of a veteran’s trauma history might relate to his or her chronic and acute risk of suicide is critical.

Also important is considering the individual and institutional reactions to trauma. For example, veterans whose behaviors during traumatic experiences violated their values and moral code (ie, moral injury) might be at increased risk for S-SDV. Similarly, veterans who believe that the military institution did not adequately protect them from or support them in the aftermath of traumatic experience(s) (ie, institutional betrayal) might be at higher risk of suicide.

During a clinical interview, mental health providers should pay attention to beliefs and behaviors the veteran is reporting. For example, endorsement of perceptions of low social support (eg, “no one likes me”) or self-esteem (eg, “I’m just not as good as I used to be”) might be indicative of TB or PB, respectively. Additionally, providers should be aware of current or lifetime exposure to painful stimuli (eg, nonsuicidal self-injury, such as cutting or burning, previous suicide attempts) because these exposures might increase the veteran’s acquired capability of future S-SDV.

Although unstructured clinical interviews are a common suicide risk assessment approach, TRM proposes that using a thorough clinical interview along with valid self-report measures could further illuminate a patient’s risk of suicide.⁹ Implementing brief measures allows mental health providers to quickly assess several risk factors and decrease the likelihood of missing important aspects of suicide risk assessment. Providers can use a number of measures to inform their suicide risk assessment, including augmenting a clinical interview of suicide risk with a valid self-report measure of recent suicidal ideation (eg, Beck Scale for Suicide Ideation, which assesses the severity of suicidal ideation in the past week).

Additionally for veterans with PTSD, mental health providers can include measures of PTSD symptoms (eg, PTSD checklist in the Diagnostic and Statistical Manual of Mental Disorders–5) and common PTSD comorbidities (eg, Beck Depression Inventory-II for depressive symptoms) that might contribute to current risk of suicide. Based on previous research, providers also might consider adding measures of trauma-related beliefs (eg, Posttraumatic Cognitions Inventory) and emotions, such as guilt (eg, Trauma-Related Guilt Inventory).⁵

These measures could aid in identifying modifiable risk factors of suicide among veterans with PTSD, such as the extent to which certain beliefs or emotions relate to an individual’s risk of suicide. In addition to asking about characteristics of traumatic events during the clinical interview, measures of moral injury (eg, Moral Injury Events Scale) and institutional betrayal (eg, Institutional Betrayal Questionnaire) might further inform understanding of contextual aspects of trauma that could help explain an individual’s risk of suicide.

Finally, interpersonal measures also could be helpful. For example, because avoidance and social isolation are risk factors for suicidal ideation among veterans with PTSD, measures of perceived interpersonal functioning (eg, Interpersonal Needs Questionnaire) might add further data to assist in suicide risk conceptualization. Although the selection of specific measures likely varies based on the specific needs of an individual patient, these are examples of measures that can be used with veterans with PTSD to inform suicide risk assessment and conceptualization.

By combining data from various measures across multiple domains with a thorough clinical interview, mental health providers can use a TRM approach to understand and conceptualize suicide risk among veterans with PTSD. This approach can facilitate mental health providers’ ability to provide optimal care and guide intervention(s) for veterans with PTSD. One brief intervention that has been used with veterans is safety planning. During safety planning, the provider assists the veteran in identifying warning signs, internal and external coping strategies, and individuals the veteran can reach out to for help (eg, friends and family, providers, Veterans Crisis Line), in addition to collaboratively brainstorming ways the veteran can make his or her environment safer (eg, reducing access to lethal means, identifying reminders of their reasons for living).

Specific to veterans with PTSD, symptoms such as avoidance, hyperarousal, social isolation, and beliefs that others and the world are unsafe might affect safety planning. Such symptoms could hinder identification and use of coping strategies while deterring openness to reach out to others for help. A collaborative method can be used to identify alternate means of coping that take into account PTSD-related avoidance and hyperarousal (eg, rather than going to a crowded store or isolating at home, taking a walk in a quiet park with few people). Similarly, because substance use and risky behaviors are common among veterans with PTSD and might further increase risk of suicide, exploring healthy (eg, exercise) vs unhealthy (eg, substance use; unprotected sex) coping strategies could be helpful.

Further, based on their lived experience, veterans with PTSD could experience difficulty identifying a support system or be reluctant to reach out to others during acute crisis. This might be particularly daunting in the presence of PB and TB. In these situations, it is important to validate the veteran’s difficulty with reaching out while simultaneously encouraging the veteran to examine the accuracy of such beliefs and/or helping the veteran develop skills to overcome these obstacles.

The mental health provider also can work with the individual to ensure that the veteran understands that if he or she does engage emergency resources (eg, Veterans Crisis Line), information likely will be held confidential. Providers can tell their patients that breaks in confidentiality are rare and occur only in circumstances in which it is necessary to protect the veteran. In doing so, the provider facilitates the veteran’s understanding of the role of crisis resources and clarifies any misconceptions the veteran might have (eg, calling the crisis line will always result in hospitalization or police presence).

Conclusion

Several PTSD-related factors might increase PB, TB, and the acquired capability for suicide among veterans with PTSD. Because suicide risk assessment and management can be time sensitive and anxiety provoking, mental health providers can use a TRM approach to increase their confidence in instituting optimal care and mitigating risk by having a structured, therapeutic assessment process that gathers appropriate suicide- and PTSD-related data to assist in developing suicide risk-related treatment. However, more research is needed to determine the most useful self-report measures and effective interventions when working with veterans with PTSD at risk of suicide.

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).

The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.

Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.

Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.

BLAST study

The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.

The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.

Patients received continuous intravenous infusions of blinatumomab at 15 μg/m²/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.

In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).

The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.

A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.

The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).

Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.

In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).

All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.

Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.

Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.

There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.

There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).

The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.

Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.

Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.

BLAST study

The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.

The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.

Patients received continuous intravenous infusions of blinatumomab at 15 μg/m²/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.

In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).

The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.

A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.

The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).

Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.

In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).

All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.

Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.

Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.

There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.

There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has expanded the approved indication for blinatumomab (Blincyto®).

The drug is now approved to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%.

Blinatumomab received accelerated approval for this indication because the drug has not yet shown a clinical benefit in these patients.

The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition.

Accelerated approval is based on surrogate or intermediate endpoints—in this case, MRD response rate and hematologic relapse-free survival (RFS)—that are reasonably likely to predict clinical benefit.

Continued approval of blinatumomab for the aforementioned indication may be contingent upon verification of clinical benefit in confirmatory trials.

“This is the first FDA-approved treatment for patients with MRD-positive ALL,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

“Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with Blincyto. Studies are being conducted to assess how Blincyto affects long-term survival outcomes in patients with MRD.”

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

In 2014, the FDA granted blinatumomab accelerated approval to treat adults with Philadelphia chromosome-negative (Ph-) relapsed/refractory BCP-ALL.

In 2016, the FDA granted the therapy accelerated approval for pediatric patients with Ph- relapsed/refractory BCP-ALL.

Last year, the FDA granted blinatumomab full approval for pediatric and adult patients with Ph- or Ph+ relapsed/refractory BCP-ALL.

The FDA-approved prescribing information for blinatumomab includes a boxed warning for cytokine release syndrome and neurologic toxicities. Blinatumomab is also under a risk evaluation and mitigation strategy program in the US.

BLAST study

The new accelerated approval for blinatumomab was supported by results from the phase 2 BLAST study, which were published in Blood in January.

The study enrolled adults with MRD-positive BCP-ALL in complete hematologic remission after 3 or more cycles of intensive chemotherapy.

Patients received continuous intravenous infusions of blinatumomab at 15 μg/m²/day for 4 weeks, followed by 2 weeks off. They received up to 4 cycles of treatment and could undergo hematopoietic stem cell transplant (HSCT) at any time after the first cycle.

In all, there were 116 patients who received at least 1 infusion of blinatumomab. Seventy-six patients went on to HSCT while in continuous CR after cycle 1 (n=27), 2 (n=36), or 3/4 (n=13).

The study’s primary endpoint was the rate of complete MRD response within the first treatment cycle, and 78% of evaluable patients (88/113) achieved this endpoint.

A key secondary endpoint was RFS at 18 months. There were 110 patients evaluable for this endpoint. They all had Ph- BCP-ALL and <5% blasts at baseline.

The estimated RFS at 18 months was 54%, and the median RFS was 18.9 months. The median RFS was 24.6 months for patients treated in first CR and 11.0 months for patients treated in a later CR (P=0.004).

Another key endpoint was overall survival (OS). The median OS was 36.5 months, both for the 110 patients in the RFS analysis and for the entire study population.

In a landmark analysis, complete MRD responders had longer OS than MRD nonresponders—38.9 months and 12.5 months, respectively (P=0.002). And complete MRD responders had longer RFS than nonresponders—23.6 months and 5.7 months, respectively (P=0.002).

All 116 patients who started cycle 1 had at least 1 adverse event (AE). The rate of grade 3 AEs was 33%, and the rate of grade 4 AEs was 27%. These AEs were considered treatment-related in 29% (grade 3) and 22% (grade 4) of patients.

Four (3%) patients developed cytokine release syndrome—2 with grade 1 and 2 with grade 3. All of these events occurred during cycle 1.

Fifty-three percent of patients (n=61) had neurologic events. In most cases (97%, n=59), these events resolved.

There were 2 fatal AEs during the treatment period, both in cycle 1. One of these events—atypical pneumonitis with H1N1 influenza—was considered treatment-related. The other event—subdural hemorrhage—was considered unrelated to treatment.

There were 4 fatal AEs reported after blinatumomab treatment. Two of these deaths—due to multifocal CNS lesions and graft-versus-host disease—occurred in HSCT recipients. The other 2 deaths—due to disease progression and multi-organ failure—occurred in nontransplanted patients after relapse.