Alzheimer disease and related dementias are a global health concern, affecting nearly 47 million people worldwide. Alzheimer disease and related dementias were among the top 10 causes of death worldwide in 2015 and are expected to increase by 10 million cases annually.¹ Despite the ethnic diversity of the US, there are considerable gaps in the literature regarding dementia and how it is diagnosed and treated among many ethnic and racial groups.

In 2012, President Barack Obama signed a declaration with the intention of decreasing ethnoracial disparities in Alzheimer disease research and treatment by increasing clinical care, research, and services targeted to racial and ethnic minorities.² Despite that declaration, in the US there are gaps in access to care for the geriatric population in general. The American Geriatrics Society estimates that the US has fewer than half the needed number of practicing geriatricians. In 2016, there was 1 geriatrician for every 1,924 Americans aged ≥ 65 years.³ Furthermore, health care providers (HCPs) are often not of the same ethnicity or adequately trained to assess and build relationships with ethnically and racially diverse populations.² Given the projected growth in the numbers of individuals worldwide with dementia, we have a responsibility to continue to develop strategies to provide more inclusive care.

By 2060, minority populations aged ≥ 65 years are expected to represent 45% of the US population, up from 22% in 2014.⁴ The growth of racial and ethnic minority groups are expected to exceed the growth of the non-Hispanic white population in the next few decades. By 2060, it is estimated that the US population will increase by 75% for non-Hispanic whites, 172% for African Americans, 270% for Asian and Pacific Islanders, 274% for American Indian and Alaska Natives, and 391% for Hispanics.⁴

A growing body of evidence suggests that Alzheimer disease and related dementias may disproportionately afflict minority groups in the US, which will become quite significant in the years ahead. The Alzheimer’s Association estimates that the prevalence of Alzheimer disease and other dementias among those aged > 65 years, is about twice the rate in African Americans and about 1.5 times the rate in Hispanics when compared with non-Hispanic whites.⁵ While increases in the incidence of Alzheimer disease and related dementias in non-Hispanic whites is expected to plateau around 2050, its incidence in ethnic and racial minority groups will continue to grow, especially among Hispanics.⁴ This stark realization provides additional compelling reasons for the US to develop preventative interventions or treatment options that may help delay the onset of the disease and to improve the quality of life of those with the disease or caregiving for those afflicted with it. Culturally competent care of these individuals is paramount.

Diagnosis

Early and accurate diagnosis of individuals with dementia confers many benefits, including early treatment; clinical trial participation; management of comorbid conditions; training, education, and support for patients and families; and legal, financial, and end of life care planning.³ Beyond the logistical concerns (such as HCP shortages), one of the challenges of assessing minority groups is finding staff who are culturally competent or speak the language necessary to accurately communicate and interact with these subgroups. Hispanics and African Americans often receive delayed or inadequate health care services or are diagnosed in an emergency department or other nontraditional setting.⁵

Even those individuals seeking or receiving care in primary care settings are not always forthcoming about their cognitive status. Only 56% of respondents in a recent survey of patients who had experienced subjective cognitive decline reported that they had discussed it with their HCP.⁴ This reticence is thought to be influenced by multiple factors, including distrust of the medical establishment, religious or spiritual beliefs, cultural or family beliefs and expectations about geriatric care, and lack of understanding about normal aging vs cognitive disorders. Furthermore, the sensitivity and specificity of current diagnostic tests for dementia have been questioned for nonwhite populations given the clinical presentation of dementia can vary across ethnoracial groups.⁵

As Luria noted, cognitive assessment tools developed and validated for use with one culture frequently results in experimental failures and are not valid for use with other cultural groups.¹ Cognitive testing results are influenced by educational and cultural factors, and this is one of the challenges in correctly diagnosing those of differing ethnoracial backgrounds. Individuals in racial and ethnic minorities may have limited formal education and/or high illiteracy rates and/or cultural nuances to problem solving, thinking, and memory that may not be reflected in current assessment tools.¹

There is hope that testing bias could be altered or eliminated using neuroimaging or biomarkers. However, the Alzheimer’s Disease Neuroimaging Initiative study of patients in the US and Canada included < 5% African American or Hispanic participants in its total sample. Few studies have systematically examined ethnoracial differences in amyloid positron emission tomography, and none have been published to date in ethnoracially diverse groups that assess the more recently developed tau imaging agents.¹

Diversity Among Caregivers

The research community must make greater efforts to improve recruitment of more diverse populations into clinical trials. Recent efforts by the National Institute on Aging in conjunction with the Alzheimer’s Association include developing a national strategy for clinical research recruitment and retention with an emphasis on local and diverse populations. This strategy should include various training modules, webinars, and similar educational opportunities for researchers and clinical HCPs, including HCPs from diverse ethnoracial backgrounds, to implement culturally appropriate research methodologies across these diverse groups. It is important that these educational materials be disseminated to caregivers in a way they can comprehend, as the impact on caregivers of those with Alzheimer disease and related dementias is considerable.

The US currently has 7 unpaid caregivers for every adult in the high-risk group of patients aged ≥ 65 years, but this will decline to a ratio of 4:1 by 2030.⁴ More than two-thirds of caregivers are non-Hispanic white, while 10% are African American, 8% are Hispanic, and 5% are Asian.³ About 34% of caregivers are themselves aged ≥ 65 years and are at risk for declines in their own health given the time and financial requirements of caring for someone else.³ In 2017, the 16.1 million family and other unpaid caregivers of people with dementia provided an estimated 18.4 billion hours of unpaid care, often resulting in considerable financial strain for these individuals. More than half of the caregivers report providing ≥ 21 hours of care per week; and 42% reported providing an average of 9 hours of care per day for people with dementia.

Caregivers report increased stress, sleep deprivation, depression and anxiety, and uncertainty in their ability to provide quality care to the individual with Alzheimer or a related dementia.³ The disproportionate prevalence of Alzheimer disease and other dementias in racially and ethnically diverse populations could further magnify already existing socioeconomic and other disparities and potentially lead to worsening of health outcomes in these groups.⁴ Given that minority populations tend to cluster geographically, community partnerships with local churches, senior centers, community centers, and other nontraditional settings may offer better opportunities for connecting with caregivers.

Conclusions

The growth and increasing diversity of the US older adult population in the coming decades require us as HCPs, researchers, and educators to dedicate more resources to ethnoracially diverse populations. There are still a great many unknowns about Alzheimer disease and dementia, most especially among nonwhites. Research, clinical care, and education must focus on outreach to marginalized groups so we may better be able to diagnose and treat the fastest growing older adult populations in the US. A complex combination of educational, cultural, social, and environmental factors likely contribute to delayed diagnosis and care of these groups, as well as lack of access to medical care, research venues, and trust issues between minority groups and the medical establishment. We all have an obligation to acknowledge these disparities and elicit the support of our colleagues and workplaces to raise awareness and dedicate necessary resources to this growing concern.

Alzheimer disease and related dementias are a global health concern, affecting nearly 47 million people worldwide. Alzheimer disease and related dementias were among the top 10 causes of death worldwide in 2015 and are expected to increase by 10 million cases annually.¹ Despite the ethnic diversity of the US, there are considerable gaps in the literature regarding dementia and how it is diagnosed and treated among many ethnic and racial groups.

In 2012, President Barack Obama signed a declaration with the intention of decreasing ethnoracial disparities in Alzheimer disease research and treatment by increasing clinical care, research, and services targeted to racial and ethnic minorities.² Despite that declaration, in the US there are gaps in access to care for the geriatric population in general. The American Geriatrics Society estimates that the US has fewer than half the needed number of practicing geriatricians. In 2016, there was 1 geriatrician for every 1,924 Americans aged ≥ 65 years.³ Furthermore, health care providers (HCPs) are often not of the same ethnicity or adequately trained to assess and build relationships with ethnically and racially diverse populations.² Given the projected growth in the numbers of individuals worldwide with dementia, we have a responsibility to continue to develop strategies to provide more inclusive care.

By 2060, minority populations aged ≥ 65 years are expected to represent 45% of the US population, up from 22% in 2014.⁴ The growth of racial and ethnic minority groups are expected to exceed the growth of the non-Hispanic white population in the next few decades. By 2060, it is estimated that the US population will increase by 75% for non-Hispanic whites, 172% for African Americans, 270% for Asian and Pacific Islanders, 274% for American Indian and Alaska Natives, and 391% for Hispanics.⁴

A growing body of evidence suggests that Alzheimer disease and related dementias may disproportionately afflict minority groups in the US, which will become quite significant in the years ahead. The Alzheimer’s Association estimates that the prevalence of Alzheimer disease and other dementias among those aged > 65 years, is about twice the rate in African Americans and about 1.5 times the rate in Hispanics when compared with non-Hispanic whites.⁵ While increases in the incidence of Alzheimer disease and related dementias in non-Hispanic whites is expected to plateau around 2050, its incidence in ethnic and racial minority groups will continue to grow, especially among Hispanics.⁴ This stark realization provides additional compelling reasons for the US to develop preventative interventions or treatment options that may help delay the onset of the disease and to improve the quality of life of those with the disease or caregiving for those afflicted with it. Culturally competent care of these individuals is paramount.

Diagnosis

Early and accurate diagnosis of individuals with dementia confers many benefits, including early treatment; clinical trial participation; management of comorbid conditions; training, education, and support for patients and families; and legal, financial, and end of life care planning.³ Beyond the logistical concerns (such as HCP shortages), one of the challenges of assessing minority groups is finding staff who are culturally competent or speak the language necessary to accurately communicate and interact with these subgroups. Hispanics and African Americans often receive delayed or inadequate health care services or are diagnosed in an emergency department or other nontraditional setting.⁵

Even those individuals seeking or receiving care in primary care settings are not always forthcoming about their cognitive status. Only 56% of respondents in a recent survey of patients who had experienced subjective cognitive decline reported that they had discussed it with their HCP.⁴ This reticence is thought to be influenced by multiple factors, including distrust of the medical establishment, religious or spiritual beliefs, cultural or family beliefs and expectations about geriatric care, and lack of understanding about normal aging vs cognitive disorders. Furthermore, the sensitivity and specificity of current diagnostic tests for dementia have been questioned for nonwhite populations given the clinical presentation of dementia can vary across ethnoracial groups.⁵

As Luria noted, cognitive assessment tools developed and validated for use with one culture frequently results in experimental failures and are not valid for use with other cultural groups.¹ Cognitive testing results are influenced by educational and cultural factors, and this is one of the challenges in correctly diagnosing those of differing ethnoracial backgrounds. Individuals in racial and ethnic minorities may have limited formal education and/or high illiteracy rates and/or cultural nuances to problem solving, thinking, and memory that may not be reflected in current assessment tools.¹

There is hope that testing bias could be altered or eliminated using neuroimaging or biomarkers. However, the Alzheimer’s Disease Neuroimaging Initiative study of patients in the US and Canada included < 5% African American or Hispanic participants in its total sample. Few studies have systematically examined ethnoracial differences in amyloid positron emission tomography, and none have been published to date in ethnoracially diverse groups that assess the more recently developed tau imaging agents.¹

Diversity Among Caregivers

The research community must make greater efforts to improve recruitment of more diverse populations into clinical trials. Recent efforts by the National Institute on Aging in conjunction with the Alzheimer’s Association include developing a national strategy for clinical research recruitment and retention with an emphasis on local and diverse populations. This strategy should include various training modules, webinars, and similar educational opportunities for researchers and clinical HCPs, including HCPs from diverse ethnoracial backgrounds, to implement culturally appropriate research methodologies across these diverse groups. It is important that these educational materials be disseminated to caregivers in a way they can comprehend, as the impact on caregivers of those with Alzheimer disease and related dementias is considerable.

The US currently has 7 unpaid caregivers for every adult in the high-risk group of patients aged ≥ 65 years, but this will decline to a ratio of 4:1 by 2030.⁴ More than two-thirds of caregivers are non-Hispanic white, while 10% are African American, 8% are Hispanic, and 5% are Asian.³ About 34% of caregivers are themselves aged ≥ 65 years and are at risk for declines in their own health given the time and financial requirements of caring for someone else.³ In 2017, the 16.1 million family and other unpaid caregivers of people with dementia provided an estimated 18.4 billion hours of unpaid care, often resulting in considerable financial strain for these individuals. More than half of the caregivers report providing ≥ 21 hours of care per week; and 42% reported providing an average of 9 hours of care per day for people with dementia.

Caregivers report increased stress, sleep deprivation, depression and anxiety, and uncertainty in their ability to provide quality care to the individual with Alzheimer or a related dementia.³ The disproportionate prevalence of Alzheimer disease and other dementias in racially and ethnically diverse populations could further magnify already existing socioeconomic and other disparities and potentially lead to worsening of health outcomes in these groups.⁴ Given that minority populations tend to cluster geographically, community partnerships with local churches, senior centers, community centers, and other nontraditional settings may offer better opportunities for connecting with caregivers.

Conclusions

The growth and increasing diversity of the US older adult population in the coming decades require us as HCPs, researchers, and educators to dedicate more resources to ethnoracially diverse populations. There are still a great many unknowns about Alzheimer disease and dementia, most especially among nonwhites. Research, clinical care, and education must focus on outreach to marginalized groups so we may better be able to diagnose and treat the fastest growing older adult populations in the US. A complex combination of educational, cultural, social, and environmental factors likely contribute to delayed diagnosis and care of these groups, as well as lack of access to medical care, research venues, and trust issues between minority groups and the medical establishment. We all have an obligation to acknowledge these disparities and elicit the support of our colleagues and workplaces to raise awareness and dedicate necessary resources to this growing concern.

Alzheimer disease and related dementias are a global health concern, affecting nearly 47 million people worldwide. Alzheimer disease and related dementias were among the top 10 causes of death worldwide in 2015 and are expected to increase by 10 million cases annually.¹ Despite the ethnic diversity of the US, there are considerable gaps in the literature regarding dementia and how it is diagnosed and treated among many ethnic and racial groups.

In 2012, President Barack Obama signed a declaration with the intention of decreasing ethnoracial disparities in Alzheimer disease research and treatment by increasing clinical care, research, and services targeted to racial and ethnic minorities.² Despite that declaration, in the US there are gaps in access to care for the geriatric population in general. The American Geriatrics Society estimates that the US has fewer than half the needed number of practicing geriatricians. In 2016, there was 1 geriatrician for every 1,924 Americans aged ≥ 65 years.³ Furthermore, health care providers (HCPs) are often not of the same ethnicity or adequately trained to assess and build relationships with ethnically and racially diverse populations.² Given the projected growth in the numbers of individuals worldwide with dementia, we have a responsibility to continue to develop strategies to provide more inclusive care.

By 2060, minority populations aged ≥ 65 years are expected to represent 45% of the US population, up from 22% in 2014.⁴ The growth of racial and ethnic minority groups are expected to exceed the growth of the non-Hispanic white population in the next few decades. By 2060, it is estimated that the US population will increase by 75% for non-Hispanic whites, 172% for African Americans, 270% for Asian and Pacific Islanders, 274% for American Indian and Alaska Natives, and 391% for Hispanics.⁴

A growing body of evidence suggests that Alzheimer disease and related dementias may disproportionately afflict minority groups in the US, which will become quite significant in the years ahead. The Alzheimer’s Association estimates that the prevalence of Alzheimer disease and other dementias among those aged > 65 years, is about twice the rate in African Americans and about 1.5 times the rate in Hispanics when compared with non-Hispanic whites.⁵ While increases in the incidence of Alzheimer disease and related dementias in non-Hispanic whites is expected to plateau around 2050, its incidence in ethnic and racial minority groups will continue to grow, especially among Hispanics.⁴ This stark realization provides additional compelling reasons for the US to develop preventative interventions or treatment options that may help delay the onset of the disease and to improve the quality of life of those with the disease or caregiving for those afflicted with it. Culturally competent care of these individuals is paramount.

Diagnosis

Early and accurate diagnosis of individuals with dementia confers many benefits, including early treatment; clinical trial participation; management of comorbid conditions; training, education, and support for patients and families; and legal, financial, and end of life care planning.³ Beyond the logistical concerns (such as HCP shortages), one of the challenges of assessing minority groups is finding staff who are culturally competent or speak the language necessary to accurately communicate and interact with these subgroups. Hispanics and African Americans often receive delayed or inadequate health care services or are diagnosed in an emergency department or other nontraditional setting.⁵

Even those individuals seeking or receiving care in primary care settings are not always forthcoming about their cognitive status. Only 56% of respondents in a recent survey of patients who had experienced subjective cognitive decline reported that they had discussed it with their HCP.⁴ This reticence is thought to be influenced by multiple factors, including distrust of the medical establishment, religious or spiritual beliefs, cultural or family beliefs and expectations about geriatric care, and lack of understanding about normal aging vs cognitive disorders. Furthermore, the sensitivity and specificity of current diagnostic tests for dementia have been questioned for nonwhite populations given the clinical presentation of dementia can vary across ethnoracial groups.⁵

As Luria noted, cognitive assessment tools developed and validated for use with one culture frequently results in experimental failures and are not valid for use with other cultural groups.¹ Cognitive testing results are influenced by educational and cultural factors, and this is one of the challenges in correctly diagnosing those of differing ethnoracial backgrounds. Individuals in racial and ethnic minorities may have limited formal education and/or high illiteracy rates and/or cultural nuances to problem solving, thinking, and memory that may not be reflected in current assessment tools.¹

There is hope that testing bias could be altered or eliminated using neuroimaging or biomarkers. However, the Alzheimer’s Disease Neuroimaging Initiative study of patients in the US and Canada included < 5% African American or Hispanic participants in its total sample. Few studies have systematically examined ethnoracial differences in amyloid positron emission tomography, and none have been published to date in ethnoracially diverse groups that assess the more recently developed tau imaging agents.¹

Diversity Among Caregivers

The research community must make greater efforts to improve recruitment of more diverse populations into clinical trials. Recent efforts by the National Institute on Aging in conjunction with the Alzheimer’s Association include developing a national strategy for clinical research recruitment and retention with an emphasis on local and diverse populations. This strategy should include various training modules, webinars, and similar educational opportunities for researchers and clinical HCPs, including HCPs from diverse ethnoracial backgrounds, to implement culturally appropriate research methodologies across these diverse groups. It is important that these educational materials be disseminated to caregivers in a way they can comprehend, as the impact on caregivers of those with Alzheimer disease and related dementias is considerable.

The US currently has 7 unpaid caregivers for every adult in the high-risk group of patients aged ≥ 65 years, but this will decline to a ratio of 4:1 by 2030.⁴ More than two-thirds of caregivers are non-Hispanic white, while 10% are African American, 8% are Hispanic, and 5% are Asian.³ About 34% of caregivers are themselves aged ≥ 65 years and are at risk for declines in their own health given the time and financial requirements of caring for someone else.³ In 2017, the 16.1 million family and other unpaid caregivers of people with dementia provided an estimated 18.4 billion hours of unpaid care, often resulting in considerable financial strain for these individuals. More than half of the caregivers report providing ≥ 21 hours of care per week; and 42% reported providing an average of 9 hours of care per day for people with dementia.

Caregivers report increased stress, sleep deprivation, depression and anxiety, and uncertainty in their ability to provide quality care to the individual with Alzheimer or a related dementia.³ The disproportionate prevalence of Alzheimer disease and other dementias in racially and ethnically diverse populations could further magnify already existing socioeconomic and other disparities and potentially lead to worsening of health outcomes in these groups.⁴ Given that minority populations tend to cluster geographically, community partnerships with local churches, senior centers, community centers, and other nontraditional settings may offer better opportunities for connecting with caregivers.

Conclusions

The growth and increasing diversity of the US older adult population in the coming decades require us as HCPs, researchers, and educators to dedicate more resources to ethnoracially diverse populations. There are still a great many unknowns about Alzheimer disease and dementia, most especially among nonwhites. Research, clinical care, and education must focus on outreach to marginalized groups so we may better be able to diagnose and treat the fastest growing older adult populations in the US. A complex combination of educational, cultural, social, and environmental factors likely contribute to delayed diagnosis and care of these groups, as well as lack of access to medical care, research venues, and trust issues between minority groups and the medical establishment. We all have an obligation to acknowledge these disparities and elicit the support of our colleagues and workplaces to raise awareness and dedicate necessary resources to this growing concern.

Like me, some of you may have been following the agonizing news about the unprecedented brushfires in Australia that have devastated human, animal, and vegetative life in that country so culturally akin to our own.¹ For many people who believe the overwhelming majority of scientific reports on climate change, these apocalyptic fires are an empirical demonstration of the truth of the dire prophecies for the future of our planet. Scientists have demonstrated that although climate change may not have caused the worst fires in Australia’s history, they may have contributed to the conditions that enabled them to spread so far and wide and reach such a destructive intensity.²The heartbreaking pictures of singed koalas and displaced people and the helpless feeling that all I can do from here is donate money set me to thinking about the relationship between the military, health, and climate change, which is the subject of this column.

As I write this in mid-January of a new decade and glance at the weather headlines, I read about an earthquake in Puerto Rico and tornadoes in the southern US. This makes it quite plausible that our comfortable lifestyle and technological civilization could in the coming decades go the way of the dinosaurs, also victims of climate change.

Initially, my first thought about this relationship is a negative one—images of scorched earth policies that stretch back to ancient wars jump to mind. Reflection and research on the topic though suggest that the relationship may be more complicated and conflicted. Alas, I can only touch on a few of the themes in this brief format.

It may not be as obvious that climate change also threatens the military, which is the guardian of that civilization. In 2018, for example, Hurricane Michael caused nearly $5 billion in damages to Tyndall Air Force Base in Florida.³ A year later, the US Department of Defense (DoD) released a report on the effects of climate change as mandated by Congress.⁴ Even though some congressional critics expressed concern about the report’s lack of depth and detail,⁵ the report asserted that, “The effects of a changing climate are a national security issue with potential impacts to Department of Defense (DoD or the Department) missions, operational plans, and installations.”⁴

The US Department of Veterans Affairs (VA) is not immune either. Natural disasters have already disrupted the delivery of health care at its many aging facilities. Climate change was called the “engine”⁶ driving Hurricane Maria, which in 2017 slammed into Puerto Rico, including its VA medical center, and resulted in shortages of supplies, staff, and basic utilities.⁷ The facility and the island are still trying to rebuild. In response to weather-exposed vulnerability in VA infrastructure, Senator and presidential candidate Elizabeth Warren (D-MA) and Senator Brian Schatz (D-HI), the ranking member of the Subcommittee on Military Construction, sent a letter to VA leadership arguing that “Strengthening VA’s resilience to climate change is consistent with the agency’s mission to deliver timely, high-quality care and benefits to America’s veterans.”⁸

It has been reported that the current administration has countered initiatives to prepare for the challenges of providing health care to service members and veterans in a climate changed world.⁹ Sadly, but predictably, in the politicized federal health care arena, the safety of our service members and, in turn, the domestic and national security and peace that depend on them are caught in the partisan debate over global warming, though it is not likely Congress or federal agency leaders will abandon planning to safeguard service members who will see duty and combat in a radically altered ecology and veterans and who will need to have VA continue to be the reliable safety net despite an increasingly erratic environment.¹⁰

Climate change is a divisive political issue; there is a proud tradition of conservatism and self-reliance in military members, active duty and veteran alike. That was why I was surprised and impressed when I saw the results of a recent survey on climate change. In January 2019, 293 active-duty service members and veterans were surveyed.

Participants were selected to reflect the ethnic makeup, educational level, and political allegiance of the military population, which enhanced the validity of the findings.¹¹Participants were asked to indicate whether they believed that the earth was warming secondary to human or natural processes; not growing warmer at all; or whether they were unsure. Similar to the general population, 46% agreed that climate change is anthropogenic.¹¹ More than three-fourths believed it was likely climate change would adversely affect the places they worked, like military installations; 61% thought it likely that global warming could lead to armed conflict over resources. Seven in 10 respondents believed that climate is changing vs 46% who did not. Of respondents who believe climate change is real, 87% see it as a threat to military bases compared with 60% who do not accept the science that the earth is warming.¹¹

This survey, though, is only a small study, and the military and VA are big tents under which a wide range of political persuasions and diverse beliefs co-exist. There are many readers of Federal Practitioner who will no doubt reject nearly every word I have written, in what I know is a controversial column. But it matters that the military and veteran constituency are thinking and speaking about the issue of climate change.¹¹ Why? The answer takes us back to the disaster in Australia. When the fires and the devastation they wrought escalated beyond the powers of the civil authorities to handle, it was the military whose technical skill, coordinated readiness, and personal courage and dedication that was called on to rescue thousands of civilians from the inferno.¹² So it will be in our country and around the world when disasters—manmade, natural, or both—threaten to engulf life in all its wondrous variety. Those who battle extreme weather will have unique health needs, and their valiant sacrifices deserve to have health care systems ready and able to treat them.

Like me, some of you may have been following the agonizing news about the unprecedented brushfires in Australia that have devastated human, animal, and vegetative life in that country so culturally akin to our own.¹ For many people who believe the overwhelming majority of scientific reports on climate change, these apocalyptic fires are an empirical demonstration of the truth of the dire prophecies for the future of our planet. Scientists have demonstrated that although climate change may not have caused the worst fires in Australia’s history, they may have contributed to the conditions that enabled them to spread so far and wide and reach such a destructive intensity.²The heartbreaking pictures of singed koalas and displaced people and the helpless feeling that all I can do from here is donate money set me to thinking about the relationship between the military, health, and climate change, which is the subject of this column.

As I write this in mid-January of a new decade and glance at the weather headlines, I read about an earthquake in Puerto Rico and tornadoes in the southern US. This makes it quite plausible that our comfortable lifestyle and technological civilization could in the coming decades go the way of the dinosaurs, also victims of climate change.

Initially, my first thought about this relationship is a negative one—images of scorched earth policies that stretch back to ancient wars jump to mind. Reflection and research on the topic though suggest that the relationship may be more complicated and conflicted. Alas, I can only touch on a few of the themes in this brief format.

It may not be as obvious that climate change also threatens the military, which is the guardian of that civilization. In 2018, for example, Hurricane Michael caused nearly $5 billion in damages to Tyndall Air Force Base in Florida.³ A year later, the US Department of Defense (DoD) released a report on the effects of climate change as mandated by Congress.⁴ Even though some congressional critics expressed concern about the report’s lack of depth and detail,⁵ the report asserted that, “The effects of a changing climate are a national security issue with potential impacts to Department of Defense (DoD or the Department) missions, operational plans, and installations.”⁴

The US Department of Veterans Affairs (VA) is not immune either. Natural disasters have already disrupted the delivery of health care at its many aging facilities. Climate change was called the “engine”⁶ driving Hurricane Maria, which in 2017 slammed into Puerto Rico, including its VA medical center, and resulted in shortages of supplies, staff, and basic utilities.⁷ The facility and the island are still trying to rebuild. In response to weather-exposed vulnerability in VA infrastructure, Senator and presidential candidate Elizabeth Warren (D-MA) and Senator Brian Schatz (D-HI), the ranking member of the Subcommittee on Military Construction, sent a letter to VA leadership arguing that “Strengthening VA’s resilience to climate change is consistent with the agency’s mission to deliver timely, high-quality care and benefits to America’s veterans.”⁸

It has been reported that the current administration has countered initiatives to prepare for the challenges of providing health care to service members and veterans in a climate changed world.⁹ Sadly, but predictably, in the politicized federal health care arena, the safety of our service members and, in turn, the domestic and national security and peace that depend on them are caught in the partisan debate over global warming, though it is not likely Congress or federal agency leaders will abandon planning to safeguard service members who will see duty and combat in a radically altered ecology and veterans and who will need to have VA continue to be the reliable safety net despite an increasingly erratic environment.¹⁰

Climate change is a divisive political issue; there is a proud tradition of conservatism and self-reliance in military members, active duty and veteran alike. That was why I was surprised and impressed when I saw the results of a recent survey on climate change. In January 2019, 293 active-duty service members and veterans were surveyed.

Participants were selected to reflect the ethnic makeup, educational level, and political allegiance of the military population, which enhanced the validity of the findings.¹¹Participants were asked to indicate whether they believed that the earth was warming secondary to human or natural processes; not growing warmer at all; or whether they were unsure. Similar to the general population, 46% agreed that climate change is anthropogenic.¹¹ More than three-fourths believed it was likely climate change would adversely affect the places they worked, like military installations; 61% thought it likely that global warming could lead to armed conflict over resources. Seven in 10 respondents believed that climate is changing vs 46% who did not. Of respondents who believe climate change is real, 87% see it as a threat to military bases compared with 60% who do not accept the science that the earth is warming.¹¹

This survey, though, is only a small study, and the military and VA are big tents under which a wide range of political persuasions and diverse beliefs co-exist. There are many readers of Federal Practitioner who will no doubt reject nearly every word I have written, in what I know is a controversial column. But it matters that the military and veteran constituency are thinking and speaking about the issue of climate change.¹¹ Why? The answer takes us back to the disaster in Australia. When the fires and the devastation they wrought escalated beyond the powers of the civil authorities to handle, it was the military whose technical skill, coordinated readiness, and personal courage and dedication that was called on to rescue thousands of civilians from the inferno.¹² So it will be in our country and around the world when disasters—manmade, natural, or both—threaten to engulf life in all its wondrous variety. Those who battle extreme weather will have unique health needs, and their valiant sacrifices deserve to have health care systems ready and able to treat them.

Like me, some of you may have been following the agonizing news about the unprecedented brushfires in Australia that have devastated human, animal, and vegetative life in that country so culturally akin to our own.¹ For many people who believe the overwhelming majority of scientific reports on climate change, these apocalyptic fires are an empirical demonstration of the truth of the dire prophecies for the future of our planet. Scientists have demonstrated that although climate change may not have caused the worst fires in Australia’s history, they may have contributed to the conditions that enabled them to spread so far and wide and reach such a destructive intensity.²The heartbreaking pictures of singed koalas and displaced people and the helpless feeling that all I can do from here is donate money set me to thinking about the relationship between the military, health, and climate change, which is the subject of this column.

As I write this in mid-January of a new decade and glance at the weather headlines, I read about an earthquake in Puerto Rico and tornadoes in the southern US. This makes it quite plausible that our comfortable lifestyle and technological civilization could in the coming decades go the way of the dinosaurs, also victims of climate change.

Initially, my first thought about this relationship is a negative one—images of scorched earth policies that stretch back to ancient wars jump to mind. Reflection and research on the topic though suggest that the relationship may be more complicated and conflicted. Alas, I can only touch on a few of the themes in this brief format.

It may not be as obvious that climate change also threatens the military, which is the guardian of that civilization. In 2018, for example, Hurricane Michael caused nearly $5 billion in damages to Tyndall Air Force Base in Florida.³ A year later, the US Department of Defense (DoD) released a report on the effects of climate change as mandated by Congress.⁴ Even though some congressional critics expressed concern about the report’s lack of depth and detail,⁵ the report asserted that, “The effects of a changing climate are a national security issue with potential impacts to Department of Defense (DoD or the Department) missions, operational plans, and installations.”⁴

The US Department of Veterans Affairs (VA) is not immune either. Natural disasters have already disrupted the delivery of health care at its many aging facilities. Climate change was called the “engine”⁶ driving Hurricane Maria, which in 2017 slammed into Puerto Rico, including its VA medical center, and resulted in shortages of supplies, staff, and basic utilities.⁷ The facility and the island are still trying to rebuild. In response to weather-exposed vulnerability in VA infrastructure, Senator and presidential candidate Elizabeth Warren (D-MA) and Senator Brian Schatz (D-HI), the ranking member of the Subcommittee on Military Construction, sent a letter to VA leadership arguing that “Strengthening VA’s resilience to climate change is consistent with the agency’s mission to deliver timely, high-quality care and benefits to America’s veterans.”⁸

It has been reported that the current administration has countered initiatives to prepare for the challenges of providing health care to service members and veterans in a climate changed world.⁹ Sadly, but predictably, in the politicized federal health care arena, the safety of our service members and, in turn, the domestic and national security and peace that depend on them are caught in the partisan debate over global warming, though it is not likely Congress or federal agency leaders will abandon planning to safeguard service members who will see duty and combat in a radically altered ecology and veterans and who will need to have VA continue to be the reliable safety net despite an increasingly erratic environment.¹⁰

Climate change is a divisive political issue; there is a proud tradition of conservatism and self-reliance in military members, active duty and veteran alike. That was why I was surprised and impressed when I saw the results of a recent survey on climate change. In January 2019, 293 active-duty service members and veterans were surveyed.

Participants were selected to reflect the ethnic makeup, educational level, and political allegiance of the military population, which enhanced the validity of the findings.¹¹Participants were asked to indicate whether they believed that the earth was warming secondary to human or natural processes; not growing warmer at all; or whether they were unsure. Similar to the general population, 46% agreed that climate change is anthropogenic.¹¹ More than three-fourths believed it was likely climate change would adversely affect the places they worked, like military installations; 61% thought it likely that global warming could lead to armed conflict over resources. Seven in 10 respondents believed that climate is changing vs 46% who did not. Of respondents who believe climate change is real, 87% see it as a threat to military bases compared with 60% who do not accept the science that the earth is warming.¹¹

This survey, though, is only a small study, and the military and VA are big tents under which a wide range of political persuasions and diverse beliefs co-exist. There are many readers of Federal Practitioner who will no doubt reject nearly every word I have written, in what I know is a controversial column. But it matters that the military and veteran constituency are thinking and speaking about the issue of climate change.¹¹ Why? The answer takes us back to the disaster in Australia. When the fires and the devastation they wrought escalated beyond the powers of the civil authorities to handle, it was the military whose technical skill, coordinated readiness, and personal courage and dedication that was called on to rescue thousands of civilians from the inferno.¹² So it will be in our country and around the world when disasters—manmade, natural, or both—threaten to engulf life in all its wondrous variety. Those who battle extreme weather will have unique health needs, and their valiant sacrifices deserve to have health care systems ready and able to treat them.

Dispensing of prescription stimulant medications, such as methylphenidate or amphetamine salts, has been expanding at a rapid rate over the past 2 decades. An astounding 58 million stimulant medications were prescribed in 2014.^1,2 Adults now exceed youths in the proportion of prescribed stimulant medications.^1,3

Off-label use of prescription stimulant medications, such as for performance enhancement, fatigue management, weight loss, medication-assisted therapy for stimulant use disorders, and adjunctive treatment for certain depressive disorders, is reported to be ≥ 40% of total stimulant use and is much more common in adults.¹ A 2017 study assessing risk of amphetamine use disorder and mortality among veterans prescribed stimulant medications within the Veterans Health Administration (VHA) reported off-label use in nearly 3 of every 5 incident users in 2012.⁴ Off-label use also is significantly more common when prescribed by nonpsychiatric physicians compared with that of psychiatrists.¹

One study assessing stimulant prescribing from 2006 to 2009 found that nearly 60% of adults were prescribed stimulant medications by nonpsychiatrist physicians, and only 34% of those adults prescribed a stimulant by a nonpsychiatrist physician had a diagnosis of attention-deficit hyperactivity disorder (ADHD).⁵ Findings from managed care plans covering years from 2000 to 2004 were similar, concluding that 30% of the adult patients who were prescribed methylphenidate had at least 1 medical claim with a diagnosis of ADHD.⁶ Of the approximately 16 million adults prescribed stimulant medications in 2017, > 5 million of them reported stimulant misuse.³ Much attention has been focused on misuse of stimulant medications by youths and young adults, but new information suggests that increased monitoring is needed among the US adult population. Per the US Department of Veterans Affairs (VA) Academic Detailing Stimulant Dashboard, as of October 2018 the national average of veterans with a documented substance use disorder (SUD) who are also prescribed stimulant medications through the VHA exceeds 20%, < 50% have an annual urine drug screen (UDS), and > 10% are coprescribed opioids and benzodiazepines.The percentage of veterans prescribed stimulant medications in the presence of a SUD has increased over the past decade, with a reported 8.7% incidence in 2002 increasing to 14.3% in 2012.⁴

There are currently no protocols, prescribing restrictions, or required monitoring parameters in place for prescription stimulant use within the Lexington VA Health Care System (LVAHCS). The purpose of this study was to evaluate the prescribing practices at LVAHCS of stimulant medications and identify opportunities for improvement in the prescribing and monitoring of this drug class.

Methods

This study was a single-center quality improvement project evaluating the prescribing practices of stimulant medications within LVAHCS and exempt from institutional review board approval. Veterans were included in the study if they were prescribed amphetamine salts, dextroamphetamine, lisdexamphetamine, or methylphenidate between January 1, 2018 and June 30, 2018; however, the veterans’ entire stimulant use history was assessed. Exclusion criteria included duration of use of < 2 months or < 2 prescriptions filled during the study period. Data for veterans who met the prespecified inclusion and exclusion criteria were collected via chart review and Microsoft SQL Server Management Studio.

Collected data included age, gender, stimulant regimen (drug name, dose, frequency), indication and duration of use, prescriber name and specialty, prescribing origin of initial stimulant medication, and whether stimulant use predated military service. Monitoring of stimulant medications was assessed via UDS at least annually, query of the prescription drug monitoring program (PDMP) at least quarterly, and average time between follow-up appointments with stimulant prescriber.

Monitoring parameters were assessed from January 1, 2017 through June 30, 2018, as it was felt that the 6-month study period would be too narrow to accurately assess monitoring trends. Mental health diagnoses, ADHD diagnostic testing if applicable, documented SUD or stimulant misuse past or present, and concomitant central nervous system (CNS) depressant use also were collected. CNS depressants evaluated were those that have abuse potential or significant psychotropic effects and included benzodiazepines, antipsychotics, opioids, gabapentin/pregabalin, Z-hypnotics, and muscle relaxants.

Results

The majority of participants were male (168/200) with an average age of 43.3 years. Dextroamphetamine/amphetamine was the most used stimulant (48.5%), followed by methylphenidate (40%), and dextroamphetamine (10%). Lisdexamphetamine was the least used stimulant, likely due to its formulary-restricted status within this facility. An extended release (ER) formulation was utilized in 1 of 4 participants, with 1 of 20 participants prescribed a combination of immediate release (IR) and ER formulations. Duration of use ranged from 3 months to 14 years, with an average duration of 4 years (Table 1).

Nearly 40% of participants reported an origin of stimulant initiation outside of LVAHCS. Fourteen percent of participants were started on prescription stimulant medications while active-duty service members. Stimulant medications were initiated at another VA facility in 10.5% of instances, and 15% of participants reported being prescribed stimulant medications by a civilian prescriber prior to receiving them at LVAHCS. Seventy-four of 79 (93.6%) participants with an origin of stimulant prescription outside of LVAHCS reported a US Federal Food and Drug Administration (FDA)-approved indication for use. The majority (87%) of stimulant medications were prescribed by the mental health service, and 25% of initial stimulant prescriptions were written by a single mental health prescriber. Eleven percent of participants were prescribed stimulant medications by multiple specialties, and nearly all participants had > 1 stimulant prescriber over the course of their treatment. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

Stimulant medications were used for FDA-approved indications (ADHD and narcolepsy) in 69.5% of participants. Note, this included patients who maintained an ADHD diagnosis in their medical record even if it was not substantiated with diagnostic testing. Of the participants reporting ADHD as an indication for stimulant use, diagnostic testing was conducted at LVAHCS to confirm an ADHD diagnosis in 58.6% (78/133) participants; 20.5% (16/78) of these diagnostic tests did not support the diagnosis of ADHD. All documented indications for use can be found in Table 2.

Discussion

The source of the initial stimulant prescription was assessed. The majority of veterans had received medical care prior to receiving care at LVAHCS, whether on active duty, from another VA facility throughout the country, or by a private civilian prescriber. The origin of initial stimulant medication and indication for stimulant medication use were patient reported. Requiring medical records from civilian providers prior to continuing stimulant medication is prescriber-dependent and was not available for all participants.

As expected, the majority of participants (87%) received their first stimulant prescription via a prescriber in the mental health specialty, 20 were prescribed stimulant medications from primary care, 4 from the emergency department (ED), and 2 from neurology. Three of the 4 stimulant prescriptions written in the ED were for continuity of care until the veteran could have an appointment with a mental health or primary care provider, and the other was prescribed by a mental health nurse practitioner for a veteran who presented to the ED with complaints of ADHD-like symptoms. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

The reasons for discontinuation included a positive UDS result for cocaine, psychosis, broken narcotic contract, ADHD diagnosis not supported by psychological testing, chronic bipolar disorder secondary to stimulant use, diversion, stimulant misuse, and lack of indication for use. There also were a handful of veterans whose VA prescribers declined to initiate prescription stimulant medications for various reasons, so the veteran sought care from a civilian prescriber who prescribed stimulant medications, then returned to the VA for medication management, and stimulant medications were continued. Fourteen percent (28/200) of participants had multiple indications for use at some point during stimulant medication therapy. Eight of those were a reasonable change from ADHD to ADHD-like symptoms when diagnosis was not substantiated by testing. The cause of other changes in indication for use was not well documented and often unclear. One veteran had 4 different indications for use documented in the medical record, often changing with each change in prescriber. It appeared that the most recent prescriber was uncertain of the actual indication for use but did not want to discontinue the medication. This prescriber documented that the stimulant medication should continue for presumed ADHD/mood/fatigue/cognitive dysfunction, which were all of the indications documented by the veteran’s previous prescribers.

Reasons for Discontinuation

ADHD was the most prominent indication for use, although the indication was changed to ADHD-like symptoms in several veterans for whom diagnostic testing did not support the ADHD diagnosis. Seventy-eight of 133 veterans prescribed stimulant medications for ADHD received diagnostic testing via a psychologist at LVAHCS. For the 11 veterans who had testing after stimulant initiation, a stimulant-free period was required prior to testing to ensure an accurate diagnosis. For 21% of veterans, the ADHD diagnosis was unsubstantiated by formal testing; however, all of these veterans continued stimulant medication use. For 1 veteran, the psychologist performing the testing documented new diagnoses, including moderate to severe stimulant use disorder and malingering both for PTSD and ADHD. The rate of stimulant prescribing inconsistency, “prescriber-hopping,” and unsupported ADHD diagnosis results warrant a conversation about expectations for transitions of care regarding stimulant medications, not only from outside to inside LVAHCS, but from prescriber to prescriber within the facility.

In some cases, stimulant medications were discontinued by a prescriber secondary to a worsening of another mental health condition. More than half of the participants in this study had an anxiety disorder diagnosis. Whether or not anxiety predated stimulant use or whether the use of stimulant medications contributed to the diagnosis and thus the addition of an additional CNS depressant to treat anxiety may be an area of research for future consideration. Although bipolar disorder, anxiety disorders, psychosis, and SUD are not contraindications for use of stimulant medications, caution must be used in patients with these diagnoses. Prescribers must weigh risks vs benefits as well as perform close monitoring during use. Similarly, one might look further into stimulant medications prescribed for fatigue and assess the role of any simultaneously prescribed CNS depressants. Is the stimulant being used to treat the adverse effect (AE) of another medication? In 2 documented instances in this study, a psychologist conducted diagnostic testing who reported that the veteran did not meet the criteria for ADHD but that a stimulant may help counteract the iatrogenic effect of anticonvulsants. In both instances stimulant use continued.

Prescription Monitoring

Polysubstance use disorder (5%) was the third most common SUD recorded among study participants. The majority of those with polysubstance use disorder reported abuse/misuse of illicit or prescribed stimulants. Stimulant abuse/misuse was documented in 25 of 200 (12.5%) study participants. In several instances, abuse/misuse was detected by the LVAHCS delivery coordination pharmacist who tracks patterns of early fill requests and prescriptions reported lost/stolen. This pharmacist may request that the prescriber obtain PDMP query, UDS, or pill count if concerning patterns are noted. Lisdexamphetamine is a formulary-restricted medication at LVAHCS, but it was noted to be approved for use when prescribers requested an abuse-deterrent formulation. Investigators noticed a trend in veterans whose prescriptions exceeded the recommended maximum dosage also having stimulant abuse/misuse documented in their medical record. The highest documented total daily dose in this study was 120-mg amphetamine salts IR for ADHD, compared with the normal recommended dosing range of 5 to 40 mg/d for the same indication.

Various modalities were used to monitor participants but less than half of veterans had an annual UDS, quarterly PDMP query, and quarterly prescriber follow-up. PDMP queries and prescriber follow-up was assessed quarterly as would be reasonable given that private sector practitioners may issue multiple prescriptions authorizing the patient to receive up to a 90-day supply.⁷ Prescriber follow-up ranged from 1 to 15 months. A longer time to follow-up was seen more frequently in stimulant medications prescribed by primary care as compared with that of mental health.

Clinical Practice Protocol

Data from this study were collected with the intent to identify opportunities for improvement in the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a facility-specific clinical practice protocol (CPP) for stimulant prescribing. It may also be beneficial to formulate a chronic stimulant management agreement between patient and prescriber to provide informed consent and clear expectations prior to stimulant medication initiation.

A CPP could be used to establish stimulant prescribing rules within a facility, which may limit who can prescribe stimulant medications or include a review process and/or required documentation in the medical record when being prescribed outside of specified dosing range and indications for use designated in the CPP or other evidence-based guidelines. Transition of care was found to be an area of opportunity in this study, which could be mitigated with the requirement of a baseline assessment prior to stimulant initiation with the expectation that it be completed regardless of prior prescription stimulant medication use. There was a lack of consistent monitoring for participants in this study, which may be improved if required monitoring parameters and frequency were provided for prescribers. For example, monitoring of heart rate and blood pressure was not assessed in this study, but a CPP may include monitoring vital signs before and after each dose change and every 6 months, per recommendation from the National Institute for Health and Care Excellence ADHD Diagnosis and Management guideline published in 2018.⁸The CPP may list the responsibilities of all those involved in the prescribing of stimulant medications, such as mental health service leadership, prescribers, nursing staff, pharmacists, social workers, psychologists, and other mental health staff. For prescribers this may include a thorough baseline assessment and criteria for use that must be met prior to stimulant initiation, documentation that must be included in the medical record and required monitoring during stimulant treatment, and expectations for increased monitoring and/or termination of treatment with nonadherence, diversion, or abuse/misuse.

The responsibilities of pharmacists may include establishing criteria for use of nonformulary and restricted agents as well as completion of nonformulary/restricted requests, reviewing dosages that exceed the recommended FDA daily maximum, reviewing uncommon off-label uses of stimulant medications, review and document early fill requests, potential nonadherence, potential drug-seeking behavior, and communication of the following information to the primary prescriber. For other mental health staff this may include documenting any reported AEs of the medication, referring the patient to their prescriber or pharmacist for any medication questions or concerns, and assessment of effectiveness and/or worsening behavior during patient contact.

Limitations

One limitation of this study was the way that data were pulled from patient charts. For example, only 3/200 participants in this study had insomnia per diagnosis codes, whereas that number was substantially higher when chart review was used to assess active prescriptions for sleep aids or documented complaints of insomnia in prescriber progress notes. For this same reason, rates of SUDs must be interpreted with caution as well. SUD diagnosis, both current and in remission were taken into account during data collection. Per diagnosis codes, 36 (18%) veterans in this study had a history of SUD, but this number was higher (31.5%) during chart review. The majority of discrepancies were found when participants reported a history of SUD to the prescriber, but this information was not captured via the problem list or encounter codes. What some may consider a minor omission in documentation can have a large impact on patient care as it is unlikely that prescribers have adequate administrative time to complete a chart review in order to find a complete past medical history as was required of investigators in this study. For this reason, incomplete provider documentation and human error that can occur as a result of a retrospective chart review were also identified as study limitations.

Conclusion

Our data show that there is still substantial room for improvement in the prescribing and monitoring of stimulant medications. The rate of stimulant prescribing inconsistency, prescriber-hopping, and unsupported ADHD diagnosis resulting from formal diagnostic testing warrant a review in the processes for transition of care regarding stimulant medications, both within and outside of this facility. A lack of consistent monitoring was also identified in this study. One of the most appreciable areas of opportunity resulting from this study is the need for consistency in both the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a CPP for stimulant prescribing as well as a chronic stimulant management agreement to provide clear expectations for patients and prescribers prior to and during prescription stimulant use.

Acknowledgments 

We thank Tori Wilhoit, PharmD candidate, and Dana Fischer, PharmD candidate, for their participation in data collection and Courtney Eatmon, PharmD, BCPP, for her general administrative support throughout this study.

Dispensing of prescription stimulant medications, such as methylphenidate or amphetamine salts, has been expanding at a rapid rate over the past 2 decades. An astounding 58 million stimulant medications were prescribed in 2014.^1,2 Adults now exceed youths in the proportion of prescribed stimulant medications.^1,3

Off-label use of prescription stimulant medications, such as for performance enhancement, fatigue management, weight loss, medication-assisted therapy for stimulant use disorders, and adjunctive treatment for certain depressive disorders, is reported to be ≥ 40% of total stimulant use and is much more common in adults.¹ A 2017 study assessing risk of amphetamine use disorder and mortality among veterans prescribed stimulant medications within the Veterans Health Administration (VHA) reported off-label use in nearly 3 of every 5 incident users in 2012.⁴ Off-label use also is significantly more common when prescribed by nonpsychiatric physicians compared with that of psychiatrists.¹

One study assessing stimulant prescribing from 2006 to 2009 found that nearly 60% of adults were prescribed stimulant medications by nonpsychiatrist physicians, and only 34% of those adults prescribed a stimulant by a nonpsychiatrist physician had a diagnosis of attention-deficit hyperactivity disorder (ADHD).⁵ Findings from managed care plans covering years from 2000 to 2004 were similar, concluding that 30% of the adult patients who were prescribed methylphenidate had at least 1 medical claim with a diagnosis of ADHD.⁶ Of the approximately 16 million adults prescribed stimulant medications in 2017, > 5 million of them reported stimulant misuse.³ Much attention has been focused on misuse of stimulant medications by youths and young adults, but new information suggests that increased monitoring is needed among the US adult population. Per the US Department of Veterans Affairs (VA) Academic Detailing Stimulant Dashboard, as of October 2018 the national average of veterans with a documented substance use disorder (SUD) who are also prescribed stimulant medications through the VHA exceeds 20%, < 50% have an annual urine drug screen (UDS), and > 10% are coprescribed opioids and benzodiazepines.The percentage of veterans prescribed stimulant medications in the presence of a SUD has increased over the past decade, with a reported 8.7% incidence in 2002 increasing to 14.3% in 2012.⁴

There are currently no protocols, prescribing restrictions, or required monitoring parameters in place for prescription stimulant use within the Lexington VA Health Care System (LVAHCS). The purpose of this study was to evaluate the prescribing practices at LVAHCS of stimulant medications and identify opportunities for improvement in the prescribing and monitoring of this drug class.

Methods

This study was a single-center quality improvement project evaluating the prescribing practices of stimulant medications within LVAHCS and exempt from institutional review board approval. Veterans were included in the study if they were prescribed amphetamine salts, dextroamphetamine, lisdexamphetamine, or methylphenidate between January 1, 2018 and June 30, 2018; however, the veterans’ entire stimulant use history was assessed. Exclusion criteria included duration of use of < 2 months or < 2 prescriptions filled during the study period. Data for veterans who met the prespecified inclusion and exclusion criteria were collected via chart review and Microsoft SQL Server Management Studio.

Collected data included age, gender, stimulant regimen (drug name, dose, frequency), indication and duration of use, prescriber name and specialty, prescribing origin of initial stimulant medication, and whether stimulant use predated military service. Monitoring of stimulant medications was assessed via UDS at least annually, query of the prescription drug monitoring program (PDMP) at least quarterly, and average time between follow-up appointments with stimulant prescriber.

Monitoring parameters were assessed from January 1, 2017 through June 30, 2018, as it was felt that the 6-month study period would be too narrow to accurately assess monitoring trends. Mental health diagnoses, ADHD diagnostic testing if applicable, documented SUD or stimulant misuse past or present, and concomitant central nervous system (CNS) depressant use also were collected. CNS depressants evaluated were those that have abuse potential or significant psychotropic effects and included benzodiazepines, antipsychotics, opioids, gabapentin/pregabalin, Z-hypnotics, and muscle relaxants.

Results

The majority of participants were male (168/200) with an average age of 43.3 years. Dextroamphetamine/amphetamine was the most used stimulant (48.5%), followed by methylphenidate (40%), and dextroamphetamine (10%). Lisdexamphetamine was the least used stimulant, likely due to its formulary-restricted status within this facility. An extended release (ER) formulation was utilized in 1 of 4 participants, with 1 of 20 participants prescribed a combination of immediate release (IR) and ER formulations. Duration of use ranged from 3 months to 14 years, with an average duration of 4 years (Table 1).

Nearly 40% of participants reported an origin of stimulant initiation outside of LVAHCS. Fourteen percent of participants were started on prescription stimulant medications while active-duty service members. Stimulant medications were initiated at another VA facility in 10.5% of instances, and 15% of participants reported being prescribed stimulant medications by a civilian prescriber prior to receiving them at LVAHCS. Seventy-four of 79 (93.6%) participants with an origin of stimulant prescription outside of LVAHCS reported a US Federal Food and Drug Administration (FDA)-approved indication for use. The majority (87%) of stimulant medications were prescribed by the mental health service, and 25% of initial stimulant prescriptions were written by a single mental health prescriber. Eleven percent of participants were prescribed stimulant medications by multiple specialties, and nearly all participants had > 1 stimulant prescriber over the course of their treatment. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

Stimulant medications were used for FDA-approved indications (ADHD and narcolepsy) in 69.5% of participants. Note, this included patients who maintained an ADHD diagnosis in their medical record even if it was not substantiated with diagnostic testing. Of the participants reporting ADHD as an indication for stimulant use, diagnostic testing was conducted at LVAHCS to confirm an ADHD diagnosis in 58.6% (78/133) participants; 20.5% (16/78) of these diagnostic tests did not support the diagnosis of ADHD. All documented indications for use can be found in Table 2.

Discussion

The source of the initial stimulant prescription was assessed. The majority of veterans had received medical care prior to receiving care at LVAHCS, whether on active duty, from another VA facility throughout the country, or by a private civilian prescriber. The origin of initial stimulant medication and indication for stimulant medication use were patient reported. Requiring medical records from civilian providers prior to continuing stimulant medication is prescriber-dependent and was not available for all participants.

As expected, the majority of participants (87%) received their first stimulant prescription via a prescriber in the mental health specialty, 20 were prescribed stimulant medications from primary care, 4 from the emergency department (ED), and 2 from neurology. Three of the 4 stimulant prescriptions written in the ED were for continuity of care until the veteran could have an appointment with a mental health or primary care provider, and the other was prescribed by a mental health nurse practitioner for a veteran who presented to the ED with complaints of ADHD-like symptoms. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

The reasons for discontinuation included a positive UDS result for cocaine, psychosis, broken narcotic contract, ADHD diagnosis not supported by psychological testing, chronic bipolar disorder secondary to stimulant use, diversion, stimulant misuse, and lack of indication for use. There also were a handful of veterans whose VA prescribers declined to initiate prescription stimulant medications for various reasons, so the veteran sought care from a civilian prescriber who prescribed stimulant medications, then returned to the VA for medication management, and stimulant medications were continued. Fourteen percent (28/200) of participants had multiple indications for use at some point during stimulant medication therapy. Eight of those were a reasonable change from ADHD to ADHD-like symptoms when diagnosis was not substantiated by testing. The cause of other changes in indication for use was not well documented and often unclear. One veteran had 4 different indications for use documented in the medical record, often changing with each change in prescriber. It appeared that the most recent prescriber was uncertain of the actual indication for use but did not want to discontinue the medication. This prescriber documented that the stimulant medication should continue for presumed ADHD/mood/fatigue/cognitive dysfunction, which were all of the indications documented by the veteran’s previous prescribers.

Reasons for Discontinuation

ADHD was the most prominent indication for use, although the indication was changed to ADHD-like symptoms in several veterans for whom diagnostic testing did not support the ADHD diagnosis. Seventy-eight of 133 veterans prescribed stimulant medications for ADHD received diagnostic testing via a psychologist at LVAHCS. For the 11 veterans who had testing after stimulant initiation, a stimulant-free period was required prior to testing to ensure an accurate diagnosis. For 21% of veterans, the ADHD diagnosis was unsubstantiated by formal testing; however, all of these veterans continued stimulant medication use. For 1 veteran, the psychologist performing the testing documented new diagnoses, including moderate to severe stimulant use disorder and malingering both for PTSD and ADHD. The rate of stimulant prescribing inconsistency, “prescriber-hopping,” and unsupported ADHD diagnosis results warrant a conversation about expectations for transitions of care regarding stimulant medications, not only from outside to inside LVAHCS, but from prescriber to prescriber within the facility.

In some cases, stimulant medications were discontinued by a prescriber secondary to a worsening of another mental health condition. More than half of the participants in this study had an anxiety disorder diagnosis. Whether or not anxiety predated stimulant use or whether the use of stimulant medications contributed to the diagnosis and thus the addition of an additional CNS depressant to treat anxiety may be an area of research for future consideration. Although bipolar disorder, anxiety disorders, psychosis, and SUD are not contraindications for use of stimulant medications, caution must be used in patients with these diagnoses. Prescribers must weigh risks vs benefits as well as perform close monitoring during use. Similarly, one might look further into stimulant medications prescribed for fatigue and assess the role of any simultaneously prescribed CNS depressants. Is the stimulant being used to treat the adverse effect (AE) of another medication? In 2 documented instances in this study, a psychologist conducted diagnostic testing who reported that the veteran did not meet the criteria for ADHD but that a stimulant may help counteract the iatrogenic effect of anticonvulsants. In both instances stimulant use continued.

Prescription Monitoring

Polysubstance use disorder (5%) was the third most common SUD recorded among study participants. The majority of those with polysubstance use disorder reported abuse/misuse of illicit or prescribed stimulants. Stimulant abuse/misuse was documented in 25 of 200 (12.5%) study participants. In several instances, abuse/misuse was detected by the LVAHCS delivery coordination pharmacist who tracks patterns of early fill requests and prescriptions reported lost/stolen. This pharmacist may request that the prescriber obtain PDMP query, UDS, or pill count if concerning patterns are noted. Lisdexamphetamine is a formulary-restricted medication at LVAHCS, but it was noted to be approved for use when prescribers requested an abuse-deterrent formulation. Investigators noticed a trend in veterans whose prescriptions exceeded the recommended maximum dosage also having stimulant abuse/misuse documented in their medical record. The highest documented total daily dose in this study was 120-mg amphetamine salts IR for ADHD, compared with the normal recommended dosing range of 5 to 40 mg/d for the same indication.

Various modalities were used to monitor participants but less than half of veterans had an annual UDS, quarterly PDMP query, and quarterly prescriber follow-up. PDMP queries and prescriber follow-up was assessed quarterly as would be reasonable given that private sector practitioners may issue multiple prescriptions authorizing the patient to receive up to a 90-day supply.⁷ Prescriber follow-up ranged from 1 to 15 months. A longer time to follow-up was seen more frequently in stimulant medications prescribed by primary care as compared with that of mental health.

Clinical Practice Protocol

Data from this study were collected with the intent to identify opportunities for improvement in the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a facility-specific clinical practice protocol (CPP) for stimulant prescribing. It may also be beneficial to formulate a chronic stimulant management agreement between patient and prescriber to provide informed consent and clear expectations prior to stimulant medication initiation.

A CPP could be used to establish stimulant prescribing rules within a facility, which may limit who can prescribe stimulant medications or include a review process and/or required documentation in the medical record when being prescribed outside of specified dosing range and indications for use designated in the CPP or other evidence-based guidelines. Transition of care was found to be an area of opportunity in this study, which could be mitigated with the requirement of a baseline assessment prior to stimulant initiation with the expectation that it be completed regardless of prior prescription stimulant medication use. There was a lack of consistent monitoring for participants in this study, which may be improved if required monitoring parameters and frequency were provided for prescribers. For example, monitoring of heart rate and blood pressure was not assessed in this study, but a CPP may include monitoring vital signs before and after each dose change and every 6 months, per recommendation from the National Institute for Health and Care Excellence ADHD Diagnosis and Management guideline published in 2018.⁸The CPP may list the responsibilities of all those involved in the prescribing of stimulant medications, such as mental health service leadership, prescribers, nursing staff, pharmacists, social workers, psychologists, and other mental health staff. For prescribers this may include a thorough baseline assessment and criteria for use that must be met prior to stimulant initiation, documentation that must be included in the medical record and required monitoring during stimulant treatment, and expectations for increased monitoring and/or termination of treatment with nonadherence, diversion, or abuse/misuse.

The responsibilities of pharmacists may include establishing criteria for use of nonformulary and restricted agents as well as completion of nonformulary/restricted requests, reviewing dosages that exceed the recommended FDA daily maximum, reviewing uncommon off-label uses of stimulant medications, review and document early fill requests, potential nonadherence, potential drug-seeking behavior, and communication of the following information to the primary prescriber. For other mental health staff this may include documenting any reported AEs of the medication, referring the patient to their prescriber or pharmacist for any medication questions or concerns, and assessment of effectiveness and/or worsening behavior during patient contact.

Limitations

One limitation of this study was the way that data were pulled from patient charts. For example, only 3/200 participants in this study had insomnia per diagnosis codes, whereas that number was substantially higher when chart review was used to assess active prescriptions for sleep aids or documented complaints of insomnia in prescriber progress notes. For this same reason, rates of SUDs must be interpreted with caution as well. SUD diagnosis, both current and in remission were taken into account during data collection. Per diagnosis codes, 36 (18%) veterans in this study had a history of SUD, but this number was higher (31.5%) during chart review. The majority of discrepancies were found when participants reported a history of SUD to the prescriber, but this information was not captured via the problem list or encounter codes. What some may consider a minor omission in documentation can have a large impact on patient care as it is unlikely that prescribers have adequate administrative time to complete a chart review in order to find a complete past medical history as was required of investigators in this study. For this reason, incomplete provider documentation and human error that can occur as a result of a retrospective chart review were also identified as study limitations.

Conclusion

Our data show that there is still substantial room for improvement in the prescribing and monitoring of stimulant medications. The rate of stimulant prescribing inconsistency, prescriber-hopping, and unsupported ADHD diagnosis resulting from formal diagnostic testing warrant a review in the processes for transition of care regarding stimulant medications, both within and outside of this facility. A lack of consistent monitoring was also identified in this study. One of the most appreciable areas of opportunity resulting from this study is the need for consistency in both the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a CPP for stimulant prescribing as well as a chronic stimulant management agreement to provide clear expectations for patients and prescribers prior to and during prescription stimulant use.

Acknowledgments 

We thank Tori Wilhoit, PharmD candidate, and Dana Fischer, PharmD candidate, for their participation in data collection and Courtney Eatmon, PharmD, BCPP, for her general administrative support throughout this study.

Dispensing of prescription stimulant medications, such as methylphenidate or amphetamine salts, has been expanding at a rapid rate over the past 2 decades. An astounding 58 million stimulant medications were prescribed in 2014.^1,2 Adults now exceed youths in the proportion of prescribed stimulant medications.^1,3

Off-label use of prescription stimulant medications, such as for performance enhancement, fatigue management, weight loss, medication-assisted therapy for stimulant use disorders, and adjunctive treatment for certain depressive disorders, is reported to be ≥ 40% of total stimulant use and is much more common in adults.¹ A 2017 study assessing risk of amphetamine use disorder and mortality among veterans prescribed stimulant medications within the Veterans Health Administration (VHA) reported off-label use in nearly 3 of every 5 incident users in 2012.⁴ Off-label use also is significantly more common when prescribed by nonpsychiatric physicians compared with that of psychiatrists.¹

One study assessing stimulant prescribing from 2006 to 2009 found that nearly 60% of adults were prescribed stimulant medications by nonpsychiatrist physicians, and only 34% of those adults prescribed a stimulant by a nonpsychiatrist physician had a diagnosis of attention-deficit hyperactivity disorder (ADHD).⁵ Findings from managed care plans covering years from 2000 to 2004 were similar, concluding that 30% of the adult patients who were prescribed methylphenidate had at least 1 medical claim with a diagnosis of ADHD.⁶ Of the approximately 16 million adults prescribed stimulant medications in 2017, > 5 million of them reported stimulant misuse.³ Much attention has been focused on misuse of stimulant medications by youths and young adults, but new information suggests that increased monitoring is needed among the US adult population. Per the US Department of Veterans Affairs (VA) Academic Detailing Stimulant Dashboard, as of October 2018 the national average of veterans with a documented substance use disorder (SUD) who are also prescribed stimulant medications through the VHA exceeds 20%, < 50% have an annual urine drug screen (UDS), and > 10% are coprescribed opioids and benzodiazepines.The percentage of veterans prescribed stimulant medications in the presence of a SUD has increased over the past decade, with a reported 8.7% incidence in 2002 increasing to 14.3% in 2012.⁴

There are currently no protocols, prescribing restrictions, or required monitoring parameters in place for prescription stimulant use within the Lexington VA Health Care System (LVAHCS). The purpose of this study was to evaluate the prescribing practices at LVAHCS of stimulant medications and identify opportunities for improvement in the prescribing and monitoring of this drug class.

Methods

This study was a single-center quality improvement project evaluating the prescribing practices of stimulant medications within LVAHCS and exempt from institutional review board approval. Veterans were included in the study if they were prescribed amphetamine salts, dextroamphetamine, lisdexamphetamine, or methylphenidate between January 1, 2018 and June 30, 2018; however, the veterans’ entire stimulant use history was assessed. Exclusion criteria included duration of use of < 2 months or < 2 prescriptions filled during the study period. Data for veterans who met the prespecified inclusion and exclusion criteria were collected via chart review and Microsoft SQL Server Management Studio.

Collected data included age, gender, stimulant regimen (drug name, dose, frequency), indication and duration of use, prescriber name and specialty, prescribing origin of initial stimulant medication, and whether stimulant use predated military service. Monitoring of stimulant medications was assessed via UDS at least annually, query of the prescription drug monitoring program (PDMP) at least quarterly, and average time between follow-up appointments with stimulant prescriber.

Monitoring parameters were assessed from January 1, 2017 through June 30, 2018, as it was felt that the 6-month study period would be too narrow to accurately assess monitoring trends. Mental health diagnoses, ADHD diagnostic testing if applicable, documented SUD or stimulant misuse past or present, and concomitant central nervous system (CNS) depressant use also were collected. CNS depressants evaluated were those that have abuse potential or significant psychotropic effects and included benzodiazepines, antipsychotics, opioids, gabapentin/pregabalin, Z-hypnotics, and muscle relaxants.

Results

The majority of participants were male (168/200) with an average age of 43.3 years. Dextroamphetamine/amphetamine was the most used stimulant (48.5%), followed by methylphenidate (40%), and dextroamphetamine (10%). Lisdexamphetamine was the least used stimulant, likely due to its formulary-restricted status within this facility. An extended release (ER) formulation was utilized in 1 of 4 participants, with 1 of 20 participants prescribed a combination of immediate release (IR) and ER formulations. Duration of use ranged from 3 months to 14 years, with an average duration of 4 years (Table 1).

Nearly 40% of participants reported an origin of stimulant initiation outside of LVAHCS. Fourteen percent of participants were started on prescription stimulant medications while active-duty service members. Stimulant medications were initiated at another VA facility in 10.5% of instances, and 15% of participants reported being prescribed stimulant medications by a civilian prescriber prior to receiving them at LVAHCS. Seventy-four of 79 (93.6%) participants with an origin of stimulant prescription outside of LVAHCS reported a US Federal Food and Drug Administration (FDA)-approved indication for use. The majority (87%) of stimulant medications were prescribed by the mental health service, and 25% of initial stimulant prescriptions were written by a single mental health prescriber. Eleven percent of participants were prescribed stimulant medications by multiple specialties, and nearly all participants had > 1 stimulant prescriber over the course of their treatment. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

Stimulant medications were used for FDA-approved indications (ADHD and narcolepsy) in 69.5% of participants. Note, this included patients who maintained an ADHD diagnosis in their medical record even if it was not substantiated with diagnostic testing. Of the participants reporting ADHD as an indication for stimulant use, diagnostic testing was conducted at LVAHCS to confirm an ADHD diagnosis in 58.6% (78/133) participants; 20.5% (16/78) of these diagnostic tests did not support the diagnosis of ADHD. All documented indications for use can be found in Table 2.

Discussion

The source of the initial stimulant prescription was assessed. The majority of veterans had received medical care prior to receiving care at LVAHCS, whether on active duty, from another VA facility throughout the country, or by a private civilian prescriber. The origin of initial stimulant medication and indication for stimulant medication use were patient reported. Requiring medical records from civilian providers prior to continuing stimulant medication is prescriber-dependent and was not available for all participants.

As expected, the majority of participants (87%) received their first stimulant prescription via a prescriber in the mental health specialty, 20 were prescribed stimulant medications from primary care, 4 from the emergency department (ED), and 2 from neurology. Three of the 4 stimulant prescriptions written in the ED were for continuity of care until the veteran could have an appointment with a mental health or primary care provider, and the other was prescribed by a mental health nurse practitioner for a veteran who presented to the ED with complaints of ADHD-like symptoms. More than 10% of veterans had their stimulant medication discontinued by one prescriber and then restarted by another prescriber.

The reasons for discontinuation included a positive UDS result for cocaine, psychosis, broken narcotic contract, ADHD diagnosis not supported by psychological testing, chronic bipolar disorder secondary to stimulant use, diversion, stimulant misuse, and lack of indication for use. There also were a handful of veterans whose VA prescribers declined to initiate prescription stimulant medications for various reasons, so the veteran sought care from a civilian prescriber who prescribed stimulant medications, then returned to the VA for medication management, and stimulant medications were continued. Fourteen percent (28/200) of participants had multiple indications for use at some point during stimulant medication therapy. Eight of those were a reasonable change from ADHD to ADHD-like symptoms when diagnosis was not substantiated by testing. The cause of other changes in indication for use was not well documented and often unclear. One veteran had 4 different indications for use documented in the medical record, often changing with each change in prescriber. It appeared that the most recent prescriber was uncertain of the actual indication for use but did not want to discontinue the medication. This prescriber documented that the stimulant medication should continue for presumed ADHD/mood/fatigue/cognitive dysfunction, which were all of the indications documented by the veteran’s previous prescribers.

Reasons for Discontinuation

ADHD was the most prominent indication for use, although the indication was changed to ADHD-like symptoms in several veterans for whom diagnostic testing did not support the ADHD diagnosis. Seventy-eight of 133 veterans prescribed stimulant medications for ADHD received diagnostic testing via a psychologist at LVAHCS. For the 11 veterans who had testing after stimulant initiation, a stimulant-free period was required prior to testing to ensure an accurate diagnosis. For 21% of veterans, the ADHD diagnosis was unsubstantiated by formal testing; however, all of these veterans continued stimulant medication use. For 1 veteran, the psychologist performing the testing documented new diagnoses, including moderate to severe stimulant use disorder and malingering both for PTSD and ADHD. The rate of stimulant prescribing inconsistency, “prescriber-hopping,” and unsupported ADHD diagnosis results warrant a conversation about expectations for transitions of care regarding stimulant medications, not only from outside to inside LVAHCS, but from prescriber to prescriber within the facility.

In some cases, stimulant medications were discontinued by a prescriber secondary to a worsening of another mental health condition. More than half of the participants in this study had an anxiety disorder diagnosis. Whether or not anxiety predated stimulant use or whether the use of stimulant medications contributed to the diagnosis and thus the addition of an additional CNS depressant to treat anxiety may be an area of research for future consideration. Although bipolar disorder, anxiety disorders, psychosis, and SUD are not contraindications for use of stimulant medications, caution must be used in patients with these diagnoses. Prescribers must weigh risks vs benefits as well as perform close monitoring during use. Similarly, one might look further into stimulant medications prescribed for fatigue and assess the role of any simultaneously prescribed CNS depressants. Is the stimulant being used to treat the adverse effect (AE) of another medication? In 2 documented instances in this study, a psychologist conducted diagnostic testing who reported that the veteran did not meet the criteria for ADHD but that a stimulant may help counteract the iatrogenic effect of anticonvulsants. In both instances stimulant use continued.

Prescription Monitoring

Polysubstance use disorder (5%) was the third most common SUD recorded among study participants. The majority of those with polysubstance use disorder reported abuse/misuse of illicit or prescribed stimulants. Stimulant abuse/misuse was documented in 25 of 200 (12.5%) study participants. In several instances, abuse/misuse was detected by the LVAHCS delivery coordination pharmacist who tracks patterns of early fill requests and prescriptions reported lost/stolen. This pharmacist may request that the prescriber obtain PDMP query, UDS, or pill count if concerning patterns are noted. Lisdexamphetamine is a formulary-restricted medication at LVAHCS, but it was noted to be approved for use when prescribers requested an abuse-deterrent formulation. Investigators noticed a trend in veterans whose prescriptions exceeded the recommended maximum dosage also having stimulant abuse/misuse documented in their medical record. The highest documented total daily dose in this study was 120-mg amphetamine salts IR for ADHD, compared with the normal recommended dosing range of 5 to 40 mg/d for the same indication.

Various modalities were used to monitor participants but less than half of veterans had an annual UDS, quarterly PDMP query, and quarterly prescriber follow-up. PDMP queries and prescriber follow-up was assessed quarterly as would be reasonable given that private sector practitioners may issue multiple prescriptions authorizing the patient to receive up to a 90-day supply.⁷ Prescriber follow-up ranged from 1 to 15 months. A longer time to follow-up was seen more frequently in stimulant medications prescribed by primary care as compared with that of mental health.

Clinical Practice Protocol

Data from this study were collected with the intent to identify opportunities for improvement in the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a facility-specific clinical practice protocol (CPP) for stimulant prescribing. It may also be beneficial to formulate a chronic stimulant management agreement between patient and prescriber to provide informed consent and clear expectations prior to stimulant medication initiation.

A CPP could be used to establish stimulant prescribing rules within a facility, which may limit who can prescribe stimulant medications or include a review process and/or required documentation in the medical record when being prescribed outside of specified dosing range and indications for use designated in the CPP or other evidence-based guidelines. Transition of care was found to be an area of opportunity in this study, which could be mitigated with the requirement of a baseline assessment prior to stimulant initiation with the expectation that it be completed regardless of prior prescription stimulant medication use. There was a lack of consistent monitoring for participants in this study, which may be improved if required monitoring parameters and frequency were provided for prescribers. For example, monitoring of heart rate and blood pressure was not assessed in this study, but a CPP may include monitoring vital signs before and after each dose change and every 6 months, per recommendation from the National Institute for Health and Care Excellence ADHD Diagnosis and Management guideline published in 2018.⁸The CPP may list the responsibilities of all those involved in the prescribing of stimulant medications, such as mental health service leadership, prescribers, nursing staff, pharmacists, social workers, psychologists, and other mental health staff. For prescribers this may include a thorough baseline assessment and criteria for use that must be met prior to stimulant initiation, documentation that must be included in the medical record and required monitoring during stimulant treatment, and expectations for increased monitoring and/or termination of treatment with nonadherence, diversion, or abuse/misuse.

The responsibilities of pharmacists may include establishing criteria for use of nonformulary and restricted agents as well as completion of nonformulary/restricted requests, reviewing dosages that exceed the recommended FDA daily maximum, reviewing uncommon off-label uses of stimulant medications, review and document early fill requests, potential nonadherence, potential drug-seeking behavior, and communication of the following information to the primary prescriber. For other mental health staff this may include documenting any reported AEs of the medication, referring the patient to their prescriber or pharmacist for any medication questions or concerns, and assessment of effectiveness and/or worsening behavior during patient contact.

Limitations

One limitation of this study was the way that data were pulled from patient charts. For example, only 3/200 participants in this study had insomnia per diagnosis codes, whereas that number was substantially higher when chart review was used to assess active prescriptions for sleep aids or documented complaints of insomnia in prescriber progress notes. For this same reason, rates of SUDs must be interpreted with caution as well. SUD diagnosis, both current and in remission were taken into account during data collection. Per diagnosis codes, 36 (18%) veterans in this study had a history of SUD, but this number was higher (31.5%) during chart review. The majority of discrepancies were found when participants reported a history of SUD to the prescriber, but this information was not captured via the problem list or encounter codes. What some may consider a minor omission in documentation can have a large impact on patient care as it is unlikely that prescribers have adequate administrative time to complete a chart review in order to find a complete past medical history as was required of investigators in this study. For this reason, incomplete provider documentation and human error that can occur as a result of a retrospective chart review were also identified as study limitations.

Conclusion

Our data show that there is still substantial room for improvement in the prescribing and monitoring of stimulant medications. The rate of stimulant prescribing inconsistency, prescriber-hopping, and unsupported ADHD diagnosis resulting from formal diagnostic testing warrant a review in the processes for transition of care regarding stimulant medications, both within and outside of this facility. A lack of consistent monitoring was also identified in this study. One of the most appreciable areas of opportunity resulting from this study is the need for consistency in both the prescribing and monitoring of stimulant medications. From the above results investigators concluded that this facility may benefit from implementation of a CPP for stimulant prescribing as well as a chronic stimulant management agreement to provide clear expectations for patients and prescribers prior to and during prescription stimulant use.

Acknowledgments 

We thank Tori Wilhoit, PharmD candidate, and Dana Fischer, PharmD candidate, for their participation in data collection and Courtney Eatmon, PharmD, BCPP, for her general administrative support throughout this study.

The Veterans Health Administration (VHA) provides care for 9 million veterans at 1,255 health care sites linked to one of 170 local medical systems.¹ Recognizing that providing timely care requires effective access management, the US Congress mandated training of VHA staff to manage and improve access to care but did not provide additional local funds for new positions.² In response, the VHA created the group practice manager (GPM), a new position responsible for improving clinical practice management and unifying access improvement across leadership levels, professions, and services within each local medical system.

In May 2015, the VHA began hiring and training GPMs to spearhead management of access to services. The US Department of Veterans Affairs (VA) Office of Veteran Access to Care spearheaded GPM training, including face-to-face sessions, national calls, webinars, and educational materials. Five local medical systems were selected by the VA Office of Veteran Access to Care to implement the GPM role to allow for an early evaluation of the program that would inform a subsequent nationwide rollout. Implementation of the GPM role remained in the hands of local medical systems.

Longer wait times are shown to impact patient health.^3,4 Open access scheduling and other patient-centered access management interventions have been shown to improve availability of primary care appointments.⁵ However, little empirical evidence exists regarding the managers who focus on clinic access interventions. While the nonpeer-reviewed literature includes references to such roles, including GPMs, the empirical literature has focused on external practice faciliators,^6-8 “mid-level managers,”⁹ and clinic staff.¹⁰ We found no peer-reviewed articles on the needs and experiences of practice managers who are focused on improving access. The purpose of this study was to examine GPM prototype sites to both enhance subsequent nationwide implementation and to advance empirical literature on managing patient access within health care.

Methods

In 2015, the VA identified 5 prototype sites representing diverse geographic locations, size, and complexity for the implementation of the GPM role (Table 1). These sites self-identified as having clinical practice management experience. GPMs attended 4 training sessions between February and August 2015.

Data Collection

Participants from each prototype site included GPMs, national trainers, clinic leaders, and frontline staff. Table 2 includes the roles and sample size. Participants were recruited through purposive sampling followed by snowball sampling until thematic saturation was reached (the point at which subsequent data fail to produce new findings across sites and roles of interest).

Guided by the Consolidated Framework for Implementation Research (CFIR), the research team developed semistructured interview guides tailored to participants’ roles to elicit rich descriptions regarding overall impressions, practice management strategies, goals, activities, relationship to clinic roles, data analytics usage, challenges, barriers, and facilitators.¹¹ These guides included open-ended questions and structured prompts utilizing participant language for follow-up probes to minimize interviewing bias (eAppendix:

Data Analysis

Data were analyzed using iterative deductive and inductive content analysis.¹² Deductive content analysis consisted of identifying quotes that fit within preidentified categories (ie, perceptions of national effort, organizational structure for GPM, challenges, facilitators, metrics and tools, and mobilizing access culture) developed by the interdisciplinary research team. Further content analysis entailed open-coding and iteratively revisiting and reconciling codes associated within each preidentified category as new codes emerged. The team analyzed the resulting codes to inductively and iteratively identify and stabilize themes regarding the GPM role: roles and tasks, GPM characteristics, issues, and challenges. Through this process we moved coded data to reconciled descriptions suited to addressing the purposes of this study. Dedoose 7.0.23 software was used for qualitative data management and analysis.

Results

The study identified participants’ overall impressions of the GPM initiative and key themes within 4 major domains regarding implementing the GPM role: roles and tasks (implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff); GPM characteristics (familiarity with clinical services, knowledge of VHA systems, ability to analyze patient data, communication skills, and the ability to work with others); and issues, and challenges (technical, social, and structural).

Overall Impressions

Interviewees perceived the GPM initiative as a consolidation of existing distributed responsibilities into one role that directly reported to local top-level management with indirect reporting to national leaders. Many of the sites reported that they had designated or planned to designate a role resembling the GPM prior to the initiative. “There are staff who’ve been doing some of this work all along,” a GPM noted. “We just didn’t have them grouped together. They weren’t necessarily all working in the same type of service under the same type of structure.”

Whether the GPM position was new or not, participants referenced the importance and challenges of engaging the local facility in recognizing the agency associated with the GPM position. According to national support, the staff are trying to get the facility to understand “why the group practice manager is so important… we’ve got to embed that standard position in the system.”

While the GPM was recognized as the hub of access management, respondents recognized that transformation regarding access involved many players. “We have to create [an] orchestrated team inside each facility,” an advisor argued.

Respondents discussed how the initiative allows local facilities to appoint a specific person with a specific title and role who helps facilitate, organize, and legitimize an access focus at their sites. One GPM interviewee noted how the initiative helped refocus some of their previously less centralized efforts. “We’ve always looked at productivity; we’ve always looked at access; we’ve always looked at efficiency. I think the bigger difference is now there are individuals identified in the clinics, as practice managers as well…I interact with them. They interact with individual clinic staff, and it’s more of a group process than a single individual.”

The value of having tools available and being able to track and manage patient care as a specific example of the positive impact of this new role was noted by participants. A GPM noted that many health care providers will be happy to have tools to better manage their services and a process “that flows from a service level all the way up to executive management, where there is a common interest in making those things happen—I think that’s going to be a tremendous help.”

Participants expressed concern that the national GPM rollout would be a one-size-fits-all approach. These respondents emphasized the need to have the flexibility to customize their activities to meet their unique site and patient needs.

GPM Roles and Tasks

Participants described 4 primary roles that the GPM was expected to fill: implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff. Some activities overlapped in that they served to support multiple role areas (Figure 1).

Implementing clinic practice management. In the early stages of the initiative, the GPM’s primary role was to prepare the facility to implement a standardized set of clinic practice management (CPM) team processes. Part of standardizing the CPM process was defining the scope and tasks of the GPM, which requires significant planning for the implementation. “My big job is to finalize what we think group practice management is going to look [like] here,” a GPM reported.

Each prototype site had latitude to interpret the GPM initiative in a way that would work in their context within given VHA boundaries and ongoing initiatives. To achieve the high-level vision and purpose, the GPM first had to develop action plans that accounted for the operating environment of the facility. According to one GPM, VA national officials are “constantly” asking for action plans, which required significant time by specific deadlines. “They want an action plan [and to] clean up all your consults, [and to] clean up all your recall reminders.”

Leading on improving access efforts. Participants saw the GPM as the central staff member responsible for providing oversight of any activities and people involved in improving access. “I ensure everybody is doing what they’re supposed to do,” one GPM reported. When the GPM sees areas that are not being addressed, the individual tries to develop a process or training to “close those gaps.”

GPMs promoted an awareness of their goals, changes in process, and new tools accompanying the initiative. However, other access initiatives were occurring simultaneously creating confusion for health care providers and patients; thus GPMs found they were managing a wide array of related initiatives.

GPMs have to negotiate with leaders across the VHA facility, many of whom operated at a higher leadership level and had different priorities, to address access problems.

“I’m a lieutenant as a GPM in a clinic, a GPM noted. “How is the lieutenant going to talk to a major or a colonel in the clinic and say your clinic has problems. How[‘s] that lieutenant...going to do that? With people skills!”

Managing expectations about the speed and to what extent a problem could be resolved was an important part of the GPM leadership role. “I see myself as managing expectations both up to the leadership and down to the frontline,” a GPM explained. “I find myself talking to leadership [about] our progress. But at the same time, we have to say, ‘not everything can be fixed overnight.’”

Providing leadership on access-related issues included developing a range of options for addressing patient access problems. One analytics manager recounted how the GPM role led to evaluating how physical space limited efficiency in clinic flow. The first step was identifying possible additional rooms to improve clinic flow. This required working with the space committee to “get someone to look at our overarching space and find someplace else for them to sit” to avoid adding to congestion in the clinic area.
 

Supporting data analytics. Given the importance of data analytics, GPMs had a critical role in helping to ensure that the data were accurate and clean. At one facility the GPM and the business managers, “are doing a tremendous amount to clean up our data to make it accurately reflect what it is that we’re doing,” reported a community clinic director.

GPMs routinely immersed themselves in the data to understand access issues. GPMs worked with clinic leaders to identify the underlying causes and various solutions. The GPMs maintained access through administrative scrubbing of the data and finding “smart ways to get patients scheduled,” a GPM explained. “I don’t think our facility would have taken care of as many veterans in the time frame as we did....We’ve cleared over 4,000 consults that were older than 90 days. We have cleared thousands and thousands of weekly reminders.”

GPMs expressed the need for aggregated (ie, dashboard) and standardized information to efficiently address access issues. “I would like to have some more standardization on what’s being reviewed; it seems to change frequently, and so [to] be able to track and trend and have something given to me to review,” one health care provider requested. On the other hand, participants also described a need for decision support tools that would lead to action aligned with best practices. “Instead of a dashboard or something that’s just measuring their performance, it’s more something that they can look at and take action” a national support staff advisor suggested.

Enabling self and staff. GPMs felt they were most effective if they enabled themselves and stakeholders through training and by cultivating relationships and team building. Figure 2 illustrates the various stakeholders GPMs reported engaging with. The GPMS should be building relationships, bridging relationships, developing trust, and then providing a higher level of hands-on management. However, “that doesn’t really happen right now, day to day,” one member of leadership reported.

Key topics in GPM leadership training included both soft skills (change management, culture change, and negotiation skills) and crucial analytic/technical training (understanding each metric and dashboard available, data analytics, and supply/demand balancing techniques). The GPMs not only wanted to understand metrics as part of their training, but also want to know what to do about them.

An “operationalization” training approach (discerning the meaning of data, data-based decision making, and determining action from multiple options) inspired by real-life situations was preferred by participants. Other effective learning structures included job aids in the form of templated Gantt charts, process maps to guide GPMs through implementation of new processes, formalized peer learning (accumulated field insights shared during training courses), and informal peer sharing of direct experiences during calls.

GPMs also emphasized training for frontline clinical and support staff, including schedulers. VHA schedulers typically have less education and experience higher turnover rates than do other clinic staff, yet they carry out complex and critical tasks. Providing training and ensuring that any materials developed for training and education were appropriate to the level of education of schedulers was an important task for GPMs. “If they don’t understand all of the scheduling principles and potential,” one GPM explained, “we will not be maximizing the utilization of our parts.”

GPMs also provided informal education to clinicians. Participants noted GPMs have to avoid appearing to overstep their positions or presuming more knowledge and expertise than clinicians. They “have to be able to teach a physician without being overbearing, in a way a physician will accept it as advisement,” one program leader reported.
 

GPM knowledge, skills, and abilities. GPMs presented a complex range of knowledge, skills, and abilities, including clinical, administrative, analytics, and people skills. All interviewees reported that their prior education and experience did not sufficiently train them for the GPM role. GPMs identified a willingness to learn quickly as a critical characteristic. Many GPMs tended to have a formal education in health administration or business (eg, MBAs); others had administrative experience (eg, administrative assistance to executive leadership) or clinical training (eg, physician assistant). Detailed clinical knowledge was not expected, but clinical familiarity was helpful.

Some interviewees also mentioned previous experience and familiarity with the VHA system specifically as an advantage. This was especially true for VA outpatient flows, clinic flows, and understanding what an outpatient is in a VA context. Interviewees noted the importance of GPMs needing to be able to analyze patient demand metrics and underlying data in order to determine supply of providers and then to allocate adequate resources to complement providers. Forecasting skills were referenced as a key point. “They need to be able to be assured that they can recruit more providers if needed,” a national support staff advisor noted.

Given the importance of developing effective relationships, communication skills were mentioned by most participants and underscored as critical to establishing trust between GPMs and others as the initiative was being implemented. Interviewees indicated that relationship building was further enhanced when GPMs possessed the ability to “work with” rather than command clinicians and staff; navigate politics; and were respectful of other people’s knowledge, skills, abilities, and status. “They have to work with the nursing staff and teach them,” a leader described, “so that people understand that we are going to a different place to achieve our primary objectives and goals.”

Issues and Challenges

Participants identified several technical, social, and structural challenges and barriers to successfully implementing the GPM role.

Technical challenges. Recurring themes across all phases of data analytics were GPMs’ capability to challenge data use and use large volumes of information from multiple data sources (entering and accessing data; “drilling down” from summaries; generating reports; and analyzing and interpreting resulting metrics). Interviewees reported that information assessment and analytic support were not consistent. One GPM had a data analyst pulling reports needed to support clinical units while other GPMs trained staff to pull data. Even with support, some GPMs had issues due to limited information technology (IT) skills or access privileges leading to inefficiencies and delays. “Whenever I need anything from a programmer, I have to go through, you know, the IT gods in the sky,” one GPM remarked. “That usually takes a few months or more.”

Social challenges. Instituting the GPM role was a cultural change, and interviewees reported needing to address resistance to CPM model efforts. Resistance to change “is particularly hard in the VA just because it has a unique culture,” one leader noted. “There is a comfort in the legacy way of doing things.” The GPM initiative was introduced during a time when other national level initiatives were being implemented throughout the VHA. Fulfilling requests for information for these initiatives became the responsibility of the GPM and their team, which diverted attention from the mandate to improve access. Furthermore, GPMs were often considered the “change communicators” to clinics putting them in the role of “bad messenger,” which degraded trust and made it difficult to partner with clinicians.

Efforts to work through change management and build relationships included general program awareness presentation to internal stakeholders; including key stakeholders in GPM committees; pre-emptive conversations with unit chiefs; creating awareness of the GPM activities and progress through formal and informal update meetings; and identifying successes regarding access.

Structural challenges. The GPM role did not have direct supervision over clinical and administrative leaders, making it challenging to enact change. GPMs reported that “they do not always have authority over the area that they are being asked to manage,” which made their work difficult, requiring strong negotiation skills and political savvy to affect change. However, as the clinic staff and providers saw how the GPM could support and positively impact their practice, these challenges began to subside.

Discussion

This study provides empirical evidence regarding the implementation of a new access management strategy for health care systems focused on improving timeliness of care. First, the GPM position was seen as critical at each facility, as a single point person, to help local system leaders respond effectively to both national mandates and local context. Second, requiring the GPMs to report to the medical center director or chief of staff was important for integrating access perspectives across service lines and to facilitate a strong GPM role in strategic planning. Third, the intentional flexibility of the access management initiative, beyond the nationally specified aspects of the GPM role, was key for allowing individual sites to adapt to unique local challenges, resources, and population demands. Fourth, the initiative provided GPMs with opportunities to learn important skills and support the acquisition, utilization, and communication of a tremendous range of data toward responsive action.

According to our respondents, the GPM role demands functioning across a broad set of responsibilities; understanding the big picture as well as the complex underlying variables; engaging facility leaders, clinical and administrative staff; and prioritizing competing national and local demands. Consistent with previous findings, effective GPMs must possess a complex set of skills (interpersonal, analytic, and leadership) and the ability to create a supporting team.¹³

In practice, improving access at individual sites of care (VA medical centers and community-based outpatient clinics) poses significant challenges, especially in the early stages, even with the assistance of a GPM. For example, some respondents reported being overwhelmed by the volume of available data and dashboards, and responding to current requests for data analysis and dissemination sometimes impeded long range planning. Multiple national access-related initiatives and local pressures also generated excessive and potentially conflicting demands. Thus, while the creation of a GPM position seemed to be essential for the pilot sites to improve local access and timeliness to care, success also requires ongoing national and facility-wide communication, education, and support. Ongoing data analysis training and support will be critical to ensuring the sustainability of the position. Last, recruiting GPMs with the needed complex skill set may prove to be challenging, and it will be important to provide resources to identify, attract, and retain well-qualified GPMs.

Limitations and Future Work

This study was based on a small initial sample of pilot sites of varying sizes and, as such, may not reflect the experience of all VHA GPMs. In addition, the use of snowball sampling, while facilitating identification of key stakeholders, may introduce bias in participant sampling. Nonetheless, the results from this study provide findings that informed the national VHA GPM initiative and can inform further studies of practice management roles outside of the VA.

Further study of the VHA GPM implementation and similar roles in other health care systems is needed. As the GPM position is fully implemented across the VHA, large scale evaluation is needed to gain a more representative picture and allow for comparison of the GPM role at various types of facilities (eg, size, rurality, complexity, ranking based on access performance metrics).

Conclusion

Improving access to care is a central goal for health care systems. The incorporation of the GPM role is an innovative approach to improve access management strategies. Early study of prototype sites provided VHA leadership with valuable insights used to influence further rollout of this initiative. Based on our findings, national and local support are important to ongoing success. National access mandates, training, and resources should focus on ensuring sufficient GPM authority, enabling GPMs to use data, and ensuring GPMs engage with frontline clinical and administrative staff to improve veteran access to care.

The Veterans Health Administration (VHA) provides care for 9 million veterans at 1,255 health care sites linked to one of 170 local medical systems.¹ Recognizing that providing timely care requires effective access management, the US Congress mandated training of VHA staff to manage and improve access to care but did not provide additional local funds for new positions.² In response, the VHA created the group practice manager (GPM), a new position responsible for improving clinical practice management and unifying access improvement across leadership levels, professions, and services within each local medical system.

In May 2015, the VHA began hiring and training GPMs to spearhead management of access to services. The US Department of Veterans Affairs (VA) Office of Veteran Access to Care spearheaded GPM training, including face-to-face sessions, national calls, webinars, and educational materials. Five local medical systems were selected by the VA Office of Veteran Access to Care to implement the GPM role to allow for an early evaluation of the program that would inform a subsequent nationwide rollout. Implementation of the GPM role remained in the hands of local medical systems.

Longer wait times are shown to impact patient health.^3,4 Open access scheduling and other patient-centered access management interventions have been shown to improve availability of primary care appointments.⁵ However, little empirical evidence exists regarding the managers who focus on clinic access interventions. While the nonpeer-reviewed literature includes references to such roles, including GPMs, the empirical literature has focused on external practice faciliators,^6-8 “mid-level managers,”⁹ and clinic staff.¹⁰ We found no peer-reviewed articles on the needs and experiences of practice managers who are focused on improving access. The purpose of this study was to examine GPM prototype sites to both enhance subsequent nationwide implementation and to advance empirical literature on managing patient access within health care.

Methods

In 2015, the VA identified 5 prototype sites representing diverse geographic locations, size, and complexity for the implementation of the GPM role (Table 1). These sites self-identified as having clinical practice management experience. GPMs attended 4 training sessions between February and August 2015.

Data Collection

Participants from each prototype site included GPMs, national trainers, clinic leaders, and frontline staff. Table 2 includes the roles and sample size. Participants were recruited through purposive sampling followed by snowball sampling until thematic saturation was reached (the point at which subsequent data fail to produce new findings across sites and roles of interest).

Guided by the Consolidated Framework for Implementation Research (CFIR), the research team developed semistructured interview guides tailored to participants’ roles to elicit rich descriptions regarding overall impressions, practice management strategies, goals, activities, relationship to clinic roles, data analytics usage, challenges, barriers, and facilitators.¹¹ These guides included open-ended questions and structured prompts utilizing participant language for follow-up probes to minimize interviewing bias (eAppendix:

Data Analysis

Data were analyzed using iterative deductive and inductive content analysis.¹² Deductive content analysis consisted of identifying quotes that fit within preidentified categories (ie, perceptions of national effort, organizational structure for GPM, challenges, facilitators, metrics and tools, and mobilizing access culture) developed by the interdisciplinary research team. Further content analysis entailed open-coding and iteratively revisiting and reconciling codes associated within each preidentified category as new codes emerged. The team analyzed the resulting codes to inductively and iteratively identify and stabilize themes regarding the GPM role: roles and tasks, GPM characteristics, issues, and challenges. Through this process we moved coded data to reconciled descriptions suited to addressing the purposes of this study. Dedoose 7.0.23 software was used for qualitative data management and analysis.

Results

The study identified participants’ overall impressions of the GPM initiative and key themes within 4 major domains regarding implementing the GPM role: roles and tasks (implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff); GPM characteristics (familiarity with clinical services, knowledge of VHA systems, ability to analyze patient data, communication skills, and the ability to work with others); and issues, and challenges (technical, social, and structural).

Overall Impressions

Interviewees perceived the GPM initiative as a consolidation of existing distributed responsibilities into one role that directly reported to local top-level management with indirect reporting to national leaders. Many of the sites reported that they had designated or planned to designate a role resembling the GPM prior to the initiative. “There are staff who’ve been doing some of this work all along,” a GPM noted. “We just didn’t have them grouped together. They weren’t necessarily all working in the same type of service under the same type of structure.”

Whether the GPM position was new or not, participants referenced the importance and challenges of engaging the local facility in recognizing the agency associated with the GPM position. According to national support, the staff are trying to get the facility to understand “why the group practice manager is so important… we’ve got to embed that standard position in the system.”

While the GPM was recognized as the hub of access management, respondents recognized that transformation regarding access involved many players. “We have to create [an] orchestrated team inside each facility,” an advisor argued.

Respondents discussed how the initiative allows local facilities to appoint a specific person with a specific title and role who helps facilitate, organize, and legitimize an access focus at their sites. One GPM interviewee noted how the initiative helped refocus some of their previously less centralized efforts. “We’ve always looked at productivity; we’ve always looked at access; we’ve always looked at efficiency. I think the bigger difference is now there are individuals identified in the clinics, as practice managers as well…I interact with them. They interact with individual clinic staff, and it’s more of a group process than a single individual.”

The value of having tools available and being able to track and manage patient care as a specific example of the positive impact of this new role was noted by participants. A GPM noted that many health care providers will be happy to have tools to better manage their services and a process “that flows from a service level all the way up to executive management, where there is a common interest in making those things happen—I think that’s going to be a tremendous help.”

Participants expressed concern that the national GPM rollout would be a one-size-fits-all approach. These respondents emphasized the need to have the flexibility to customize their activities to meet their unique site and patient needs.

GPM Roles and Tasks

Participants described 4 primary roles that the GPM was expected to fill: implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff. Some activities overlapped in that they served to support multiple role areas (Figure 1).

Implementing clinic practice management. In the early stages of the initiative, the GPM’s primary role was to prepare the facility to implement a standardized set of clinic practice management (CPM) team processes. Part of standardizing the CPM process was defining the scope and tasks of the GPM, which requires significant planning for the implementation. “My big job is to finalize what we think group practice management is going to look [like] here,” a GPM reported.

Each prototype site had latitude to interpret the GPM initiative in a way that would work in their context within given VHA boundaries and ongoing initiatives. To achieve the high-level vision and purpose, the GPM first had to develop action plans that accounted for the operating environment of the facility. According to one GPM, VA national officials are “constantly” asking for action plans, which required significant time by specific deadlines. “They want an action plan [and to] clean up all your consults, [and to] clean up all your recall reminders.”

Leading on improving access efforts. Participants saw the GPM as the central staff member responsible for providing oversight of any activities and people involved in improving access. “I ensure everybody is doing what they’re supposed to do,” one GPM reported. When the GPM sees areas that are not being addressed, the individual tries to develop a process or training to “close those gaps.”

GPMs promoted an awareness of their goals, changes in process, and new tools accompanying the initiative. However, other access initiatives were occurring simultaneously creating confusion for health care providers and patients; thus GPMs found they were managing a wide array of related initiatives.

GPMs have to negotiate with leaders across the VHA facility, many of whom operated at a higher leadership level and had different priorities, to address access problems.

“I’m a lieutenant as a GPM in a clinic, a GPM noted. “How is the lieutenant going to talk to a major or a colonel in the clinic and say your clinic has problems. How[‘s] that lieutenant...going to do that? With people skills!”

Managing expectations about the speed and to what extent a problem could be resolved was an important part of the GPM leadership role. “I see myself as managing expectations both up to the leadership and down to the frontline,” a GPM explained. “I find myself talking to leadership [about] our progress. But at the same time, we have to say, ‘not everything can be fixed overnight.’”

Providing leadership on access-related issues included developing a range of options for addressing patient access problems. One analytics manager recounted how the GPM role led to evaluating how physical space limited efficiency in clinic flow. The first step was identifying possible additional rooms to improve clinic flow. This required working with the space committee to “get someone to look at our overarching space and find someplace else for them to sit” to avoid adding to congestion in the clinic area.
 

Supporting data analytics. Given the importance of data analytics, GPMs had a critical role in helping to ensure that the data were accurate and clean. At one facility the GPM and the business managers, “are doing a tremendous amount to clean up our data to make it accurately reflect what it is that we’re doing,” reported a community clinic director.

GPMs routinely immersed themselves in the data to understand access issues. GPMs worked with clinic leaders to identify the underlying causes and various solutions. The GPMs maintained access through administrative scrubbing of the data and finding “smart ways to get patients scheduled,” a GPM explained. “I don’t think our facility would have taken care of as many veterans in the time frame as we did....We’ve cleared over 4,000 consults that were older than 90 days. We have cleared thousands and thousands of weekly reminders.”

GPMs expressed the need for aggregated (ie, dashboard) and standardized information to efficiently address access issues. “I would like to have some more standardization on what’s being reviewed; it seems to change frequently, and so [to] be able to track and trend and have something given to me to review,” one health care provider requested. On the other hand, participants also described a need for decision support tools that would lead to action aligned with best practices. “Instead of a dashboard or something that’s just measuring their performance, it’s more something that they can look at and take action” a national support staff advisor suggested.

Enabling self and staff. GPMs felt they were most effective if they enabled themselves and stakeholders through training and by cultivating relationships and team building. Figure 2 illustrates the various stakeholders GPMs reported engaging with. The GPMS should be building relationships, bridging relationships, developing trust, and then providing a higher level of hands-on management. However, “that doesn’t really happen right now, day to day,” one member of leadership reported.

Key topics in GPM leadership training included both soft skills (change management, culture change, and negotiation skills) and crucial analytic/technical training (understanding each metric and dashboard available, data analytics, and supply/demand balancing techniques). The GPMs not only wanted to understand metrics as part of their training, but also want to know what to do about them.

An “operationalization” training approach (discerning the meaning of data, data-based decision making, and determining action from multiple options) inspired by real-life situations was preferred by participants. Other effective learning structures included job aids in the form of templated Gantt charts, process maps to guide GPMs through implementation of new processes, formalized peer learning (accumulated field insights shared during training courses), and informal peer sharing of direct experiences during calls.

GPMs also emphasized training for frontline clinical and support staff, including schedulers. VHA schedulers typically have less education and experience higher turnover rates than do other clinic staff, yet they carry out complex and critical tasks. Providing training and ensuring that any materials developed for training and education were appropriate to the level of education of schedulers was an important task for GPMs. “If they don’t understand all of the scheduling principles and potential,” one GPM explained, “we will not be maximizing the utilization of our parts.”

GPMs also provided informal education to clinicians. Participants noted GPMs have to avoid appearing to overstep their positions or presuming more knowledge and expertise than clinicians. They “have to be able to teach a physician without being overbearing, in a way a physician will accept it as advisement,” one program leader reported.
 

GPM knowledge, skills, and abilities. GPMs presented a complex range of knowledge, skills, and abilities, including clinical, administrative, analytics, and people skills. All interviewees reported that their prior education and experience did not sufficiently train them for the GPM role. GPMs identified a willingness to learn quickly as a critical characteristic. Many GPMs tended to have a formal education in health administration or business (eg, MBAs); others had administrative experience (eg, administrative assistance to executive leadership) or clinical training (eg, physician assistant). Detailed clinical knowledge was not expected, but clinical familiarity was helpful.

Some interviewees also mentioned previous experience and familiarity with the VHA system specifically as an advantage. This was especially true for VA outpatient flows, clinic flows, and understanding what an outpatient is in a VA context. Interviewees noted the importance of GPMs needing to be able to analyze patient demand metrics and underlying data in order to determine supply of providers and then to allocate adequate resources to complement providers. Forecasting skills were referenced as a key point. “They need to be able to be assured that they can recruit more providers if needed,” a national support staff advisor noted.

Given the importance of developing effective relationships, communication skills were mentioned by most participants and underscored as critical to establishing trust between GPMs and others as the initiative was being implemented. Interviewees indicated that relationship building was further enhanced when GPMs possessed the ability to “work with” rather than command clinicians and staff; navigate politics; and were respectful of other people’s knowledge, skills, abilities, and status. “They have to work with the nursing staff and teach them,” a leader described, “so that people understand that we are going to a different place to achieve our primary objectives and goals.”

Issues and Challenges

Participants identified several technical, social, and structural challenges and barriers to successfully implementing the GPM role.

Technical challenges. Recurring themes across all phases of data analytics were GPMs’ capability to challenge data use and use large volumes of information from multiple data sources (entering and accessing data; “drilling down” from summaries; generating reports; and analyzing and interpreting resulting metrics). Interviewees reported that information assessment and analytic support were not consistent. One GPM had a data analyst pulling reports needed to support clinical units while other GPMs trained staff to pull data. Even with support, some GPMs had issues due to limited information technology (IT) skills or access privileges leading to inefficiencies and delays. “Whenever I need anything from a programmer, I have to go through, you know, the IT gods in the sky,” one GPM remarked. “That usually takes a few months or more.”

Social challenges. Instituting the GPM role was a cultural change, and interviewees reported needing to address resistance to CPM model efforts. Resistance to change “is particularly hard in the VA just because it has a unique culture,” one leader noted. “There is a comfort in the legacy way of doing things.” The GPM initiative was introduced during a time when other national level initiatives were being implemented throughout the VHA. Fulfilling requests for information for these initiatives became the responsibility of the GPM and their team, which diverted attention from the mandate to improve access. Furthermore, GPMs were often considered the “change communicators” to clinics putting them in the role of “bad messenger,” which degraded trust and made it difficult to partner with clinicians.

Efforts to work through change management and build relationships included general program awareness presentation to internal stakeholders; including key stakeholders in GPM committees; pre-emptive conversations with unit chiefs; creating awareness of the GPM activities and progress through formal and informal update meetings; and identifying successes regarding access.

Structural challenges. The GPM role did not have direct supervision over clinical and administrative leaders, making it challenging to enact change. GPMs reported that “they do not always have authority over the area that they are being asked to manage,” which made their work difficult, requiring strong negotiation skills and political savvy to affect change. However, as the clinic staff and providers saw how the GPM could support and positively impact their practice, these challenges began to subside.

Discussion

This study provides empirical evidence regarding the implementation of a new access management strategy for health care systems focused on improving timeliness of care. First, the GPM position was seen as critical at each facility, as a single point person, to help local system leaders respond effectively to both national mandates and local context. Second, requiring the GPMs to report to the medical center director or chief of staff was important for integrating access perspectives across service lines and to facilitate a strong GPM role in strategic planning. Third, the intentional flexibility of the access management initiative, beyond the nationally specified aspects of the GPM role, was key for allowing individual sites to adapt to unique local challenges, resources, and population demands. Fourth, the initiative provided GPMs with opportunities to learn important skills and support the acquisition, utilization, and communication of a tremendous range of data toward responsive action.

According to our respondents, the GPM role demands functioning across a broad set of responsibilities; understanding the big picture as well as the complex underlying variables; engaging facility leaders, clinical and administrative staff; and prioritizing competing national and local demands. Consistent with previous findings, effective GPMs must possess a complex set of skills (interpersonal, analytic, and leadership) and the ability to create a supporting team.¹³

In practice, improving access at individual sites of care (VA medical centers and community-based outpatient clinics) poses significant challenges, especially in the early stages, even with the assistance of a GPM. For example, some respondents reported being overwhelmed by the volume of available data and dashboards, and responding to current requests for data analysis and dissemination sometimes impeded long range planning. Multiple national access-related initiatives and local pressures also generated excessive and potentially conflicting demands. Thus, while the creation of a GPM position seemed to be essential for the pilot sites to improve local access and timeliness to care, success also requires ongoing national and facility-wide communication, education, and support. Ongoing data analysis training and support will be critical to ensuring the sustainability of the position. Last, recruiting GPMs with the needed complex skill set may prove to be challenging, and it will be important to provide resources to identify, attract, and retain well-qualified GPMs.

Limitations and Future Work

This study was based on a small initial sample of pilot sites of varying sizes and, as such, may not reflect the experience of all VHA GPMs. In addition, the use of snowball sampling, while facilitating identification of key stakeholders, may introduce bias in participant sampling. Nonetheless, the results from this study provide findings that informed the national VHA GPM initiative and can inform further studies of practice management roles outside of the VA.

Further study of the VHA GPM implementation and similar roles in other health care systems is needed. As the GPM position is fully implemented across the VHA, large scale evaluation is needed to gain a more representative picture and allow for comparison of the GPM role at various types of facilities (eg, size, rurality, complexity, ranking based on access performance metrics).

Conclusion

Improving access to care is a central goal for health care systems. The incorporation of the GPM role is an innovative approach to improve access management strategies. Early study of prototype sites provided VHA leadership with valuable insights used to influence further rollout of this initiative. Based on our findings, national and local support are important to ongoing success. National access mandates, training, and resources should focus on ensuring sufficient GPM authority, enabling GPMs to use data, and ensuring GPMs engage with frontline clinical and administrative staff to improve veteran access to care.

The Veterans Health Administration (VHA) provides care for 9 million veterans at 1,255 health care sites linked to one of 170 local medical systems.¹ Recognizing that providing timely care requires effective access management, the US Congress mandated training of VHA staff to manage and improve access to care but did not provide additional local funds for new positions.² In response, the VHA created the group practice manager (GPM), a new position responsible for improving clinical practice management and unifying access improvement across leadership levels, professions, and services within each local medical system.

In May 2015, the VHA began hiring and training GPMs to spearhead management of access to services. The US Department of Veterans Affairs (VA) Office of Veteran Access to Care spearheaded GPM training, including face-to-face sessions, national calls, webinars, and educational materials. Five local medical systems were selected by the VA Office of Veteran Access to Care to implement the GPM role to allow for an early evaluation of the program that would inform a subsequent nationwide rollout. Implementation of the GPM role remained in the hands of local medical systems.

Longer wait times are shown to impact patient health.^3,4 Open access scheduling and other patient-centered access management interventions have been shown to improve availability of primary care appointments.⁵ However, little empirical evidence exists regarding the managers who focus on clinic access interventions. While the nonpeer-reviewed literature includes references to such roles, including GPMs, the empirical literature has focused on external practice faciliators,^6-8 “mid-level managers,”⁹ and clinic staff.¹⁰ We found no peer-reviewed articles on the needs and experiences of practice managers who are focused on improving access. The purpose of this study was to examine GPM prototype sites to both enhance subsequent nationwide implementation and to advance empirical literature on managing patient access within health care.

Methods

In 2015, the VA identified 5 prototype sites representing diverse geographic locations, size, and complexity for the implementation of the GPM role (Table 1). These sites self-identified as having clinical practice management experience. GPMs attended 4 training sessions between February and August 2015.

Data Collection

Participants from each prototype site included GPMs, national trainers, clinic leaders, and frontline staff. Table 2 includes the roles and sample size. Participants were recruited through purposive sampling followed by snowball sampling until thematic saturation was reached (the point at which subsequent data fail to produce new findings across sites and roles of interest).

Guided by the Consolidated Framework for Implementation Research (CFIR), the research team developed semistructured interview guides tailored to participants’ roles to elicit rich descriptions regarding overall impressions, practice management strategies, goals, activities, relationship to clinic roles, data analytics usage, challenges, barriers, and facilitators.¹¹ These guides included open-ended questions and structured prompts utilizing participant language for follow-up probes to minimize interviewing bias (eAppendix:

Data Analysis

Data were analyzed using iterative deductive and inductive content analysis.¹² Deductive content analysis consisted of identifying quotes that fit within preidentified categories (ie, perceptions of national effort, organizational structure for GPM, challenges, facilitators, metrics and tools, and mobilizing access culture) developed by the interdisciplinary research team. Further content analysis entailed open-coding and iteratively revisiting and reconciling codes associated within each preidentified category as new codes emerged. The team analyzed the resulting codes to inductively and iteratively identify and stabilize themes regarding the GPM role: roles and tasks, GPM characteristics, issues, and challenges. Through this process we moved coded data to reconciled descriptions suited to addressing the purposes of this study. Dedoose 7.0.23 software was used for qualitative data management and analysis.

Results

The study identified participants’ overall impressions of the GPM initiative and key themes within 4 major domains regarding implementing the GPM role: roles and tasks (implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff); GPM characteristics (familiarity with clinical services, knowledge of VHA systems, ability to analyze patient data, communication skills, and the ability to work with others); and issues, and challenges (technical, social, and structural).

Overall Impressions

Interviewees perceived the GPM initiative as a consolidation of existing distributed responsibilities into one role that directly reported to local top-level management with indirect reporting to national leaders. Many of the sites reported that they had designated or planned to designate a role resembling the GPM prior to the initiative. “There are staff who’ve been doing some of this work all along,” a GPM noted. “We just didn’t have them grouped together. They weren’t necessarily all working in the same type of service under the same type of structure.”

Whether the GPM position was new or not, participants referenced the importance and challenges of engaging the local facility in recognizing the agency associated with the GPM position. According to national support, the staff are trying to get the facility to understand “why the group practice manager is so important… we’ve got to embed that standard position in the system.”

While the GPM was recognized as the hub of access management, respondents recognized that transformation regarding access involved many players. “We have to create [an] orchestrated team inside each facility,” an advisor argued.

Respondents discussed how the initiative allows local facilities to appoint a specific person with a specific title and role who helps facilitate, organize, and legitimize an access focus at their sites. One GPM interviewee noted how the initiative helped refocus some of their previously less centralized efforts. “We’ve always looked at productivity; we’ve always looked at access; we’ve always looked at efficiency. I think the bigger difference is now there are individuals identified in the clinics, as practice managers as well…I interact with them. They interact with individual clinic staff, and it’s more of a group process than a single individual.”

The value of having tools available and being able to track and manage patient care as a specific example of the positive impact of this new role was noted by participants. A GPM noted that many health care providers will be happy to have tools to better manage their services and a process “that flows from a service level all the way up to executive management, where there is a common interest in making those things happen—I think that’s going to be a tremendous help.”

Participants expressed concern that the national GPM rollout would be a one-size-fits-all approach. These respondents emphasized the need to have the flexibility to customize their activities to meet their unique site and patient needs.

GPM Roles and Tasks

Participants described 4 primary roles that the GPM was expected to fill: implementing clinic practice management, leading patient access, supporting data analytics, and enabling self and staff. Some activities overlapped in that they served to support multiple role areas (Figure 1).

Implementing clinic practice management. In the early stages of the initiative, the GPM’s primary role was to prepare the facility to implement a standardized set of clinic practice management (CPM) team processes. Part of standardizing the CPM process was defining the scope and tasks of the GPM, which requires significant planning for the implementation. “My big job is to finalize what we think group practice management is going to look [like] here,” a GPM reported.

Each prototype site had latitude to interpret the GPM initiative in a way that would work in their context within given VHA boundaries and ongoing initiatives. To achieve the high-level vision and purpose, the GPM first had to develop action plans that accounted for the operating environment of the facility. According to one GPM, VA national officials are “constantly” asking for action plans, which required significant time by specific deadlines. “They want an action plan [and to] clean up all your consults, [and to] clean up all your recall reminders.”

Leading on improving access efforts. Participants saw the GPM as the central staff member responsible for providing oversight of any activities and people involved in improving access. “I ensure everybody is doing what they’re supposed to do,” one GPM reported. When the GPM sees areas that are not being addressed, the individual tries to develop a process or training to “close those gaps.”

GPMs promoted an awareness of their goals, changes in process, and new tools accompanying the initiative. However, other access initiatives were occurring simultaneously creating confusion for health care providers and patients; thus GPMs found they were managing a wide array of related initiatives.

GPMs have to negotiate with leaders across the VHA facility, many of whom operated at a higher leadership level and had different priorities, to address access problems.

“I’m a lieutenant as a GPM in a clinic, a GPM noted. “How is the lieutenant going to talk to a major or a colonel in the clinic and say your clinic has problems. How[‘s] that lieutenant...going to do that? With people skills!”

Managing expectations about the speed and to what extent a problem could be resolved was an important part of the GPM leadership role. “I see myself as managing expectations both up to the leadership and down to the frontline,” a GPM explained. “I find myself talking to leadership [about] our progress. But at the same time, we have to say, ‘not everything can be fixed overnight.’”

Providing leadership on access-related issues included developing a range of options for addressing patient access problems. One analytics manager recounted how the GPM role led to evaluating how physical space limited efficiency in clinic flow. The first step was identifying possible additional rooms to improve clinic flow. This required working with the space committee to “get someone to look at our overarching space and find someplace else for them to sit” to avoid adding to congestion in the clinic area.
 

Supporting data analytics. Given the importance of data analytics, GPMs had a critical role in helping to ensure that the data were accurate and clean. At one facility the GPM and the business managers, “are doing a tremendous amount to clean up our data to make it accurately reflect what it is that we’re doing,” reported a community clinic director.

GPMs routinely immersed themselves in the data to understand access issues. GPMs worked with clinic leaders to identify the underlying causes and various solutions. The GPMs maintained access through administrative scrubbing of the data and finding “smart ways to get patients scheduled,” a GPM explained. “I don’t think our facility would have taken care of as many veterans in the time frame as we did....We’ve cleared over 4,000 consults that were older than 90 days. We have cleared thousands and thousands of weekly reminders.”

GPMs expressed the need for aggregated (ie, dashboard) and standardized information to efficiently address access issues. “I would like to have some more standardization on what’s being reviewed; it seems to change frequently, and so [to] be able to track and trend and have something given to me to review,” one health care provider requested. On the other hand, participants also described a need for decision support tools that would lead to action aligned with best practices. “Instead of a dashboard or something that’s just measuring their performance, it’s more something that they can look at and take action” a national support staff advisor suggested.

Enabling self and staff. GPMs felt they were most effective if they enabled themselves and stakeholders through training and by cultivating relationships and team building. Figure 2 illustrates the various stakeholders GPMs reported engaging with. The GPMS should be building relationships, bridging relationships, developing trust, and then providing a higher level of hands-on management. However, “that doesn’t really happen right now, day to day,” one member of leadership reported.

Key topics in GPM leadership training included both soft skills (change management, culture change, and negotiation skills) and crucial analytic/technical training (understanding each metric and dashboard available, data analytics, and supply/demand balancing techniques). The GPMs not only wanted to understand metrics as part of their training, but also want to know what to do about them.

An “operationalization” training approach (discerning the meaning of data, data-based decision making, and determining action from multiple options) inspired by real-life situations was preferred by participants. Other effective learning structures included job aids in the form of templated Gantt charts, process maps to guide GPMs through implementation of new processes, formalized peer learning (accumulated field insights shared during training courses), and informal peer sharing of direct experiences during calls.

GPMs also emphasized training for frontline clinical and support staff, including schedulers. VHA schedulers typically have less education and experience higher turnover rates than do other clinic staff, yet they carry out complex and critical tasks. Providing training and ensuring that any materials developed for training and education were appropriate to the level of education of schedulers was an important task for GPMs. “If they don’t understand all of the scheduling principles and potential,” one GPM explained, “we will not be maximizing the utilization of our parts.”

GPMs also provided informal education to clinicians. Participants noted GPMs have to avoid appearing to overstep their positions or presuming more knowledge and expertise than clinicians. They “have to be able to teach a physician without being overbearing, in a way a physician will accept it as advisement,” one program leader reported.
 

GPM knowledge, skills, and abilities. GPMs presented a complex range of knowledge, skills, and abilities, including clinical, administrative, analytics, and people skills. All interviewees reported that their prior education and experience did not sufficiently train them for the GPM role. GPMs identified a willingness to learn quickly as a critical characteristic. Many GPMs tended to have a formal education in health administration or business (eg, MBAs); others had administrative experience (eg, administrative assistance to executive leadership) or clinical training (eg, physician assistant). Detailed clinical knowledge was not expected, but clinical familiarity was helpful.

Some interviewees also mentioned previous experience and familiarity with the VHA system specifically as an advantage. This was especially true for VA outpatient flows, clinic flows, and understanding what an outpatient is in a VA context. Interviewees noted the importance of GPMs needing to be able to analyze patient demand metrics and underlying data in order to determine supply of providers and then to allocate adequate resources to complement providers. Forecasting skills were referenced as a key point. “They need to be able to be assured that they can recruit more providers if needed,” a national support staff advisor noted.

Given the importance of developing effective relationships, communication skills were mentioned by most participants and underscored as critical to establishing trust between GPMs and others as the initiative was being implemented. Interviewees indicated that relationship building was further enhanced when GPMs possessed the ability to “work with” rather than command clinicians and staff; navigate politics; and were respectful of other people’s knowledge, skills, abilities, and status. “They have to work with the nursing staff and teach them,” a leader described, “so that people understand that we are going to a different place to achieve our primary objectives and goals.”

Issues and Challenges

Participants identified several technical, social, and structural challenges and barriers to successfully implementing the GPM role.

Technical challenges. Recurring themes across all phases of data analytics were GPMs’ capability to challenge data use and use large volumes of information from multiple data sources (entering and accessing data; “drilling down” from summaries; generating reports; and analyzing and interpreting resulting metrics). Interviewees reported that information assessment and analytic support were not consistent. One GPM had a data analyst pulling reports needed to support clinical units while other GPMs trained staff to pull data. Even with support, some GPMs had issues due to limited information technology (IT) skills or access privileges leading to inefficiencies and delays. “Whenever I need anything from a programmer, I have to go through, you know, the IT gods in the sky,” one GPM remarked. “That usually takes a few months or more.”

Social challenges. Instituting the GPM role was a cultural change, and interviewees reported needing to address resistance to CPM model efforts. Resistance to change “is particularly hard in the VA just because it has a unique culture,” one leader noted. “There is a comfort in the legacy way of doing things.” The GPM initiative was introduced during a time when other national level initiatives were being implemented throughout the VHA. Fulfilling requests for information for these initiatives became the responsibility of the GPM and their team, which diverted attention from the mandate to improve access. Furthermore, GPMs were often considered the “change communicators” to clinics putting them in the role of “bad messenger,” which degraded trust and made it difficult to partner with clinicians.

Efforts to work through change management and build relationships included general program awareness presentation to internal stakeholders; including key stakeholders in GPM committees; pre-emptive conversations with unit chiefs; creating awareness of the GPM activities and progress through formal and informal update meetings; and identifying successes regarding access.

Structural challenges. The GPM role did not have direct supervision over clinical and administrative leaders, making it challenging to enact change. GPMs reported that “they do not always have authority over the area that they are being asked to manage,” which made their work difficult, requiring strong negotiation skills and political savvy to affect change. However, as the clinic staff and providers saw how the GPM could support and positively impact their practice, these challenges began to subside.

Discussion

This study provides empirical evidence regarding the implementation of a new access management strategy for health care systems focused on improving timeliness of care. First, the GPM position was seen as critical at each facility, as a single point person, to help local system leaders respond effectively to both national mandates and local context. Second, requiring the GPMs to report to the medical center director or chief of staff was important for integrating access perspectives across service lines and to facilitate a strong GPM role in strategic planning. Third, the intentional flexibility of the access management initiative, beyond the nationally specified aspects of the GPM role, was key for allowing individual sites to adapt to unique local challenges, resources, and population demands. Fourth, the initiative provided GPMs with opportunities to learn important skills and support the acquisition, utilization, and communication of a tremendous range of data toward responsive action.

According to our respondents, the GPM role demands functioning across a broad set of responsibilities; understanding the big picture as well as the complex underlying variables; engaging facility leaders, clinical and administrative staff; and prioritizing competing national and local demands. Consistent with previous findings, effective GPMs must possess a complex set of skills (interpersonal, analytic, and leadership) and the ability to create a supporting team.¹³

In practice, improving access at individual sites of care (VA medical centers and community-based outpatient clinics) poses significant challenges, especially in the early stages, even with the assistance of a GPM. For example, some respondents reported being overwhelmed by the volume of available data and dashboards, and responding to current requests for data analysis and dissemination sometimes impeded long range planning. Multiple national access-related initiatives and local pressures also generated excessive and potentially conflicting demands. Thus, while the creation of a GPM position seemed to be essential for the pilot sites to improve local access and timeliness to care, success also requires ongoing national and facility-wide communication, education, and support. Ongoing data analysis training and support will be critical to ensuring the sustainability of the position. Last, recruiting GPMs with the needed complex skill set may prove to be challenging, and it will be important to provide resources to identify, attract, and retain well-qualified GPMs.

Limitations and Future Work

This study was based on a small initial sample of pilot sites of varying sizes and, as such, may not reflect the experience of all VHA GPMs. In addition, the use of snowball sampling, while facilitating identification of key stakeholders, may introduce bias in participant sampling. Nonetheless, the results from this study provide findings that informed the national VHA GPM initiative and can inform further studies of practice management roles outside of the VA.

Further study of the VHA GPM implementation and similar roles in other health care systems is needed. As the GPM position is fully implemented across the VHA, large scale evaluation is needed to gain a more representative picture and allow for comparison of the GPM role at various types of facilities (eg, size, rurality, complexity, ranking based on access performance metrics).

Conclusion

Improving access to care is a central goal for health care systems. The incorporation of the GPM role is an innovative approach to improve access management strategies. Early study of prototype sites provided VHA leadership with valuable insights used to influence further rollout of this initiative. Based on our findings, national and local support are important to ongoing success. National access mandates, training, and resources should focus on ensuring sufficient GPM authority, enabling GPMs to use data, and ensuring GPMs engage with frontline clinical and administrative staff to improve veteran access to care.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition in the veteran population and is associated with significant sleep disturbances and trauma-related nightmares.¹ PTSD can present with intrusive symptoms, such as recurrent memories or dreams, which are associated with traumatic events.² Clinical studies have described an increase in central nervous system (CNS) noradrenergic activity in PTSD; specifically, noradrenergic outflow and/or postsynaptic adrenoreceptor responsiveness is increased.^3,4 Targeting a reduction in noradrenergic activity via antagonism of noradrenergic receptors has been a therapeutic treatment strategy in PTSD.

Prazosin crosses the blood-brain barrier and works to antagonize α-1 adrenoreceptors to decrease noradrenergic outflow.⁵ It has been shown in multiple trials to effectively reduce nightmares and improve sleep quality in the veteran population.^6-12 However, a recent negative trial contributed to a downgraded recommendation for prazosin in the treatment of PTSD-related nightmares in the joint PTSD guideline from the US Department of Veterans Affairs (VA) and US Department of Defense (DoD).^13,14

The diagnosis of PTSD in veterans aged ≥ 65 years has been increasing due to improved recognition.¹⁵ As a result, prazosin may be considered more frequently as a treatment option for those patients who report PTSD-related nightmares. It is important to recognize that the normal physiologic process of aging is associated with increased noradrenergic outflow, which may change the pharmacodynamics of prazosin in geriatric patients.^12,16 This may necessitate increased doses to adequately antagonize the α-1 adenoreceptor.¹⁷ High doses of prazosin may increase the risk of hypotension in older patients.¹² This increased risk is especially concerning for patients who already receive multiple medications or have comorbid conditions that impact blood pressure (BP).

The existing literature has few studies that have reported on outcomes with prazosin use in older veterans.^11,12 The few existing reports provide clinically valuable descriptions of tolerability and efficacy with prazosin. For example, Peskind and colleagues showed prazosin to be an effective agent in the treatment of PTSD-related nightmares.¹² However, in older veterans prazosin dosing > 4 mg has not been described or reported in the literature.

There appears to be a lack of clinical guidance with regards to dosing of prazosin in older patients. The goal of the current study was to assess the outcomes of older veterans with PTSD under pharmacist management of prazosin at our outpatient Prazosin Titration Clinic (PTC) in order to contribute to the minimal, yet valuable, existing clinical literature.

Methods

This study was approved by the University of Iowa Institutional Review Board and Iowa City Veterans Affairs Health Care System (ICVAHCS) research and development committee. The study was a retrospective chart review of older patients with consultations referred to the ICVAHCS PTC. To be eligible for inclusion, veterans with a PTSD diagnosis must have been evaluated at an initial consult appointment with a mental health clinical pharmacy specialist (MH CPS) from February 1, 2016 to August 31, 2018, and had at least 1 follow-up appointment. Follow-up visits were conducted either by telephone or in a face-to-face clinic visit.

Prazosin Titration Clinics

VA health care systems use pharmacists to manage veterans prescribed prazosin through PTC consultations. PTCs provide a process for close follow-up and assessment of PTSD-related outcomes. Due to the frequency of follow-up, this service may be beneficial for older veterans with more complex comorbidities and medication regimens. Any veteran with PTSD-related nightmares may be referred to the PTC for a consultation by any health care provider. Once referred to the clinic, MH CPSs assume responsibility for the prazosin prescription, including dose adjustments. For example, if a veteran reported no issues with tolerability but continued to have frequent and distressing nightmares, the dose may be increased, typically by 1-mg to 2-mg increments. Once the veteran reaches a stable and tolerable dose of prazosin, they are discharged from the PTC, and the referring health care provider resumes responsibility for the prazosin prescription.

Clinically Measured Outcomes

Nightmare frequency and intensity were measured using the Recurrent Distressing Dreams item B2 of the Clinician Administered PTSD Scale (CAPS) (Table 1). The PTSD Checklist (PCL-5), Insomnia Severity Index (ISI), and total sleep hours were used to determine the effect of prazosin on symptom severity (Table 2). The PCL-5 is a 20-item self-report used to monitor and quantify symptom level and change over time. It evaluates the frequency over the past month that a patient was bothered by any of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) PTSD criterion.² Scores range from 0 (not at all) to 4 (extreme), with a maximum score of 80. The ISI is a 7-item self-report of sleep symptoms, with a total score of 28, where increasing scores indicate increasing severity of insomnia (Table 3).

Clinically measured outcome scales were performed and assessed by MH CPSs. CAPS frequency and intensity were measured at each clinic visit. PCL-5 and ISI scores were assessed at baseline and at the endpoint of study or discharge from clinic (Table 4). Patients who continued in the PTC after the end of the study date or who were lost to follow-up did not complete these measures at time of discharge.

Data Analysis

The primary outcome was change in CAPS nightmare frequency and intensity from time of initial clinic visit to time of discharge or end of study. The secondary outcomes included change in PCL-5, ISI, and sleep hours. Other secondary outcomes included measures of tolerability: BP changes, adverse effects (AEs) reported, and outcome of prazosin therapy when AEs were reported. Change in PTSD symptoms, PCL-5, and ISI were assessed using the Wilcoxon signed rank tests. Findings were considered to be statistically significant at P ≤ .05. Other variables were reported descriptively.

Results

Thirty-two veterans, aged ≥ 65 years, with clinical diagnosis of PTSD at the time of referral to the PTC were reviewed (Table 5). All patients were male and 93.8% were white. Thirty were Vietnam era veterans, 1 served in the Persian Gulf era, and 2 served in the post-Korean War era. Twenty-eight veterans had a combat history. Severe PTSD symptoms were reported as indicated by baseline PCL-5 scores, and moderate severity insomnia symptoms as indicated by baseline ISI scores.

All veterans had at least 1 comorbid medical condition, and the majority had multiple medical comorbidities. All were taking multiple medical and psychiatric medications. More than 80% of veterans were taking antihypertensive agents at baseline (Table 6). Twenty-two of the 32 veterans were prescribed a VA/DoD PTSD guideline-recommended antidepressant.

Primary Outcomes

The baseline, final, and changes in the primary outcomes are included in the Figure. Treatment with prazosin was associated with significant improvement in median scores from baseline to endpoint for CAPS nightmare frequency (-2, P = .0001), CAPS nightmare intensity (-2, P = .001), and total CAPS item score (-4, P < .001).

Secondary Outcomes

Of the 32 patients included in the study, PCL-5 was obtained from 20 veterans and ISI from 17 veterans at discharge from clinic. Thirty veterans reported final sleep hours, 2 veterans were unable to quantify average sleep hours per night at their final visit. PTSD symptom severity showed significant median change from baseline to endpoint of management in PTC for PCL-5 (-20.5, P = .0002) and ISI (-6.5, P = .002). Total sleep hours also showed significant improvement from baseline to endpoint (1.5, P = .003) (Table 7).

Prazosin Dosing

Maximum prazosin total daily doses were evaluated from the study baseline to the endpoint (Table 8). The mean (SD) maximum total daily dose of prazosin reached was 5.6 (5.1) mg (median, 3.5 mg; range, 1-17 mg). The mean (SD) total daily dose of prazosin at endpoint of study was 5.1 (5.3) mg (median, 2.5 mg; range, 0-17 mg). The average (SD) change of prazosin dose from baseline to endpoint was 3.5 (4.6) mg (median, 2 mg; range, -2 to 15 mg).

Tolerability

The average (SD) baseline systolic BP (SBP) was 135.8 (20.5) mm Hg and diastolic BP (DBP) was 77.2 (11.0) mm Hg. The average SBP and DBP at study endpoint were 131.8 (16.6) mm Hg and 75.9 (13.7) mm Hg, respectively. Endpoint BP values were missing for 6 patients.

Nine of 32 veterans reported AEs during PTC management of prazosin. Dizziness was the most common AE reported. Other AEs noted included orthostatic hypotension, headache, and falls. Of 12 reported AEs, 8 were related to dizziness, 5 of which were transient or tolerable. One veteran had a dose reduction of prazosin due to dizziness, and 3 veterans discontinued prazosin due to orthostasis. Several veterans had changes made to their antihypertensive medication regimen during prazosin titration, including dose reductions and/or decreased number of medications. If indicated, the MH CPS collaborated with the antihypertensive prescriber to make dosing adjustments. Two veterans reported a fall during prazosin titration; 1 veteran had other mobility-related factors thought to precipitate to their fall, and neither veterans were injured because of the falls.

Discussion

The existing literature reports few outcomes for older veterans prescribed prazosin for PTSD. One report included a 75-year-old otherwise-healthy veteran, who received 2-mg prazosin at bedtime. At this dose, he reported good tolerability and response, as indicated by a reduction in his CAPS nightmare severity score.¹¹ An open-label trial assessed prazosin in 9 geriatric men with chronic PTSD and found low-dose prazosin (average [SD] maximum prazosin dose reported was 2.3 [0.7] mg, range 2-4 mg per day) greatly reduced nightmares and overall PTSD severity in 8 of 9 subjects.¹² Despite the veterans in that study having multiple medical comorbid conditions and taking concomitant medications, prazosin was reported to be well tolerated, and changes in BP were determined to be clinically insignificant.¹² A recent study of middle-aged veterans (average [SD] age 52 [14] years) reported prazosin did not significantly alleviate PTSD-related nightmares.¹³ However, we observed prazosin therapy significantly reduced nightmares and sleep disturbances, and significantly improved PTSD severity in our older veteran population.

To our knowledge, the current study is the largest retrospective study that evaluates prazosin therapy for the treatment of PTSD-related nightmares in older veterans. The findings of this study are similar to a previous study in older veterans as well as studies of prazosin in younger and middle-aged adult veterans, with the average age ranging from 30 to 56 years.^6-12 Like the previously reported studies, prazosin also was well tolerated in our sample of veterans with multiple comorbidities and concomitant medications. Changes in BP were not clinically significant.

Studies have demonstrated increased noradrenergic activity as a component of the normal aging process.^16,17 This may require utilizing caution during prazosin dose titration and frequent patient assessment, due to the concern for risk of hypotension in older patients and in particular those who may require increased doses to achieve efficacy. In our study, favorable outcomes were achieved at an average (SD) total daily dose of 5.1 (5.3) mg (median, 2.5 mg; range 0-17 mg). A previous report showed efficacy of prazosin around an average (SD) maximum dose of 2.3 (0.7) mg, which is lower than the doses reported in the current study.¹² In addition, 13 veterans (40.6%) from our sample reached doses of ≥ 5 mg per day, and 8 veterans (25.0%) reached doses of ≥ 10 mg per day.

The doses reached in this study were reflective of a management approach using assessment of patient-reported symptoms at weekly to biweekly follow-up visits. The individualized management approach applied in the PTC by MH CPSs aids in uncovering the most efficacious and tolerated dose of prazosin for each veteran. Evaluation of symptom change during treatment in PTC was facilitated use of objective rating scales, which helped measure nightmare frequency and intensity, sleep satisfaction, and global PTSD severity. Given the variability in dosing of prazosin reported in the literature, further studies may be warranted to provide more definitive clinical guidance as far as dosing prazosin in older patients.

The study by Peskind and colleaguesrationalized that lower doses of prazosin may be used in older patients given pharmacokinetic effects of aging, age-associated changes in PTSD pathophysiology, and effects and interactions of concomitant medications.¹² However, our study found that prazosin could be well tolerated at higher doses. The rate of discontinuation due to intolerable AEs was low. AEs reported were consistent with the established AE profile of prazosin, with dizziness, orthostasis, and headache most commonly reported. Similar to the Peskind and colleagues study, BP had a tendency to decrease in this current study; however, the change was not clinically significant.¹² That study also reported transient dizziness with prazosin titration, which was shown to be tolerable in the majority of our veterans reporting dizziness.¹² Other common AEs with prazosin, such as rash, priapism, sedation, syncope, other cardiac AEs, and sleep disturbance were not reported in our study population.

MH CPS-managed PTCs are one venue that may allow veterans to achieve favorable outcomes through frequent follow-up. As prazosin dosing is specific to each individual patient, frequent follow-up visits are helpful in determining optimal doses that maximize efficacy while minimizing intolerable AEs. The majority of veterans treated in our PTC continued use of prazosin 6 months postdischarge, while 3 veterans required a postdischarge dose change.

The 2017 VA/DoD PTSD guidelines recommend individual, trauma-focused psychotherapy over pharmacologic therapy for the primary treatment of PTSD.¹⁴ About half of the veterans in the current study participated in either group or individual psychotherapy during enrollment in the PTC. A systematic review of psychotherapy in older veterans reported mixed results, with 4 studies indicating positive effects of therapy, while the other 3 studies reported no benefit or mixed effects for PTSD symptoms. The review concluded that fewer older adults experience complete remission of symptoms with psychotherapy alone.¹⁸ A previous study of older veterans described improvement in PTSD-related symptoms with prazosin without concurrent psychotherapy.¹²

Limitations and Strengths

While this study is the largest study to evaluate outcomes of prazosin in older patients with PTSD, there are several important limitations. The study population was small and all were male. The results of this study may not be applicable to women. Another limitation was several missing values in our data set, as some secondary outcomes were not collected via telephone follow-up visits. This could potentially contribute a measurement bias in the reported secondary outcomes results, specifically for the PCL-5 and ISI. Additionally, some veterans in this study may have reported symptomatic improvement based on the additional supportive intervention that clinical pharmacists were able to offer, as well as concomitant participation in psychotherapy. This may be reflected in the study results. This study did not have a true placebo group, as we may find a reduction in symptoms with placebo.

Strengths of this study include multiple data points for assessment of prazosin tolerability and a pre- and poststudy design, which allowed for the veterans to serve as their own control. Another strength of this study is that data were complete for primary outcome measures, including the CAPS Recurrent and Distressing Dreams Item, where prazosin showed significant benefit in reduction of PTSD-related nightmares. While the results of this study are reassuring, further randomized, double-blind, placebo-controlled trials are likely needed in order to establish efficacy and tolerability of prazosin in older veterans for PTSD related nightmares.

Conclusion

These results demonstrate prazosin therapy in older veterans can significantly improve PTSD-related nightmares and PTSD severity. Prazosin was well tolerated in this population at doses higher than previously reported in other studies. This study shows that prazosin therapy can be effectively managed and tolerated in older veterans with complex medical and psychiatric comorbidities to provide favorable patient outcomes.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Iowa City VA Health Care System and by the Health Services Research and Development Service, US Department of Veterans Affairs.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

Sporadic porphyria cutanea tarda (PCT) is the most common cause of porphyria worldwide.^1,2 Unlike other forms of porphyria, PCT usually is an acquired disease precipitated by extrinsic risk factors that commonly include excessive alcohol consumption, smoking, and chronic hepatitis C virus (HCV) infection. Additional risk factors include myeloproliferative disorders, exposure to polyhalogenated compounds, estrogen therapy, diseases of iron overload like hereditary hemochromatosis (HH), and potentially, HIV infection.^1-3

In this case report, we present a patient with an iron overload (due in part to an HFE gene mutation) and concomitant PCT, HCV infection, and coronary artery disease (CAD). We will discuss the relationship that his iron overload may play in each of these disease states.

Case Presentation

Mr. M is a 59-year-old white male of Irish background with a medical history that includes coronary artery disease. He is status post ST-elevation myocardial infarction and percutaneous coronary intervention with placement of 2 drug-eluting stents. Additional medical issues include PCT and HCV infection with cirrhosis. He is an active smoker.

The patient has a long history of developing blisters with minor trauma, such as rubbing against his mattress/bed sheets or bumping into doors. These blisters primarily occur on his upper extremities, but also can occur on his face after shaving. Mr. M was diagnosed with HCV infection in 1979 while on active military duty. At that time, he had an acute HCV infection and jaundice that required a prolonged hospitalization. He reported no IV drug use and that many others on his military base had similar manifestations. He drinks 1 to 2 beers daily, but reports no binge drinking.

Porphyria Cutanea Tarda

The pathogenesis of PCT is related to the intrahepatic deficiency of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway (Figure 1). Decreased activity of UROD leads to accumulation of uroporphyrinogen and its derivatives, which most likely are oxidized in presence of cytochrome P450 1A2. Up to 80% of PCT cases are sporadic, in which the deficiency of UROD is acquired by exogenous risk factors as mentioned above. However, the remaining 20% of PCT cases are due to an autosomal dominant mutation of UROD that causes the partial deficiency (up to 50%) of UROD. In these cases, additional risk factors are needed to decrease UROD activity to < 75% for symptoms to occur.

Clinical Manifestation

Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.³ The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.² In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.

Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.

Diagnosis and Treatment

PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.

Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.^1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.

In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.

Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.

The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.^3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.⁶

Hemochromatosis

Human cells need iron for aerobic respiration. The intestinal mucosa controls iron uptake and its transfer to the blood stream. Aside from variations in intestinal absorption with fecal excretion, humans do not have another pathway to excrete excess iron. HH is the most common genetic disorder in whites.⁷ It is an autosomal recessive disorder that increases the intestinal absorption of iron. The most common mutation in the hemochromatosis (HFE) gene results in a substitution of tyrosine for cysteine at amino acid number 282 and is referred to as the C282Y mutation. A second mutation changes histidine at position 63 to aspartic acid and is referred to as a H63D mutation. H63D is present in a minority of the patients with phenotypically expressed HH and its clinical impact is unknown.

Homozygosity of the C282Y mutation is the most common genotype associated with clinical hemochromatosis. While carriers of the C282Y gene heterozygote mutation typically do not develop enough iron overload to cause clinical hemochromatosis, they can if other risk factors, such as PCT, excess alcohol use, liver disease, or HCV, are present.⁸ Additionally, an associated genetic defect, like a compound heterozygotes C282Y/H63D mutation, a private HFE mutation in trans, or other iron-related genes, can cause manifestations of iron overload. Lastly, about 20% of patients that are heterozygous for both mutations can express the HH phenotype.⁸

Clinical Manifestation

Patients with HH absorb only a few extra milligrams of iron daily. The clinical manifestation begins to occur when the total body iron store reaches 15-40 g (normal, 4 g). While the genetic mutation is present from birth, iron stores start to rise slowly to around 10 g > age 15 years, at which point serum iron levels are elevated. After age 20 years, the speed with which the iron is stored increases, and by 30 years, liver damage and tissue injury will occur. Cirrhosis is possible by 40 years.⁷ Age, sex, dietary iron intake, blood loss (menstruation), pregnancy, and other unknown factors greatly influence the disease progression. Homozygote C282Y mutation is as common in women as it is in men, but women are less likely to express the HH phenotype, presumably due, in part, to menstruation. When diagnosed early, most of the clinical manifestations of HH are preventable. Additional manifestations of HH include hyperpigmentation, cardiomyopathy, diabetes mellitus, hypogonadism, hypothyroidism, and arthropathy due to pseudogout.

Iron overload due to HH should be distinguished from other causes of iron overload including exogenous iron overload, anemia (thalassemia, sideroblastic), and chronic liver diseases like PCT, viral hepatitis, nonalcoholic steatohepatitis, and alcoholic liver disease.

Diagnosis

HH should be suspected in patients with a high serum transferrin saturation and elevated serum ferritin concentrations. Typically, transferrin saturation is > 50% and ferritin levels are > 300 ng/mL in men and > 200 ng/mL in women. In early stages of the disease, transferrin saturation can be normal. Additionally, in patients with chronic inflammation, ferritin may be high due to acute-phase reactants and the iron panel should be interpreted with caution. When the secondary causes of abnormalities in a patient’s iron studies are excluded, genetic testing for HFE gene is recommended.

The majority of patients (60-93%) with clinically evident hemochromatosis are homozygous for C282Y mutation. In a heterozygous C282Y mutation with a high transferrin saturation and HH phenotype, additional genetic testing for a heterozygous compound mutation C282Y/H63D is recommended.⁸ Additional studies could include evaluation for a private HFE mutation in trans or other iron-related genes. Liver biopsy is the gold standard for assessing the degree of hepatic fibrosis. Determining the degree of fibrosis by some means is needed due to the increased risk of hepatocellular carcinoma (HCC) in HH patients with advanced fibrosis and cirrhosis.⁹

Treatment

Iron depletion with phlebotomy is the cornerstone of treatment in HH. Phlebotomy initially is done weekly with goal of achieving a transferrin saturation < 50%, a serum ferritin level < 50 ng/mL, and a hemoglobin of 12 to 13 ng/mL. When these goals are achieved, patients typically need 4 to 8 phlebotomies per year to maintain a transferrin saturation < 50% (Figure 3).

Hemochromatosis and PCT

Many studies have investigated the relevance of C282Y and/or H63D mutations in patients with PCT.^9,10 It appears that ≥ 1 mutation of the HFE gene in PCT may be an important susceptibility factor in the development of clinical PCT. Various studies have shown an incidence of C282Y mutations of 44 to 47% in patients with PCT, compared with 9 to 12% in control populations.^9,10 The incidence of the H63D mutation in PCT has been more variable, with some studies showing no difference between patients with PCT and a control group, while other studies showed 31% incidence of H63D mutation in patients with PCT.^9,10 A higher incidence of C282Y and H63D mutations in PCT may be a sign that the HFE mutation could be an important factor in developing PCT.

Hemochromatosis and Hepatitis C

Transferrin saturation is frequently elevated in patients with HCV. It is yet unclear whether the pathology of liver disease in patients with HCV is influenced by iron overload or limited to the direct cell damage from replication of the virus and subsequent inflammation. It is believed that the pathology of iron overload in the patients with HCV is different from HH. Like other secondary causes of iron overload, the excess iron is stored in the Kupffer cells of patients with HCV. In HH, excess iron is stored in hepatocytes.

The prevalence of the HFE mutation is the same in the patients with chronic HCV and healthy individuals.^10,11 However, HFE mutations are more prevalent in 30 to 60% of the patients with chronic HCV who have elevated transferrin saturations. Alone, C282Y heterozygosity, H63D heterozygosity, or C282Y/H63D compound heterozygosity could not lead to clinically significant iron overload in otherwise healthy individuals; however, these could be a significant cause of iron overload in patients with chronic HCV. Theoretically, the combination of iron overload and HFE gene mutations could increase the rate of advanced fibrosis/cirrhosis in chronic HCV. An increase serum ferritin level of 200 ng/dL in women and 250 ng/dL in men has been observed in 32% of patients with chronic HCV. In this subset of patients, phlebotomy reduced the progression of their liver disease and reduction in their liver enzymes.

Iron Overload and Cardiovascular Risk

In 1987, a Framingham cohort of > 2,800 patients showed a higher incident of CAD in postmenopausal women when compared with premenopausal women.¹² In the 1980s, Sullivan hypothesized that the reason for higher incidence of CAD in men when compared with premenopausal women was due to their higher body iron storage.^13-16 A study of 1,930 Finnish men reported that the men with ferritin level ≥ 200 ng/dL had a risk 2.2 times higher of acute myocardial infarction when compared to men with lower serum ferritin level.¹⁷

A prospective study published in 1997 by Klechl showed the role of iron stores in early atherogenesis via promotion of lipid oxidation.¹⁸ Other epidemiological studies have shown a decreased risk of myocardial infarction in blood donors, and while arguments have been made that the blood donors tend to be healthier individuals, 2 studies were published in 1997 matching healthy blood donors to healthy nonblood donors, and both showed a lower risk of CVD in the donors when compared with nondonors.^19,20 Furthermore, in an animal model of atherosclerosis, an iron depleted diet showed a reduction of atherosclerosis progression.²¹ Multiple studies have shown that the heterozygosity for HFE is significantly linked to the risk of cardiovascular events, including the fact that heterozygosity for C282Y has been shown to be a risk factor for myocardial infarction in men and cerebrovascular death in women.^22-25

Conclusion

Multiple studies have shown an association between the elevated iron levels associated with the HFE genotype and the disease states of our patient. These include an increased risk of CAD, the increased risk of cirrhosis in HCV and the development of PCT. Indeed, in this case, our patient likely acquired PCT from the combined risks of HCV and his heterozygous HFE genetic mutation.

With regard to Mr. M’s treatment, the use of an antiviral agent in the treatment of his HCV is fundamental, along with avoidance of alcohol and smoking. If he were to accept HCV treatment, we would anticipate resolution of the PCT, but the ongoing progression of his liver and cardiovascular conditions, due perhaps in part, to relative iron overload from his heterozygous HFE mutation. In this situation, we expect that an ongoing course of therapeutic phlebotomy could help to delay the progression of his chronic liver and cardiovascular diseases.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

NEW ORLEANS – With more than 10% of children receiving complementary or alternative medicine (CAM), you should be familiar with what does and doesn’t work when it comes to using supplements for various medical issues, said Cora Breuner, MD, a professor of pediatrics at the University of Washington, Seattle, and attending physician at Seattle Children’s Hospital.

Dr. Breuner presented an overview of more than a dozen popular supplements with their uses and evidence at the American Academy of Pediatrics annual meeting. Most of the evidence comes from studies in adults, not children, and the evidence overall is sometimes scant, but it can guide physicians in discussing options with parents interested in CAM.
 

Butterbur

This root primarily is used to treat migraines via anti-inflammatory effects. The ideal dose is 50-75 mg daily in 2-3 divided doses for children aged 8-9 years and 100-150 mg daily in 2-3 divided doses for those aged 10 and older (Headache. 2005 Mar;45:196-203; Eur J Pain. 2008;12:301-13; Neurology. 2012 Apr 24;78[17]:1346-53).

Adverse effects are mostly gastrointestinal, such as diarrhea and stomach upset, and dermal/allergic reactions, such as itchy eyes, asthma, and itching.
 

Caffeine

Caffeine is the most popular drug of choice for reducing drowsiness and increasing alertness and has the strongest evidence base, including for improving sports and work performance (J Strength Cond Res. 2010 Jan;24[1]:257-65). Regular caffeine use can lead to dependence, however, and it can cause anxiety, nervousness, irritability, insomnia, peptic ulcers, palpitations, gastroesophageal reflux disease (GERD), and tremors. Withdrawal can involve headaches, irritability, and anxiety.

Cannabidiol

Marijuana has more than 80 cannabinoids, and a nonpsychoactive one, cannabidiol, makes up about 40% of cannabis extracts, Dr. Breuner said. It’s been used as an anticonvulsant and to combat anxiety, psychosis, nausea and rheumatoid arthritis pain. In a study using a rat model for arthritis, inflammation and pain-related behaviors decreased in rats that received cannabidiol (Eur J Pain. 2016 Jul;20[6]:936-48).

A human dose would be about 160-300 mg daily, but side effects can include dry mouth, hypotension, lightheadedness, psychomotor slowing, sedation, and sleepiness.
 

Coenzyme Q10

This antioxidant is fat-soluble and has a chemical structure similar to vitamin K. It has been used in people with autism, chronic fatigue syndrome, fatigue from chemotherapy, Lyme disease, and muscular dystrophy, but the evidence focuses on fibromyalgia. One study of patients with fibromyalgia found that a 300-mg daily dose for 40 days reduced pain by 52%-56%, fatigue by 47%, morning tiredness by 56%, and tender points by 44%, compared with baseline (Antioxid Redox Signal. 2013;19[12]:1356-61.)

In another, 200 mg of coenzyme Q10 with 200 mg ginkgo daily for 3 months resulted in improvement of quality of life measures, including physical fitness levels, emotional feelings, social activities, overall health, and pain (J Int Med Res. 2002;30:195-9).

Potential adverse effects of coenzyme Q10 include nausea, vomiting, diarrhea, appetite suppression, and heartburn, albeit typically in less than 1% of patients.
 

Echinacea

magicflute002/Thinkstock

Echinacea actually is approved in Germany for supportive therapy in treating upper respiratory tract infections, urogenital infections, and wound healing, Dr. Breuner said. Hypothesized mechanisms of action include stimulation of the alternate complement pathway, immune-modulating effects, activating nonspecific T cells, inhibiting viral replication, and enhancing phagocytosis.

However, in clinical studies, echinacea did not reduce the duration or severity of upper respiratory tract infections or the occurrence or severity of infection, compared with placebo (JAMA. 2003 Dec 3;290[21]:2824-30; N Engl J Med. 2005 Jul 28;353[4]:341-8); this was tested in children aged 2-11 years in the first study, and the mean age of the subjects in the second study was 21 years. A 2014 Cochrane review found no overall benefits for treating common colds but noted the possibility of “a weak benefit from some echinacea products” based on individual trials with consistently positive, yet nonsignificant, trends, albeit with “questionable clinical relevance” (Cochrane Database Syst Rev. 2014 Feb 20;[2]:CD000530).

People with autoimmune conditions or who are immunocompromised should not use echinacea.
 

Magnesium

Magnesium also is used to treat migraines with a dose of 300-500 mg daily, although also it can be consumed in food, such as soy beans, black beans, tofu, seeds, nuts, whole grains, and shellfish (Expert Rev Neurother. 2009 Mar;9[3]:369-79; Neurology. 2012 Apr 24;78[17]:1346-53).

Side effects can include diarrhea and interactions with bisphosphonates, antibiotics] and diuretics. Taking proton pump inhibitors also may reduce magnesium levels.
 

Melatonin

Wjeger/Thinkstockphotos

Melatonin, a synthetic version of the hormone produced in humans to signal the onset of nighttime, has been studied extensively for jet lag, insomnia, shift-work disorder, circadian rhythm disorders, and withdrawal from benzodiazepine and nicotine.

Research shows that melatonin can improve sleep onset, duration, and quality. Some research has shown increased total sleep time (PLoS One. 2013 May 17;8(5):e63773).

Some evidence suggests it has endocrine-disrupting adverse effects, such as inhibiting ovulation and impairing glucose utilization.
 

N-acetyl cysteine (NAC)

Although it’s primarily an antidote for acetaminophen and carbon monoxide poisoning, NAC has been used for a wide range of conditions, including reducing lipoprotein levels with hyperlipidemia and reducing risk of cardiovascular events in people with end-stage renal disease and other conditions. It also has been used in people with bipolar disorder, schizophrenia, PTSD, substance disorders, and Tourette syndrome.

“Some clinical research shows that taking NAC 900 mg daily for 4 weeks, followed by 900 mg twice daily for 4 weeks and then 900 mg three times daily for 4 weeks improves symptoms of irritability in children with autism,” Dr. Breuner said. Other research showed reduced irritability in children with autism when they took 1,200 mg of NAC daily with risperidone, compared with risperidone alone. One study also has found “that NAC adds to the effect of citalopram in improving resistance/control to compulsions in OCD children and adolescents” (Iran J Psychiatry. 2017 Apr;12[2]:134-141).

Side effects can include diarrhea, nausea, and heartburn.
 

Omega-3 fatty acids: DHA and EHA

Docosahexanoic acid (DHA) and eicosapentanoic acid (EHA) have been used to treat ADHD, depression, heart disease, and also to lower the risk of macular degeneration.

A systematic review of 25 randomized controlled trials of more than 3,600 subjects found that “omega-3 supplementation generally correlated with improvements in blood biomarkers” (Nutrients. 2018 Aug 15;10[8]. pii: E1094). A small study in children with Tourette syndrome found that omega-3 fatty acids did not reduce tic scores, but “may be beneficial in reduction of tic-related impairment” for some children and teens (Pediatrics. 2012 Jun;129[6]:e1493-500).

Possible adverse effects include fishy taste, belching, nosebleeds, nausea, loose stools, and – at higher doses – decreased blood coagulation.
 

St. John’s wort

Alexandru Magurean/Thinkstock

This herb has long been used to treat depression and appears to work by inhibiting serotonin reuptake, monoamine oxidase (MAO), 5-hydroxytryptamine (5-HT), dopamine, noradrenaline, gamma aminobutyric acid (GABA), and glutamate. A 2005 Cochrane review found St. John’s wort to work better than placebo with similar effectiveness as standard antidepressants for mild to moderate depression, but its benefit for major depression is questionable (Cochrane Database Syst Rev. 2005 Apr 18;[2]:CD000448).

An ideal dose is 300 mg daily, but physicians should be aware of the herb’s potential for certain drug interactions. It may increase metabolism of warfarin, cyclosporin, HIV protease inhibitors, theophylline, digoxin, and oral contraceptives (Expert Opin Drug Metab Toxicol. 2012 Jun;8[6]:691-708). Other potential side effects include decreased platelet aggregation, serotonin syndrome, and photosensitivity.
 

Turmeric (curcumin)

SyedMirazurRahman/Thinkstock

Turmeric is an anti-inflammatory agent used for a wide range of complaints, but research primarily has focused on its use for pain. No studies exist in children, but a handful of studies have found reduction in joint pain and rheumatoid arthritis symptoms in adults with 500-mg doses twice daily (Phytother Res. 2012 Nov;26[11]:1719-25; J Med Food. 2017 Oct;20[10]:1022-30). One of these studies focused on a specific product, Instaflex, that contained turmeric among multiple other active ingredients (Nutr J. 2013 Nov 25;12[1]:154).

Potential adverse effects of turmeric/curcumin include constipation, dyspepsia, diarrhea, dissension, reflux, nausea, vomiting, itching, and hives.
 

Zinc

ilkab/Thinkstock

Like echinacea, zinc is commonly used to treat the common cold. A 2013 Cochrane review of randomized, controlled trials found that taking zinc “within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people, but some caution is needed due to the heterogeneity of the data” (Cochrane Database Syst Rev. 2013 Jun 18;[6]:CD001364). The dose is 75 mg a day, and potential adverse effects include bad taste, nausea, and anosmia.

Dr. Breuner said she had no relevant financial disclosures.

NEW ORLEANS – With more than 10% of children receiving complementary or alternative medicine (CAM), you should be familiar with what does and doesn’t work when it comes to using supplements for various medical issues, said Cora Breuner, MD, a professor of pediatrics at the University of Washington, Seattle, and attending physician at Seattle Children’s Hospital.

Dr. Breuner presented an overview of more than a dozen popular supplements with their uses and evidence at the American Academy of Pediatrics annual meeting. Most of the evidence comes from studies in adults, not children, and the evidence overall is sometimes scant, but it can guide physicians in discussing options with parents interested in CAM.
 

Butterbur

This root primarily is used to treat migraines via anti-inflammatory effects. The ideal dose is 50-75 mg daily in 2-3 divided doses for children aged 8-9 years and 100-150 mg daily in 2-3 divided doses for those aged 10 and older (Headache. 2005 Mar;45:196-203; Eur J Pain. 2008;12:301-13; Neurology. 2012 Apr 24;78[17]:1346-53).

Adverse effects are mostly gastrointestinal, such as diarrhea and stomach upset, and dermal/allergic reactions, such as itchy eyes, asthma, and itching.
 

Caffeine

Caffeine is the most popular drug of choice for reducing drowsiness and increasing alertness and has the strongest evidence base, including for improving sports and work performance (J Strength Cond Res. 2010 Jan;24[1]:257-65). Regular caffeine use can lead to dependence, however, and it can cause anxiety, nervousness, irritability, insomnia, peptic ulcers, palpitations, gastroesophageal reflux disease (GERD), and tremors. Withdrawal can involve headaches, irritability, and anxiety.

Cannabidiol

Marijuana has more than 80 cannabinoids, and a nonpsychoactive one, cannabidiol, makes up about 40% of cannabis extracts, Dr. Breuner said. It’s been used as an anticonvulsant and to combat anxiety, psychosis, nausea and rheumatoid arthritis pain. In a study using a rat model for arthritis, inflammation and pain-related behaviors decreased in rats that received cannabidiol (Eur J Pain. 2016 Jul;20[6]:936-48).

A human dose would be about 160-300 mg daily, but side effects can include dry mouth, hypotension, lightheadedness, psychomotor slowing, sedation, and sleepiness.
 

Coenzyme Q10

This antioxidant is fat-soluble and has a chemical structure similar to vitamin K. It has been used in people with autism, chronic fatigue syndrome, fatigue from chemotherapy, Lyme disease, and muscular dystrophy, but the evidence focuses on fibromyalgia. One study of patients with fibromyalgia found that a 300-mg daily dose for 40 days reduced pain by 52%-56%, fatigue by 47%, morning tiredness by 56%, and tender points by 44%, compared with baseline (Antioxid Redox Signal. 2013;19[12]:1356-61.)

In another, 200 mg of coenzyme Q10 with 200 mg ginkgo daily for 3 months resulted in improvement of quality of life measures, including physical fitness levels, emotional feelings, social activities, overall health, and pain (J Int Med Res. 2002;30:195-9).

Potential adverse effects of coenzyme Q10 include nausea, vomiting, diarrhea, appetite suppression, and heartburn, albeit typically in less than 1% of patients.
 

Echinacea

magicflute002/Thinkstock

Echinacea actually is approved in Germany for supportive therapy in treating upper respiratory tract infections, urogenital infections, and wound healing, Dr. Breuner said. Hypothesized mechanisms of action include stimulation of the alternate complement pathway, immune-modulating effects, activating nonspecific T cells, inhibiting viral replication, and enhancing phagocytosis.

However, in clinical studies, echinacea did not reduce the duration or severity of upper respiratory tract infections or the occurrence or severity of infection, compared with placebo (JAMA. 2003 Dec 3;290[21]:2824-30; N Engl J Med. 2005 Jul 28;353[4]:341-8); this was tested in children aged 2-11 years in the first study, and the mean age of the subjects in the second study was 21 years. A 2014 Cochrane review found no overall benefits for treating common colds but noted the possibility of “a weak benefit from some echinacea products” based on individual trials with consistently positive, yet nonsignificant, trends, albeit with “questionable clinical relevance” (Cochrane Database Syst Rev. 2014 Feb 20;[2]:CD000530).

People with autoimmune conditions or who are immunocompromised should not use echinacea.
 

Magnesium

Magnesium also is used to treat migraines with a dose of 300-500 mg daily, although also it can be consumed in food, such as soy beans, black beans, tofu, seeds, nuts, whole grains, and shellfish (Expert Rev Neurother. 2009 Mar;9[3]:369-79; Neurology. 2012 Apr 24;78[17]:1346-53).

Side effects can include diarrhea and interactions with bisphosphonates, antibiotics] and diuretics. Taking proton pump inhibitors also may reduce magnesium levels.
 

Melatonin

Wjeger/Thinkstockphotos

Melatonin, a synthetic version of the hormone produced in humans to signal the onset of nighttime, has been studied extensively for jet lag, insomnia, shift-work disorder, circadian rhythm disorders, and withdrawal from benzodiazepine and nicotine.

Research shows that melatonin can improve sleep onset, duration, and quality. Some research has shown increased total sleep time (PLoS One. 2013 May 17;8(5):e63773).

Some evidence suggests it has endocrine-disrupting adverse effects, such as inhibiting ovulation and impairing glucose utilization.
 

N-acetyl cysteine (NAC)

Although it’s primarily an antidote for acetaminophen and carbon monoxide poisoning, NAC has been used for a wide range of conditions, including reducing lipoprotein levels with hyperlipidemia and reducing risk of cardiovascular events in people with end-stage renal disease and other conditions. It also has been used in people with bipolar disorder, schizophrenia, PTSD, substance disorders, and Tourette syndrome.

“Some clinical research shows that taking NAC 900 mg daily for 4 weeks, followed by 900 mg twice daily for 4 weeks and then 900 mg three times daily for 4 weeks improves symptoms of irritability in children with autism,” Dr. Breuner said. Other research showed reduced irritability in children with autism when they took 1,200 mg of NAC daily with risperidone, compared with risperidone alone. One study also has found “that NAC adds to the effect of citalopram in improving resistance/control to compulsions in OCD children and adolescents” (Iran J Psychiatry. 2017 Apr;12[2]:134-141).

Side effects can include diarrhea, nausea, and heartburn.
 

Omega-3 fatty acids: DHA and EHA

Docosahexanoic acid (DHA) and eicosapentanoic acid (EHA) have been used to treat ADHD, depression, heart disease, and also to lower the risk of macular degeneration.

A systematic review of 25 randomized controlled trials of more than 3,600 subjects found that “omega-3 supplementation generally correlated with improvements in blood biomarkers” (Nutrients. 2018 Aug 15;10[8]. pii: E1094). A small study in children with Tourette syndrome found that omega-3 fatty acids did not reduce tic scores, but “may be beneficial in reduction of tic-related impairment” for some children and teens (Pediatrics. 2012 Jun;129[6]:e1493-500).

Possible adverse effects include fishy taste, belching, nosebleeds, nausea, loose stools, and – at higher doses – decreased blood coagulation.
 

St. John’s wort

Alexandru Magurean/Thinkstock

This herb has long been used to treat depression and appears to work by inhibiting serotonin reuptake, monoamine oxidase (MAO), 5-hydroxytryptamine (5-HT), dopamine, noradrenaline, gamma aminobutyric acid (GABA), and glutamate. A 2005 Cochrane review found St. John’s wort to work better than placebo with similar effectiveness as standard antidepressants for mild to moderate depression, but its benefit for major depression is questionable (Cochrane Database Syst Rev. 2005 Apr 18;[2]:CD000448).

An ideal dose is 300 mg daily, but physicians should be aware of the herb’s potential for certain drug interactions. It may increase metabolism of warfarin, cyclosporin, HIV protease inhibitors, theophylline, digoxin, and oral contraceptives (Expert Opin Drug Metab Toxicol. 2012 Jun;8[6]:691-708). Other potential side effects include decreased platelet aggregation, serotonin syndrome, and photosensitivity.
 

Turmeric (curcumin)

SyedMirazurRahman/Thinkstock

Turmeric is an anti-inflammatory agent used for a wide range of complaints, but research primarily has focused on its use for pain. No studies exist in children, but a handful of studies have found reduction in joint pain and rheumatoid arthritis symptoms in adults with 500-mg doses twice daily (Phytother Res. 2012 Nov;26[11]:1719-25; J Med Food. 2017 Oct;20[10]:1022-30). One of these studies focused on a specific product, Instaflex, that contained turmeric among multiple other active ingredients (Nutr J. 2013 Nov 25;12[1]:154).

Potential adverse effects of turmeric/curcumin include constipation, dyspepsia, diarrhea, dissension, reflux, nausea, vomiting, itching, and hives.
 

Zinc

ilkab/Thinkstock

Like echinacea, zinc is commonly used to treat the common cold. A 2013 Cochrane review of randomized, controlled trials found that taking zinc “within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people, but some caution is needed due to the heterogeneity of the data” (Cochrane Database Syst Rev. 2013 Jun 18;[6]:CD001364). The dose is 75 mg a day, and potential adverse effects include bad taste, nausea, and anosmia.

Dr. Breuner said she had no relevant financial disclosures.

NEW ORLEANS – With more than 10% of children receiving complementary or alternative medicine (CAM), you should be familiar with what does and doesn’t work when it comes to using supplements for various medical issues, said Cora Breuner, MD, a professor of pediatrics at the University of Washington, Seattle, and attending physician at Seattle Children’s Hospital.

Dr. Breuner presented an overview of more than a dozen popular supplements with their uses and evidence at the American Academy of Pediatrics annual meeting. Most of the evidence comes from studies in adults, not children, and the evidence overall is sometimes scant, but it can guide physicians in discussing options with parents interested in CAM.
 

Butterbur

This root primarily is used to treat migraines via anti-inflammatory effects. The ideal dose is 50-75 mg daily in 2-3 divided doses for children aged 8-9 years and 100-150 mg daily in 2-3 divided doses for those aged 10 and older (Headache. 2005 Mar;45:196-203; Eur J Pain. 2008;12:301-13; Neurology. 2012 Apr 24;78[17]:1346-53).

Adverse effects are mostly gastrointestinal, such as diarrhea and stomach upset, and dermal/allergic reactions, such as itchy eyes, asthma, and itching.
 

Caffeine

Caffeine is the most popular drug of choice for reducing drowsiness and increasing alertness and has the strongest evidence base, including for improving sports and work performance (J Strength Cond Res. 2010 Jan;24[1]:257-65). Regular caffeine use can lead to dependence, however, and it can cause anxiety, nervousness, irritability, insomnia, peptic ulcers, palpitations, gastroesophageal reflux disease (GERD), and tremors. Withdrawal can involve headaches, irritability, and anxiety.

Cannabidiol

Marijuana has more than 80 cannabinoids, and a nonpsychoactive one, cannabidiol, makes up about 40% of cannabis extracts, Dr. Breuner said. It’s been used as an anticonvulsant and to combat anxiety, psychosis, nausea and rheumatoid arthritis pain. In a study using a rat model for arthritis, inflammation and pain-related behaviors decreased in rats that received cannabidiol (Eur J Pain. 2016 Jul;20[6]:936-48).

A human dose would be about 160-300 mg daily, but side effects can include dry mouth, hypotension, lightheadedness, psychomotor slowing, sedation, and sleepiness.
 

Coenzyme Q10

This antioxidant is fat-soluble and has a chemical structure similar to vitamin K. It has been used in people with autism, chronic fatigue syndrome, fatigue from chemotherapy, Lyme disease, and muscular dystrophy, but the evidence focuses on fibromyalgia. One study of patients with fibromyalgia found that a 300-mg daily dose for 40 days reduced pain by 52%-56%, fatigue by 47%, morning tiredness by 56%, and tender points by 44%, compared with baseline (Antioxid Redox Signal. 2013;19[12]:1356-61.)

In another, 200 mg of coenzyme Q10 with 200 mg ginkgo daily for 3 months resulted in improvement of quality of life measures, including physical fitness levels, emotional feelings, social activities, overall health, and pain (J Int Med Res. 2002;30:195-9).

Potential adverse effects of coenzyme Q10 include nausea, vomiting, diarrhea, appetite suppression, and heartburn, albeit typically in less than 1% of patients.
 

Echinacea

magicflute002/Thinkstock

Echinacea actually is approved in Germany for supportive therapy in treating upper respiratory tract infections, urogenital infections, and wound healing, Dr. Breuner said. Hypothesized mechanisms of action include stimulation of the alternate complement pathway, immune-modulating effects, activating nonspecific T cells, inhibiting viral replication, and enhancing phagocytosis.

However, in clinical studies, echinacea did not reduce the duration or severity of upper respiratory tract infections or the occurrence or severity of infection, compared with placebo (JAMA. 2003 Dec 3;290[21]:2824-30; N Engl J Med. 2005 Jul 28;353[4]:341-8); this was tested in children aged 2-11 years in the first study, and the mean age of the subjects in the second study was 21 years. A 2014 Cochrane review found no overall benefits for treating common colds but noted the possibility of “a weak benefit from some echinacea products” based on individual trials with consistently positive, yet nonsignificant, trends, albeit with “questionable clinical relevance” (Cochrane Database Syst Rev. 2014 Feb 20;[2]:CD000530).

People with autoimmune conditions or who are immunocompromised should not use echinacea.
 

Magnesium

Magnesium also is used to treat migraines with a dose of 300-500 mg daily, although also it can be consumed in food, such as soy beans, black beans, tofu, seeds, nuts, whole grains, and shellfish (Expert Rev Neurother. 2009 Mar;9[3]:369-79; Neurology. 2012 Apr 24;78[17]:1346-53).

Side effects can include diarrhea and interactions with bisphosphonates, antibiotics] and diuretics. Taking proton pump inhibitors also may reduce magnesium levels.
 

Melatonin

Wjeger/Thinkstockphotos

Melatonin, a synthetic version of the hormone produced in humans to signal the onset of nighttime, has been studied extensively for jet lag, insomnia, shift-work disorder, circadian rhythm disorders, and withdrawal from benzodiazepine and nicotine.

Research shows that melatonin can improve sleep onset, duration, and quality. Some research has shown increased total sleep time (PLoS One. 2013 May 17;8(5):e63773).

Some evidence suggests it has endocrine-disrupting adverse effects, such as inhibiting ovulation and impairing glucose utilization.
 

N-acetyl cysteine (NAC)

Although it’s primarily an antidote for acetaminophen and carbon monoxide poisoning, NAC has been used for a wide range of conditions, including reducing lipoprotein levels with hyperlipidemia and reducing risk of cardiovascular events in people with end-stage renal disease and other conditions. It also has been used in people with bipolar disorder, schizophrenia, PTSD, substance disorders, and Tourette syndrome.

“Some clinical research shows that taking NAC 900 mg daily for 4 weeks, followed by 900 mg twice daily for 4 weeks and then 900 mg three times daily for 4 weeks improves symptoms of irritability in children with autism,” Dr. Breuner said. Other research showed reduced irritability in children with autism when they took 1,200 mg of NAC daily with risperidone, compared with risperidone alone. One study also has found “that NAC adds to the effect of citalopram in improving resistance/control to compulsions in OCD children and adolescents” (Iran J Psychiatry. 2017 Apr;12[2]:134-141).

Side effects can include diarrhea, nausea, and heartburn.
 

Omega-3 fatty acids: DHA and EHA

Docosahexanoic acid (DHA) and eicosapentanoic acid (EHA) have been used to treat ADHD, depression, heart disease, and also to lower the risk of macular degeneration.

A systematic review of 25 randomized controlled trials of more than 3,600 subjects found that “omega-3 supplementation generally correlated with improvements in blood biomarkers” (Nutrients. 2018 Aug 15;10[8]. pii: E1094). A small study in children with Tourette syndrome found that omega-3 fatty acids did not reduce tic scores, but “may be beneficial in reduction of tic-related impairment” for some children and teens (Pediatrics. 2012 Jun;129[6]:e1493-500).

Possible adverse effects include fishy taste, belching, nosebleeds, nausea, loose stools, and – at higher doses – decreased blood coagulation.
 

St. John’s wort

Alexandru Magurean/Thinkstock

This herb has long been used to treat depression and appears to work by inhibiting serotonin reuptake, monoamine oxidase (MAO), 5-hydroxytryptamine (5-HT), dopamine, noradrenaline, gamma aminobutyric acid (GABA), and glutamate. A 2005 Cochrane review found St. John’s wort to work better than placebo with similar effectiveness as standard antidepressants for mild to moderate depression, but its benefit for major depression is questionable (Cochrane Database Syst Rev. 2005 Apr 18;[2]:CD000448).

An ideal dose is 300 mg daily, but physicians should be aware of the herb’s potential for certain drug interactions. It may increase metabolism of warfarin, cyclosporin, HIV protease inhibitors, theophylline, digoxin, and oral contraceptives (Expert Opin Drug Metab Toxicol. 2012 Jun;8[6]:691-708). Other potential side effects include decreased platelet aggregation, serotonin syndrome, and photosensitivity.
 

Turmeric (curcumin)

SyedMirazurRahman/Thinkstock

Turmeric is an anti-inflammatory agent used for a wide range of complaints, but research primarily has focused on its use for pain. No studies exist in children, but a handful of studies have found reduction in joint pain and rheumatoid arthritis symptoms in adults with 500-mg doses twice daily (Phytother Res. 2012 Nov;26[11]:1719-25; J Med Food. 2017 Oct;20[10]:1022-30). One of these studies focused on a specific product, Instaflex, that contained turmeric among multiple other active ingredients (Nutr J. 2013 Nov 25;12[1]:154).

Potential adverse effects of turmeric/curcumin include constipation, dyspepsia, diarrhea, dissension, reflux, nausea, vomiting, itching, and hives.
 

Zinc

ilkab/Thinkstock

Like echinacea, zinc is commonly used to treat the common cold. A 2013 Cochrane review of randomized, controlled trials found that taking zinc “within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people, but some caution is needed due to the heterogeneity of the data” (Cochrane Database Syst Rev. 2013 Jun 18;[6]:CD001364). The dose is 75 mg a day, and potential adverse effects include bad taste, nausea, and anosmia.

Dr. Breuner said she had no relevant financial disclosures.

Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.

The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.

The research has been hailed as groundbreaking.

Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].

“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.

“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.

“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.

The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.

In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.

“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.

Need for guidance

Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.

Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.

The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.

Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.

To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.

To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.

“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.

The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.

Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.

Egg harvest and T

The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.

The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).

Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.

“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.

Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.

A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).

Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.

Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.

The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.

“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.

“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.

“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.

Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”

Higher yield

The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.

“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”

“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.

But this is “speculative,” she acknowledged, given the low numbers.

Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.

Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.

Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.

Puberty blocking and fertility

When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.

“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”

“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.

Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.

“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.

Dr. Resetkova has reported no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.

Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.

The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.

The research has been hailed as groundbreaking.

Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].

“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.

“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.

“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.

The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.

In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.

“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.

Need for guidance

Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.

Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.

The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.

Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.

To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.

To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.

“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.

The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.

Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.

Egg harvest and T

The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.

The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).

Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.

“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.

Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.

A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).

Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.

Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.

The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.

“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.

“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.

“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.

Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”

Higher yield

The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.

“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”

“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.

But this is “speculative,” she acknowledged, given the low numbers.

Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.

Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.

Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.

Puberty blocking and fertility

When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.

“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”

“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.

Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.

“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.

Dr. Resetkova has reported no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.

Transgender men who were assigned female sex at birth show a similar response to ovarian stimulation as cisgender women, even after using testosterone, shows the first formal study of its kind in this patient group.

The transgender patients each had an average of 20 eggs retrieved, and all who transferred embryos eventually achieved a successful pregnancy and delivery, “representing the largest cohort of transgender male patients to be described in the literature thus far,” wrote Nina Resetkova, MD, and colleagues in their article, published in Fertility and Sterility.

The research has been hailed as groundbreaking.

Dr. Resetkova, a reproductive endocrinologist at Boston IVF, Beth Israel Deaconess Medical Center, said in an interview that “these new data show it is reasonable for transmen [female-to-male transition], even those who have used testosterone for some time, to undergo assisted reproductive technology [ART].

“We’ve found that there isn’t a decrease in oocyte retrieval and may actually be a slight increase. We found this to be remarkable,” she said, emphasizing that these findings should be very reassuring for transgender male patients concerned about fertility.

“Transmales worry that they’ve thrown in the towel, and by committing to testosterone have started on a pathway with no return, but these data suggest they still have options,” Dr. Resetkova explained.

“Our study shows that these patients can have ovarian stimulation outcomes that are similar to those of cisgender counterparts, and this seems to be true even in cases of patients who have already initiated hormonal transition with the use of testosterone,” she said.

The researcher hopes the results will encourage more referrals for transgender men wishing to explore their fertility options. “Previously, many doctors were reluctant to refer to a fertility practice if their transmale patient had already started testosterone therapy or they had been on it for several years,” she said.

In a comment, Joshua Safer, MD, a spokesperson on transgender issues for the Endocrine Society, said that “fertility compromise may represent the single largest risk of medical treatment for some transgender persons. At meetings and in personal communications, several clinical groups have reported successful egg harvest from transgender men.

“However, this is the first careful study of a defined cohort published formally. As such, it serves as an important reference in advancing transgender medical care,” noted Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York.

Need for guidance

Previously, there has been an assumption that transgender individuals were not interested in maintaining their reproductive potential, but this has proven untrue. “Several recent studies have demonstrated that transgender people do desire parenthood, or at the least wish to preserve that possibility,” noted Dr. Resetkova and colleagues.

Both the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology have issued opinions that transgender patients should have the same access to fertility options as cisgender patients and that fertility preservation options should be discussed before gender transition, they noted.

The first and key intervention needed is the ability to preserve fertility through the cryopreservation of gametes before medical or surgical transition. In transgender men, this can be done via oocyte, embryo, or ovarian tissue cryopreservation.

Dr. Resetkova and the team at Boston IVF realized there was no published evidence, bar a couple of case reports, to guide clinicians caring for transgender men who wanted to preserve their fertility.

To help fill the research gap, they drew data from a retrospective cohort using electronic medical records from a single large in vitro fertilization (IVF) clinic. The search was conducted from January 2010 to July 2018, because the first transgender man was treated at the clinic in 2010.

To be included in the study, the patient had to identify as a transgender man and have completed an ovarian stimulation cycle for oocyte cryopreservation, embryo cryopreservation, or intended uterine transfer.

“This is the first study to describe transgender cycle parameters and outcomes in such detail and scope,” the authors noted in their article.

The study aimed to investigate ART outcomes in a female-to-male transgender cohort (n = 26) who wished to preserve fertility through egg freezing and/or undergo IVF with the intention of pregnancy.

Each transgender man was matched with five cisgender women for age, body mass index, and anti-Müllerian hormone level, and egg yield was compared. The 130 cisgender women were in straight relationships where there was difficulty conceiving, mostly because of male-factor, or tubal-factor, infertility; cisgender women with ovulatory dysfunction were excluded.

Egg harvest and T

The transgender patients were aged 14-39 years, with an average age at cycle start of 28 years. Some patients had not yet undergone any form of medical transition but planned to do so after ART.

The majority (61%) had received testosterone hormonal therapy, and a small number had undergone surgery, for example mastectomy and reconstruction, but none had undergone a hysterectomy or ovary removal (so-called “bottom” or gender-reassignment surgery).

Prior to ART, all patients taking testosterone came off the hormone on average 4 months prior to starting treatment. The mean time on testosterone before seeking ART treatment was 3.7 years and ranged from 3 months to 17 years.

“All patients had intact uterus and ovaries, and all patients had gone through puberty and had not received puberty blocking. This was required for ovarian stimulation and egg freezing,” Dr. Resetkova explained in an interview.

Researchers tracked patient records for outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak estradiol levels.

A mean of 19.9 +/– 8.7 oocytes were retrieved per cycle in the transgender cohort, compared with 15.9 +/– 9.6 in the cisgender female group; peak estradiol levels were similar between the two groups. However, the total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU).

Of the 26 transgender men, 16 had egg preservation (oocyte banking) only. Seven couples had fresh or frozen embryo transfers, with all achieving live births.

Among the patients who planned for IVF with embryo transfer, two intended to carry the pregnancy themselves and the remaining five transferred embryos to their cisgender female partner.

The authors noted that many of the transgender patients who ultimately did not choose to proceed with treatment did so because of the need to stop testosterone therapy before initiating a cycle or the burden of cost.

“For many transgender patients, stopping androgen therapy can be both physically and psychologically distressing, especially because many experience the resumption of menses,” they observed.

“A logical follow-up question is whether ovarian stimulation can be done with any measure of success without the cessation of testosterone,” they noted.

“Although our findings are certainly reassuring for patients who have already initiated androgens, they were still all required to stop therapy to proceed with stimulation. This is a barrier to access that should be investigated, and if overcome may increase utilization of ART by transgender male patients,” they wrote.

Dr. Safer said that, to his knowledge, “a couple of fertility groups ... have been clear that the egg harvest could take place while the transgender men were using testosterone.”

Higher yield

The results with regard to the use of testosterone prior to ART were particularly enlightening, said Dr. Resetkova, who noted that testosterone therapy did not seem to affect ovarian stimulation.

“Before this study, we did not know if long-term testosterone use had a negative impact on egg reserve but, remarkably, testosterone does not appear to have an effect on the ovarian reserve as measured by egg count,” she noted, although she acknowledged that the “study is small.”

“In fact, in some ways, it looks like testosterone might even have a beneficial effect on egg count with a trend towards a higher number of eggs in the transmales who used it,” she added.

But this is “speculative,” she acknowledged, given the low numbers.

Reflecting on why long-term testosterone use may have shown a trend towards greater egg retrieval, Dr. Resetkova explained that the environment might be more similar to an individual with underlying elevated testosterone as seen in polycystic ovarian syndrome, and she noted these patients typically have a higher egg yield during IVF therapy.

Commenting on the higher doses of gonadotropins used in transgender patients, Dr. Resetkova suggested there could be various reasons for this, given that dosing was at the physician’s discretion, including the possibility that they knew the patient only had one chance and therefore higher doses of gonadotropins may have been administered.

Furthermore, each round of treatment is expensive. The researcher stressed, however, there was no conclusion in this respect based on their data.

Puberty blocking and fertility

When asked whether a transgender man who had undergone puberty blocking before transitioning (i.e., someone who had not gone through natural puberty) would be able to follow a similar course to pregnancy as the study participants, Dr. Resetkova acknowledged that is a more challenging area.

“We have little data so it’s hard to be conclusive, but it’s unlikely these patients would have mature hormonal responses and the ovaries might be in a naive state,” she hypothesized. “I don’t know that they would retain so many options as someone who had gone through natural puberty.”

“However, there are research protocols in place at some academic institutions for transgender patients planning to undergo puberty blocking,” she observed.

Finally, referring to individuals who transition from male to female using estrogen therapy, Dr. Resetkova said that the quality of sperm production might be impaired with long-term estrogen exposure. She added that other centers are looking at this.

“As transgender individuals increasingly seek access to reproductive services, we seek to shed light on the optimal way to provide effective care to these patients,” Dr. Dr. Resetkova and colleagues conclude.

Dr. Resetkova has reported no relevant financial relationships.

This article first appeared on Medscape.com.

SOURCE: Resetkova N et al. Fertil Steril. 2019;112:858-65.

The Diagnosis: Herpes Zoster Opthalmicus 

Due to the potential concern of vision loss, the patient was directed to a local emergency department for immediate ophthalmologic evaluation. He was diagnosed with herpes zoster ophthalmicus (HZO) and treated with oral acyclovir and prednisone. The rash and periorbital swelling resolved within 2 weeks of treatment, and he remained asymptomatic at follow-up 3 months later.  

Herpes zoster ophthalmicus presents with an erythematous and vesicular rash in the distribution of cranial nerve V1. The herpetiform grouping of lesions on the forehead is diagnostic of HZO. Varicella-zoster virus (VZV) infection presents in 2 distinct forms. Primary infection (commonly known as chickenpox) presents clinically as a vesicular rash usually located on the face, arms, and trunk. Although the initial presentation usually occurs in childhood and is self-limited, the virus becomes latent in the dorsal root ganglia of sensory neurons. Varicella-zoster virus may become reactivated later in life and is termed herpes zoster (commonly known as shingles). It most often presents as a painful vesicular rash that may later form pustules.  

Zoster outbreaks typically do not cross the midline but may in disseminated disease. Patients may experience a prodrome in the form of pain or less commonly pruritus or paresthesia along the dermatome between 1 and 10 days before the rash appears. Triggers for herpes zoster include illness, medications, malnutrition, surgery, or the natural decline in immune function due to aging. Trauma is another important precipitating event for VZV reactivation; one case-control study showed that zoster patients were 3.4 times more likely than controls to have had trauma the week prior.¹ Patients with cranial zoster are more than 25 times more likely to have experienced trauma in the preceding week. Local trauma may predispose these patients to VZV reactivation by stimulating local sensory nerves or by disrupting local cutaneous immunity.² 

Herpes zoster ophthalmicus occurs when zoster presents in the ophthalmic division of the fifth cranial nerve. It is a serious, vision-threatening condition with a presentation that can include conjunctivitis, scleritis, keratitis, optic neuritis, exophthalmos, lid retraction, ptosis, and extraocular muscle palsies. Treatment includes antiviral medication (eg, acyclovir, valacyclovir, famciclovir) and prompt ophthalmologic consultation due to potential vision-threatening complications, such as acute retinal necrosis. Acute pain control may be necessary with nonsteroidal anti-inflammatory drugs, opioids, steroids, tricyclic antidepressants, or anticonvulsants.³ Wet-to-dry dressings with sterile saline or Burow solution and/or calamine lotion can provide symptomatic relief of itching.  

Periorbital and preseptal cellulitis typically present with more erythema of the skin surrounding the eye and without the accompanying rash. Periorbital cellulitis is the more serious infection and may be clinically distinguished by the presence of pain with extraocular muscle movement. Contact dermatitis and pemphigus vulgaris are possibilities, but both were less likely than HZO in this case presentation given the distribution of the rash and the patient history. Contact dermatitis typically presents with no prodrome with a main concern of pruritus. Pemphigus vulgaris nearly always includes involvement of the oral mucous membranes. 

The Diagnosis: Herpes Zoster Opthalmicus 

Due to the potential concern of vision loss, the patient was directed to a local emergency department for immediate ophthalmologic evaluation. He was diagnosed with herpes zoster ophthalmicus (HZO) and treated with oral acyclovir and prednisone. The rash and periorbital swelling resolved within 2 weeks of treatment, and he remained asymptomatic at follow-up 3 months later.  

Herpes zoster ophthalmicus presents with an erythematous and vesicular rash in the distribution of cranial nerve V1. The herpetiform grouping of lesions on the forehead is diagnostic of HZO. Varicella-zoster virus (VZV) infection presents in 2 distinct forms. Primary infection (commonly known as chickenpox) presents clinically as a vesicular rash usually located on the face, arms, and trunk. Although the initial presentation usually occurs in childhood and is self-limited, the virus becomes latent in the dorsal root ganglia of sensory neurons. Varicella-zoster virus may become reactivated later in life and is termed herpes zoster (commonly known as shingles). It most often presents as a painful vesicular rash that may later form pustules.  

Zoster outbreaks typically do not cross the midline but may in disseminated disease. Patients may experience a prodrome in the form of pain or less commonly pruritus or paresthesia along the dermatome between 1 and 10 days before the rash appears. Triggers for herpes zoster include illness, medications, malnutrition, surgery, or the natural decline in immune function due to aging. Trauma is another important precipitating event for VZV reactivation; one case-control study showed that zoster patients were 3.4 times more likely than controls to have had trauma the week prior.¹ Patients with cranial zoster are more than 25 times more likely to have experienced trauma in the preceding week. Local trauma may predispose these patients to VZV reactivation by stimulating local sensory nerves or by disrupting local cutaneous immunity.² 

Herpes zoster ophthalmicus occurs when zoster presents in the ophthalmic division of the fifth cranial nerve. It is a serious, vision-threatening condition with a presentation that can include conjunctivitis, scleritis, keratitis, optic neuritis, exophthalmos, lid retraction, ptosis, and extraocular muscle palsies. Treatment includes antiviral medication (eg, acyclovir, valacyclovir, famciclovir) and prompt ophthalmologic consultation due to potential vision-threatening complications, such as acute retinal necrosis. Acute pain control may be necessary with nonsteroidal anti-inflammatory drugs, opioids, steroids, tricyclic antidepressants, or anticonvulsants.³ Wet-to-dry dressings with sterile saline or Burow solution and/or calamine lotion can provide symptomatic relief of itching.  

Periorbital and preseptal cellulitis typically present with more erythema of the skin surrounding the eye and without the accompanying rash. Periorbital cellulitis is the more serious infection and may be clinically distinguished by the presence of pain with extraocular muscle movement. Contact dermatitis and pemphigus vulgaris are possibilities, but both were less likely than HZO in this case presentation given the distribution of the rash and the patient history. Contact dermatitis typically presents with no prodrome with a main concern of pruritus. Pemphigus vulgaris nearly always includes involvement of the oral mucous membranes. 

The Diagnosis: Herpes Zoster Opthalmicus 

Due to the potential concern of vision loss, the patient was directed to a local emergency department for immediate ophthalmologic evaluation. He was diagnosed with herpes zoster ophthalmicus (HZO) and treated with oral acyclovir and prednisone. The rash and periorbital swelling resolved within 2 weeks of treatment, and he remained asymptomatic at follow-up 3 months later.  

Herpes zoster ophthalmicus presents with an erythematous and vesicular rash in the distribution of cranial nerve V1. The herpetiform grouping of lesions on the forehead is diagnostic of HZO. Varicella-zoster virus (VZV) infection presents in 2 distinct forms. Primary infection (commonly known as chickenpox) presents clinically as a vesicular rash usually located on the face, arms, and trunk. Although the initial presentation usually occurs in childhood and is self-limited, the virus becomes latent in the dorsal root ganglia of sensory neurons. Varicella-zoster virus may become reactivated later in life and is termed herpes zoster (commonly known as shingles). It most often presents as a painful vesicular rash that may later form pustules.  

Zoster outbreaks typically do not cross the midline but may in disseminated disease. Patients may experience a prodrome in the form of pain or less commonly pruritus or paresthesia along the dermatome between 1 and 10 days before the rash appears. Triggers for herpes zoster include illness, medications, malnutrition, surgery, or the natural decline in immune function due to aging. Trauma is another important precipitating event for VZV reactivation; one case-control study showed that zoster patients were 3.4 times more likely than controls to have had trauma the week prior.¹ Patients with cranial zoster are more than 25 times more likely to have experienced trauma in the preceding week. Local trauma may predispose these patients to VZV reactivation by stimulating local sensory nerves or by disrupting local cutaneous immunity.² 

Herpes zoster ophthalmicus occurs when zoster presents in the ophthalmic division of the fifth cranial nerve. It is a serious, vision-threatening condition with a presentation that can include conjunctivitis, scleritis, keratitis, optic neuritis, exophthalmos, lid retraction, ptosis, and extraocular muscle palsies. Treatment includes antiviral medication (eg, acyclovir, valacyclovir, famciclovir) and prompt ophthalmologic consultation due to potential vision-threatening complications, such as acute retinal necrosis. Acute pain control may be necessary with nonsteroidal anti-inflammatory drugs, opioids, steroids, tricyclic antidepressants, or anticonvulsants.³ Wet-to-dry dressings with sterile saline or Burow solution and/or calamine lotion can provide symptomatic relief of itching.  

Periorbital and preseptal cellulitis typically present with more erythema of the skin surrounding the eye and without the accompanying rash. Periorbital cellulitis is the more serious infection and may be clinically distinguished by the presence of pain with extraocular muscle movement. Contact dermatitis and pemphigus vulgaris are possibilities, but both were less likely than HZO in this case presentation given the distribution of the rash and the patient history. Contact dermatitis typically presents with no prodrome with a main concern of pruritus. Pemphigus vulgaris nearly always includes involvement of the oral mucous membranes.