Geriatrics

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

Since the beginning of the American Republic, servicemen have been captured and held as prisoners of war (POWs), including > 130,000 in World War II , > 7,100 in the Korean War, > 700 in the Vietnam War, and 37 in Operation Desert Storm and recent conflicts.^1,2 Also, > 80 servicewomen have been held during these conflicts.^1-3 Of those living former POWs (FPOWs), almost all are geriatric (aged > 65 years) with a significant portion aged ≥ 85 years.

The physical hardships and psychological stress endured by FPOWs have lifelong deleterious sequelae on health and social functioning.^3-5 The experiences of FPOWs are associated with higher prevalence of chronic diseases and diminished functional performance in later life as demonstrated by a survey of FPOWs from World War II.⁴ The survey assessed health and functional status in a random sample of 101 FPOWs and a group of 107 non-POW combatants from the same military operations. FPOWs reported a higher mean number of somatic symptoms than did non-POWs (7.2 vs 5.4, respectively; P = .002), a higher mean number of diagnosed health conditions (9.4 vs 7.7, respectively; P < .001), and used a greater mean number of medications (4.5 vs 3.4, respectively; P = .001). Among 15 broad categories of diagnoses, differences were found in gastrointestinal disorders (FPOWs 63% vs non-POWs 49%, P = .032), musculoskeletal disorders (FPOWs 76% vs non-POWs 60%, P = .001), and cognitive disorders (FPOWs 31% vs non-POWs 15%, P = .006). FPOWs had a significantly higher proportion of 7 extrapyramidal signs and 6 signs relating to ataxia. On the Instrumental Activities of Daily Living scale, FPOWs were more likely to be impaired than were non-POWs (33% vs 17%, respectively; P = .01). In addition, FPOWs have an increased risk of developing dementia, and this risk is doubled in FPOWs with posttraumatic stress disorder (PTSD) compared with non-FPOWs without PTSD.⁵

These data indicate that FPOW status is associated with increased risk of disability and loss of independence. Federal statutes established the presumption of a relationship between FPOW status and many comorbidities for VA disability determinations in recognition of such data and to overcome lack of medical records during POW confinement and to accord benefit of the doubt where medical science cannot conclusively link disease etiology to FPOW status, to FPOWs.

Service-Connected Conditions

The historical development of conditions with a presumption of service connection for adjudication of VA compensation/disability claims began in 1921 with the Act to Establish a Veterans’ Bureau and to Improve the Facilities.¹ The act simplified and streamlined the claims adjudication process by eliminating the need to obtain evidence on the part of the veteran. The presumption of service connection also facilitated increased accuracy and consistency in adjudications by requiring similar treatment for similar claims. This “presumptive” process relieved claimants and VA of the necessity of producing direct evidence when it was impractical to do so.

In 1970, the first presumptives specific to FPOWs were legislatively established and covered 17 diseases for a FPOW who had been confined for ≥ 30 days (Pub. L. 91-376). The 30-day confinement requirement was later relaxed, and additional presumptives were established that related to diseases that were more common among FPOWs than they were among non-FPOWs. These disorders included traumatic arthritis, stroke, heart disease, osteoporosis, peripheral neuropathy, cold injuries, as well as a variety of digestive and neuropsychiatric disorders. If a FPOW is diagnosed as having ≥ 1 of these conditions and it is judged to be ≥ 10% disabling, the condition is presumed to be a sequelae of the POW experience, and it is classified as a service-connected disability (Table).

FPOW Care And Benefits Teams

Several Veterans Health Administration (VHA) directives have been issued, including the recent VHA directive 1650, which requires that each VHA medical facility have a special Care and Benefits Team (CBT) that is charged with the evaluation and treatment of FPOWs to ensure that “FPOWs receive the highest quality care and benefit services.”⁶ CBTs must be composed of a clinician trained in internal medicine or family practice; a clinician who is certified through the VA Office of Disability and Medical Assessment to conduct General Medical Compensation and Pension evaluations; a FPOW advocate who typically is a VHA clinical social worker; and a Veterans Benefits Administration (VBA) FPOW coordinator appointed by the local VBA regional office. CBTs can be expanded to include other members as needed. The CBTs are tasked with facilitating interactions between FPOWs, the VHA, and the VBA.

CBTs face several challenges in meeting their responsibilities. For example, the POW experience often results in psychological trauma that foments denial and distrust; hence, thoughtful sensitivity to the sequelae of captivity when approaching FPOWs about personal issues, such as health care, is required. Establishing trusting relationships with FPOWs is necessary if their needs are to be effectively addressed.

While the VHA is mandated to provide priority treatment for FPOWs, including hospital, nursing home, dental, and outpatient treatment, a significant number of FPOWs do not avail themselves of benefits to which they are entitled. Often these FPOWs have not used VA programs and facilities because they are uninformed or confused about VA benefits for FPOWs. As a result, referrals of eligible FPOWs to appropriate programs can be overlooked. Maximizing the service-connected disability rating of FPOWs not only impacts the disability pensions received by these veterans, but also impacts their eligibility for VHA programs, including long-term care and Dependency and Indemnity Compensation, a monthly benefit paid to spouses, children, and/or surviving parents.

In 2013, the FPOW Committee of the South Texas Veterans Health Care System (STVHCS) noted that 40% of FPOWs in our region had no VA primary care or clinic assignment. In consideration of the commitment of the VA to care for FPOWs, the unique POW-related medical and psychological issues, the geriatric age of many FPOWs, and the surprising number of FPOWs currently not receiving VA care, we expanded the concept of the CBT team to create a specialized interdisciplinary FPOW Clinic to address the unique needs of this predominantly elderly population and to involve more FPOWs in the VA system.

The main purpose of this clinic was to advise FPOWs of all VA benefits and services to which they may be entitled by identifying overlooked FPOW presumptives. As the number of FPOWs continues to decrease, outreach to FPOWs and family members has become critical, especially as increased benefits and special services might be available to this increasingly dependent older population. An informal survey of FPOW advocates across the nation found that 21% of FPOWs had disability ratings from the VA of ≤ 60%, including some who had no VA disability rating at all. Thus, an additional goal of the project was to develop a clinic model that could be disseminated throughout the VHA.

Design

The design of the FPOW Clinic team is based on an interdisciplinary model that has proven successful in geriatric medicine.⁷ The team comprises a physician, a social worker, and a registered nurse.⁸ All members have expertise in geriatric medicine and specific training in FPOW-related issues by completing a VA employee education training session on FPOW case management. Completion of this training ensured that team members were:

• Familiar with the experiences of FPOWs as well as about the medical, psychosocial, and mental health conditions that affect FPOWs;
• Knowledgeable about FPOW presumptive conditions;
• Familiar with the VBA process for rating FPOW disability claims; and
• Capable of FPOW case coordination, workflow, and communications between the FPOW Clinic team and the VBA to avail FPOWs and their families of all eligible benefits.

In-person FPOW clinic visits and chart reviews helped identify overlooked FPOW benefits. To facilitate case management, a representative of the VBA attended the initial evaluation of each FPOW in the clinic to confirm any overlooked presumptive benefits and to familiarize FPOWs with the claims process. FPOWs were also given the choice to officially enroll in the FPOW clinic for primary care or to remain with their current health care provider. Special efforts were made to enroll those FPOWs who had no STVHCS assigned primary care clinic.

The clinic was scheduled for 4 hours every week. Initial patient visits were 2 hours each and consisted of separate evaluations by each of the 3 FPOW Clinic team members who then met as a team with the addition of the VBA representative. The purpose of this meeting was to discuss overlooked benefits, address any other specific issues noted, and to devise an appropriate interdisciplinary plan. Findings of overlooked benefits and other relevant outcomes then were conveyed to the FPOW. For FPOWs who opted to continue in the clinic for their primary care, subsequent appointments were 1 hour.

Implementation 

STVHCS FPOW advocates identified and sent letters to FPOWs announcing the opening of the clinic and its goals. Phone calls were made to each FPOW to address questions and to ascertain their interest. The FPOW advocates then worked directly with schedulers to make clinic appointments. Forty-one FPOWs responded to this initial invitation and attended the new clinic. Subsequently, this number increased through FPOW consults placed by STVHCS primary care providers.

The service-connected disability rating of clinic patients ranged from none (6% of attendees) to 100% (28% of attendees). For 34% of patients, clinic attendance resulted in identification application for overlooked presumptives. VBA evaluation resulted in increased service-connected disability ratings for nearly one-third of clinic patients. All clinic patients without a service-connected disability prior to FPOW clinic evaluation received an increased service-connected disability rating. Overall, 60% of the FPOWs who attended the clinic opted to receive their primary care at the FPOW clinic.

The FPOW Clinic successfully identified overlooked presumptives and facilitated the determination of appropriate service-connected disabilities. Interestingly, the FPOW Clinic encountered an unanticipated challenge to identifying overlooked FPOW benefits—veterans’ medical conditions that are listed by the VHA as being service-connected in the Computerized Patient Record System did not always reflect those listed officially in VBA records. This led to occasional identification of apparently overlooked FPOW presumptives that were already recognized by the VBA but not reflected in VHA records. This issue was addressed by ensuring that VBA representatives attended postclinic meetings with clinic staff and avoided the need to pursue supposedly unrecognized benefits that were recognized.

Telehealth 

At present, FPOWs from World War II outnumber those of all other conflicts; however, this group is rapidly dwindling in numbers. World War II FPOWs are aged > 85 years, and therefore among the most frail and dependent of veterans. Often they are homebound and unable to physically travel to clinics for assessment. To serve these veterans, we are modifying the FPOW Clinic to utilize telehealth. The Telehealth FPOW Clinic will obtain relevant data from review of the electronic health record and telehealth-based clinic visits. Telehealth also may be used for assessments of Vietnam War veterans (eg, Agent Orange exposure), atomic veterans, and Gulf War veterans. Once fully designed and implemented, we believe that telehealth will prove to be a cost-effective way to provide clinic benefits to rural and older veterans.

Conclusions

The VHA provides priority medical treatment to FPOWs as well as timely and appropriate assessment of their eligibility for veterans’ benefits. The complexities benefit programs established for FPOWs is often beyond the ken of VHA physicians, social workers, and nurses. Because of this unfamiliarity, referrals of eligible FPOWs to appropriate programs can be overlooked. We established a clinic-based interdisciplinary team (FPOW Clinic) that was fully trained in FPOW benefit programs to identify overlooked benefits for FPOWs and were able to increase the disability rating on approximately one-third of the FPOWs seen in the FPOW Clinic. A telehealth-based version of the FPOW clinic is now being developed.

ILLUSTRATIVE CASE

A healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Mrs. B, age 66, presents to the emergency department with altered mental status, impaired gait, and tremors. Her son says she has had these symptoms for 3 days. He adds that she has been experiencing more knee pain than usual, and began taking naproxen, 220 mg twice daily, approximately 1 week ago.

Mrs. B’s medical history includes coronary artery disease (CAD), gastroesophageal reflux disease (GERD), hip fracture, osteoarthritis, and osteoporosis. She also has a history of insomnia and bipolar disorder.

Further, Mrs. B reports that 2 months ago, after watching a television program about mental health, she began taking ginkgo biloba, 60 mg/d by mouth for “memory,” and kava kava, 100 mg by mouth 3 times a day for “anxiety.” She did not tell her physician or pharmacist that she began using these supplements because she believes that “natural supplements wouldn’t affect her prescription medications.”

In addition to naproxen, gingko biloba, and kava kava, Mrs. B takes the following medications orally: atorvastatin, 80 mg/d; aspirin, 325 mg/d; omeprazole, 20 mg twice daily; lithium, 300 mg twice daily; trazodone, 50 mg nightly; diphenhydramine, 50 mg nightly; calcium, 500 mg/d; vitamin D, 400 IU/d; and a daily multivitamin.

Mrs. B’s blood pressure is 132/74 mm Hg (at goal for her age) and her laboratory workup is unremarkable, except for the following results: serum creatinine level of 1.1 mg/dL, blood urea nitrogen/serum creatinine ratio of 40, and creatinine clearance rate of approximately 85 mL/min. An electrocardiogram shows normal sinus rhythm with a QTc of 489 ms. A lithium serum concentration level, drawn randomly, is 1.6 mEq/mL, suggesting lithium toxicity.

Although there is no consensus definition of polypharmacy, the most commonly referenced is concurrent use of ≥5 medications.¹ During the last 2 decades, the percentage of adults who report receiving polypharmacy has markedly increased, from 8.2% to 15%.² Geriatric patients, defined as those age >65, typically receive ≥5 prescription medications.² Polypharmacy is associated with increased¹:

• mortality
• adverse drug reactions
• falls
• length of hospital stay
• readmission rates.

Older adults are particularly vulnerable to the negative outcomes associated with polypharmacy because both increasing age and number of medications received are positively correlated with the risk of adverse events.³ However, the use of multiple medications may be clinically appropriate and necessary in patients with multiple chronic conditions. Recent research suggests that in addition to prescription medications, over-the-counter (OTC) medications and dietary supplements also pose polypharmacy concerns for geriatric patients.³ Here we discuss the risks of OTC medications and dietary supplements for older patients who may be receiving polypharmacy, and highlight specific agents and interactions to watch for in these individuals based on Mrs. B’s case.

Continue to: Factors that increase the risks of OTC medications

Although older adults account for only 15% of the present population, they purchase 40% of all OTC medications.⁴ These patients may inadvertently use OTC medications containing unnecessary or potentially harmful active ingredients because of unfamiliarity with the specific product, variability among products, or decreased health literacy. According to research presented at a 2010 Institute of Medicine Workshop on Safe Use Initiative and Health Literacy, many patients have a limited understanding of OTC medication indications and therapeutic duplication.⁵ For example, researchers found that almost 70% of patients thought they could take 2 products containing the same ingredient.⁵ Most patients were not able to determine the active ingredients or maximum daily dose of an OTC medication. Patients who were older, had lower literacy, or were African American were more likely to misunderstand medication labeling.⁵ Additional literature suggests that up to 20% of medical admissions can be attributed to adverse effects of OTC medications.⁶

Misconceptions regarding dietary supplements

The use of alternative and complementary medicine also is on the rise among geriatric patients.^7-9 A recent study found that 70% of older adults in the United States consumed at least 1 dietary supplement in the past 30 days, with 29% consuming ≥4 natural products. Women consumed twice as many supplements as men.¹⁰

The perceived safety of natural medicines and dietary supplements is a common and potentially dangerous misconception.¹¹ Because patients typically assume dietary supplements are safe, they often do not report their use to their clinicians, especially if clinicians do not explicitly ask them about supplement use.¹² This is especially concerning because the FDA does not have the authority to review or regulate natural medicines or dietary supplements.^13,14

With no requirements or regulations regarding quality control of these products, the obvious question is: “How do patients know what they’re ingesting?” The uncertainty regarding the true composition of dietary supplements is a cause for concern because federal regulations do not provide a standard way to verify the purity, quality, and safety. As a result, there is a dearth of information regarding drug–dietary supplement interactions and drug–dietary supplement–disease state interactions.^8,15

What to watch for

Table 1^16-22 outlines OTC medication classes and potential medication and/or disease state interactions. Table 2^23-45 outlines potential interactions between select dietary supplements, medications, and disease states. Here we discuss several of these potential interactions based on the medications that Mrs. B was taking.

Continue to: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs). All OTC NSAIDs, except aspirin and salicylates, increase the risk for lithium toxicity by decreasing glomerular filtration rate and promoting lithium reabsorption in the kidneys.¹⁶ Additionally, NSAIDs increase the risk of developing gastric ulcers and may initiate or exacerbate GERD by suppressing gastric prostaglandin synthesis. Gastric prostaglandins facilitate the formation of a protective lipid-layer in the gastrointestinal (GI) tract.^18,46-48 For Mrs. B, the naproxen she was taking resulted in lithium toxicity.

Ginkgo biloba is a plant used most commonly for its reported effect on memory. However, many drug–dietary supplement interactions have been associated with ginkgo biloba that may pose a problem for geriatric patients who receive polypharmacy.⁴⁹ Mrs. B may have experienced decreased effectiveness of omeprazole and increased sedation or orthostatic hypotension with trazodone.

Kava kava is a natural sedative that can worsen cognition, increase the risk of falls, and potentially cause hepatotoxicity.⁵⁰ The sedative effects of kava kava are thought to be a direct result of gamma-aminobutyric acid (GABA) modulation via the blockage of voltage-gated sodium ion channels.⁵¹ In Mrs. B’s case, when used in combination with diphenhydramine and trazodone, kava kava had the potential to further increase her risk of sedation and falls.

Gastroesophageal reflux disease medications. Older adults may be at an increased risk of GERD due to diseases that affect the esophagus and GI tract, such as diabetes, Parkinson’s disease, and Alzheimer’s disease. Medications may also contribute to gastric reflux by loosening the esophageal tone. Nitrates, benzodiazepines, anticholinergics, antidepressants, and lidocaine have been implicated in precipitating or exacerbating GERD.⁵²

Numerous OTC products can be used to treat heartburn. Calcium carbonate supplements are typically recommended as first-line agents to treat occasional heartburn; histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) generally are reserved for patients who experience heartburn more frequently.⁴⁷ Per the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, H2RAs were removed from the “avoid” list for patients with dementia or cognitive impairment due to a lack of strong evidence; however, H2RAs remain on the “avoid” list for patients with delirium.¹⁷ Low-dose H2RAs can be used safely in geriatric patients who have renal impairment. Although PPIs are not listedon the Beers Criteria, they have been associated with an increased risk of dementia, osteoporosis, and infections.^53,54 There is robust evidence to support bone loss and fractures associated with chronic use of PPIs. However, the data linking PPI use and dementia is controversial due to multiple confounders identified in the studies, such as concomitant use of benzodiazepines.⁴⁸ PPIs should be prescribed sparingly and judiciously in geriatric patients, and the need for continued PPI therapy should frequently be reassessed.⁴⁸ Mrs. B’s use of omeprazole, a PPI, may put her at an increased risk for hip fracture compounded by an elevated fall risk associated with other medications she was taking.

Continue to: Trazodone

Trazodone causes sedative effects via anti-alpha 1 activity, which is thought to be responsible for orthostasis and may further increase the risk of falls.⁵¹ Mrs. B’s use of trazodone may have increased her risk of sedation and falls.

Antihistaminergic medications are associated with sedation, confusion, cognitive dysfunction, falls, and delirium in geriatric patients. Medications that act on histamine receptors can be particularly detrimental in the geriatric population because of their decreased clearance, smaller volume of distribution, and decreased tolerance.^17,18

Anticholinergic medications. Although atropine and benztropine are widely recognized as anticholinergic agents, other medications, such as digoxin, paroxetine, and colchicine, also demonstrate anticholinergic activity that can cause problematic central and peripheral effects in geriatric patients.⁵⁵ Central anticholinergic inhibition can lead to reduced cognitive function and impairments in attention and short-term memory. The peripheral effects of anticholinergic medications are similar to those of antihistamines and may include, but are not limited to, dry eyes and mouth via increased inhibition of acetylcholine-mediated muscle contraction of salivary glands.⁵⁵ These effects can be compounded by the use of OTC medications that exhibit anticholinergic activity.

Diphenhydramine causes sedation through its activity on cholinergic and histaminergic receptors. Patients may not be aware that many OTC cough-and-cold combination products (such as NyQuil, Theraflu, etc.) and OTC nighttime analgesic products (such as Tylenol PM, Aleve PM, Motrin PM, etc.) contain diphenhydramine. For a geriatric patient, such as Mrs. B, diphenhydramine may increase the risk of falls and worsen cognition.

Teach patients to disclose everything they take

Polypharmacy can be detrimental to older patients’ health due to the increased risk of toxicity caused by therapeutic duplication, drug–drug interactions, and drug-disease interactions. Most patients are unable to navigate the nuances of medication indications, maximum dosages, and therapeutic duplications. Older adults frequently take OTC medications and have the greatest risk of developing adverse effects from these medications due to decreased renal and hepatic clearance, increased drug sensitivity, and decreased volume of distribution. Dietary supplements pose a unique risk because they are not FDA-regulated and their purity, quality, and content cannot be verified. Educating patients and family members about the importance of reporting all their prescription medications, OTC medications, and dietary supplements to their pharmacists and clinicians is critical in order to identify and mitigate the risks associated with polypharmacy in geriatric patients.

Continue to: CASE

Mrs. B is diagnosed with lithium toxicity due to a drug–drug interaction with naproxen. Her lithium is held, and IV fluids are administered. Her symptoms resolve over the next few days. Mrs. B and her son are taught about the interaction between lithium and NSAIDs, and she is counseled to avoid all OTC NSAIDs other than aspirin. Her clinician recommends taking acetaminophen because it will not interact with her medications and is the recommended OTC treatment for mild or moderate pain in geriatric patients.^17,56

Next, the clinician addresses Mrs. B’s GERD. Although Mrs. B had been taking PPIs twice daily, her physician recommends decreasing the omeprazole frequency to once daily to minimize adverse effects and pill burden. She also decreases Mrs. B’s aspirin from 325 to 81 mg/d because evidence suggests that when used to prevent CAD, lower-dose aspirin is effective as high-dose aspirin and has fewer adverse effects.⁵⁷ Finally, she advises Mrs. B to stop taking ginkgo biloba and kava kava and to always check with her primary care physician or pharmacist before beginning any new medication, dietary supplement, or vitamin.

Mrs. B agrees to first check with her clinicians before following advice from mass media. A follow-up appointment is scheduled for 2 weeks to assess renal function, a lithium serum concentration, and adherence to her simplified medication regimen.

Related Resources

• US Department of Health and Human Services. National Institutes of Health. MedlinePlus. Herbs and supplements. https://medlineplus.gov/druginfo/herb_All.html.
• US Department of Health and Human Services. National Center for Complementary and Integrative Health. https://nccih.nih.gov/.

Drug Brand Names

Atorvastatin • Lipitor
Atropine • Atropen
Benztropine • Cogentin
Clozapine • Clozaril
Clopidogrel • Plavix
Colchicine • Colcrys, Gloperba
Digoxin • Cardoxin, Digitek
Lidocaine • Lidoderm, Xylocaine Viscous
Lithium • Eskalith, Lithobid
Methadone • Methadose
Morphine • Kadian, Morphabond
Paroxetine • Paxil
Trazodone • Desyrel
Warfarin • Coumadin, Jantoven

Mrs. B, age 66, presents to the emergency department with altered mental status, impaired gait, and tremors. Her son says she has had these symptoms for 3 days. He adds that she has been experiencing more knee pain than usual, and began taking naproxen, 220 mg twice daily, approximately 1 week ago.

Mrs. B’s medical history includes coronary artery disease (CAD), gastroesophageal reflux disease (GERD), hip fracture, osteoarthritis, and osteoporosis. She also has a history of insomnia and bipolar disorder.

Further, Mrs. B reports that 2 months ago, after watching a television program about mental health, she began taking ginkgo biloba, 60 mg/d by mouth for “memory,” and kava kava, 100 mg by mouth 3 times a day for “anxiety.” She did not tell her physician or pharmacist that she began using these supplements because she believes that “natural supplements wouldn’t affect her prescription medications.”

In addition to naproxen, gingko biloba, and kava kava, Mrs. B takes the following medications orally: atorvastatin, 80 mg/d; aspirin, 325 mg/d; omeprazole, 20 mg twice daily; lithium, 300 mg twice daily; trazodone, 50 mg nightly; diphenhydramine, 50 mg nightly; calcium, 500 mg/d; vitamin D, 400 IU/d; and a daily multivitamin.

Mrs. B’s blood pressure is 132/74 mm Hg (at goal for her age) and her laboratory workup is unremarkable, except for the following results: serum creatinine level of 1.1 mg/dL, blood urea nitrogen/serum creatinine ratio of 40, and creatinine clearance rate of approximately 85 mL/min. An electrocardiogram shows normal sinus rhythm with a QTc of 489 ms. A lithium serum concentration level, drawn randomly, is 1.6 mEq/mL, suggesting lithium toxicity.

Although there is no consensus definition of polypharmacy, the most commonly referenced is concurrent use of ≥5 medications.¹ During the last 2 decades, the percentage of adults who report receiving polypharmacy has markedly increased, from 8.2% to 15%.² Geriatric patients, defined as those age >65, typically receive ≥5 prescription medications.² Polypharmacy is associated with increased¹:

• mortality
• adverse drug reactions
• falls
• length of hospital stay
• readmission rates.

Older adults are particularly vulnerable to the negative outcomes associated with polypharmacy because both increasing age and number of medications received are positively correlated with the risk of adverse events.³ However, the use of multiple medications may be clinically appropriate and necessary in patients with multiple chronic conditions. Recent research suggests that in addition to prescription medications, over-the-counter (OTC) medications and dietary supplements also pose polypharmacy concerns for geriatric patients.³ Here we discuss the risks of OTC medications and dietary supplements for older patients who may be receiving polypharmacy, and highlight specific agents and interactions to watch for in these individuals based on Mrs. B’s case.

Continue to: Factors that increase the risks of OTC medications

Although older adults account for only 15% of the present population, they purchase 40% of all OTC medications.⁴ These patients may inadvertently use OTC medications containing unnecessary or potentially harmful active ingredients because of unfamiliarity with the specific product, variability among products, or decreased health literacy. According to research presented at a 2010 Institute of Medicine Workshop on Safe Use Initiative and Health Literacy, many patients have a limited understanding of OTC medication indications and therapeutic duplication.⁵ For example, researchers found that almost 70% of patients thought they could take 2 products containing the same ingredient.⁵ Most patients were not able to determine the active ingredients or maximum daily dose of an OTC medication. Patients who were older, had lower literacy, or were African American were more likely to misunderstand medication labeling.⁵ Additional literature suggests that up to 20% of medical admissions can be attributed to adverse effects of OTC medications.⁶

Misconceptions regarding dietary supplements

The use of alternative and complementary medicine also is on the rise among geriatric patients.^7-9 A recent study found that 70% of older adults in the United States consumed at least 1 dietary supplement in the past 30 days, with 29% consuming ≥4 natural products. Women consumed twice as many supplements as men.¹⁰

The perceived safety of natural medicines and dietary supplements is a common and potentially dangerous misconception.¹¹ Because patients typically assume dietary supplements are safe, they often do not report their use to their clinicians, especially if clinicians do not explicitly ask them about supplement use.¹² This is especially concerning because the FDA does not have the authority to review or regulate natural medicines or dietary supplements.^13,14

With no requirements or regulations regarding quality control of these products, the obvious question is: “How do patients know what they’re ingesting?” The uncertainty regarding the true composition of dietary supplements is a cause for concern because federal regulations do not provide a standard way to verify the purity, quality, and safety. As a result, there is a dearth of information regarding drug–dietary supplement interactions and drug–dietary supplement–disease state interactions.^8,15

What to watch for

Table 1^16-22 outlines OTC medication classes and potential medication and/or disease state interactions. Table 2^23-45 outlines potential interactions between select dietary supplements, medications, and disease states. Here we discuss several of these potential interactions based on the medications that Mrs. B was taking.

Continue to: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs). All OTC NSAIDs, except aspirin and salicylates, increase the risk for lithium toxicity by decreasing glomerular filtration rate and promoting lithium reabsorption in the kidneys.¹⁶ Additionally, NSAIDs increase the risk of developing gastric ulcers and may initiate or exacerbate GERD by suppressing gastric prostaglandin synthesis. Gastric prostaglandins facilitate the formation of a protective lipid-layer in the gastrointestinal (GI) tract.^18,46-48 For Mrs. B, the naproxen she was taking resulted in lithium toxicity.

Ginkgo biloba is a plant used most commonly for its reported effect on memory. However, many drug–dietary supplement interactions have been associated with ginkgo biloba that may pose a problem for geriatric patients who receive polypharmacy.⁴⁹ Mrs. B may have experienced decreased effectiveness of omeprazole and increased sedation or orthostatic hypotension with trazodone.

Kava kava is a natural sedative that can worsen cognition, increase the risk of falls, and potentially cause hepatotoxicity.⁵⁰ The sedative effects of kava kava are thought to be a direct result of gamma-aminobutyric acid (GABA) modulation via the blockage of voltage-gated sodium ion channels.⁵¹ In Mrs. B’s case, when used in combination with diphenhydramine and trazodone, kava kava had the potential to further increase her risk of sedation and falls.

Gastroesophageal reflux disease medications. Older adults may be at an increased risk of GERD due to diseases that affect the esophagus and GI tract, such as diabetes, Parkinson’s disease, and Alzheimer’s disease. Medications may also contribute to gastric reflux by loosening the esophageal tone. Nitrates, benzodiazepines, anticholinergics, antidepressants, and lidocaine have been implicated in precipitating or exacerbating GERD.⁵²

Numerous OTC products can be used to treat heartburn. Calcium carbonate supplements are typically recommended as first-line agents to treat occasional heartburn; histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) generally are reserved for patients who experience heartburn more frequently.⁴⁷ Per the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, H2RAs were removed from the “avoid” list for patients with dementia or cognitive impairment due to a lack of strong evidence; however, H2RAs remain on the “avoid” list for patients with delirium.¹⁷ Low-dose H2RAs can be used safely in geriatric patients who have renal impairment. Although PPIs are not listedon the Beers Criteria, they have been associated with an increased risk of dementia, osteoporosis, and infections.^53,54 There is robust evidence to support bone loss and fractures associated with chronic use of PPIs. However, the data linking PPI use and dementia is controversial due to multiple confounders identified in the studies, such as concomitant use of benzodiazepines.⁴⁸ PPIs should be prescribed sparingly and judiciously in geriatric patients, and the need for continued PPI therapy should frequently be reassessed.⁴⁸ Mrs. B’s use of omeprazole, a PPI, may put her at an increased risk for hip fracture compounded by an elevated fall risk associated with other medications she was taking.

Continue to: Trazodone

Trazodone causes sedative effects via anti-alpha 1 activity, which is thought to be responsible for orthostasis and may further increase the risk of falls.⁵¹ Mrs. B’s use of trazodone may have increased her risk of sedation and falls.

Antihistaminergic medications are associated with sedation, confusion, cognitive dysfunction, falls, and delirium in geriatric patients. Medications that act on histamine receptors can be particularly detrimental in the geriatric population because of their decreased clearance, smaller volume of distribution, and decreased tolerance.^17,18

Anticholinergic medications. Although atropine and benztropine are widely recognized as anticholinergic agents, other medications, such as digoxin, paroxetine, and colchicine, also demonstrate anticholinergic activity that can cause problematic central and peripheral effects in geriatric patients.⁵⁵ Central anticholinergic inhibition can lead to reduced cognitive function and impairments in attention and short-term memory. The peripheral effects of anticholinergic medications are similar to those of antihistamines and may include, but are not limited to, dry eyes and mouth via increased inhibition of acetylcholine-mediated muscle contraction of salivary glands.⁵⁵ These effects can be compounded by the use of OTC medications that exhibit anticholinergic activity.

Diphenhydramine causes sedation through its activity on cholinergic and histaminergic receptors. Patients may not be aware that many OTC cough-and-cold combination products (such as NyQuil, Theraflu, etc.) and OTC nighttime analgesic products (such as Tylenol PM, Aleve PM, Motrin PM, etc.) contain diphenhydramine. For a geriatric patient, such as Mrs. B, diphenhydramine may increase the risk of falls and worsen cognition.

Teach patients to disclose everything they take

Polypharmacy can be detrimental to older patients’ health due to the increased risk of toxicity caused by therapeutic duplication, drug–drug interactions, and drug-disease interactions. Most patients are unable to navigate the nuances of medication indications, maximum dosages, and therapeutic duplications. Older adults frequently take OTC medications and have the greatest risk of developing adverse effects from these medications due to decreased renal and hepatic clearance, increased drug sensitivity, and decreased volume of distribution. Dietary supplements pose a unique risk because they are not FDA-regulated and their purity, quality, and content cannot be verified. Educating patients and family members about the importance of reporting all their prescription medications, OTC medications, and dietary supplements to their pharmacists and clinicians is critical in order to identify and mitigate the risks associated with polypharmacy in geriatric patients.

Continue to: CASE

Mrs. B is diagnosed with lithium toxicity due to a drug–drug interaction with naproxen. Her lithium is held, and IV fluids are administered. Her symptoms resolve over the next few days. Mrs. B and her son are taught about the interaction between lithium and NSAIDs, and she is counseled to avoid all OTC NSAIDs other than aspirin. Her clinician recommends taking acetaminophen because it will not interact with her medications and is the recommended OTC treatment for mild or moderate pain in geriatric patients.^17,56

Next, the clinician addresses Mrs. B’s GERD. Although Mrs. B had been taking PPIs twice daily, her physician recommends decreasing the omeprazole frequency to once daily to minimize adverse effects and pill burden. She also decreases Mrs. B’s aspirin from 325 to 81 mg/d because evidence suggests that when used to prevent CAD, lower-dose aspirin is effective as high-dose aspirin and has fewer adverse effects.⁵⁷ Finally, she advises Mrs. B to stop taking ginkgo biloba and kava kava and to always check with her primary care physician or pharmacist before beginning any new medication, dietary supplement, or vitamin.

Mrs. B agrees to first check with her clinicians before following advice from mass media. A follow-up appointment is scheduled for 2 weeks to assess renal function, a lithium serum concentration, and adherence to her simplified medication regimen.

Related Resources

• US Department of Health and Human Services. National Institutes of Health. MedlinePlus. Herbs and supplements. https://medlineplus.gov/druginfo/herb_All.html.
• US Department of Health and Human Services. National Center for Complementary and Integrative Health. https://nccih.nih.gov/.

Drug Brand Names

Atorvastatin • Lipitor
Atropine • Atropen
Benztropine • Cogentin
Clozapine • Clozaril
Clopidogrel • Plavix
Colchicine • Colcrys, Gloperba
Digoxin • Cardoxin, Digitek
Lidocaine • Lidoderm, Xylocaine Viscous
Lithium • Eskalith, Lithobid
Methadone • Methadose
Morphine • Kadian, Morphabond
Paroxetine • Paxil
Trazodone • Desyrel
Warfarin • Coumadin, Jantoven

Mrs. B, age 66, presents to the emergency department with altered mental status, impaired gait, and tremors. Her son says she has had these symptoms for 3 days. He adds that she has been experiencing more knee pain than usual, and began taking naproxen, 220 mg twice daily, approximately 1 week ago.

Mrs. B’s medical history includes coronary artery disease (CAD), gastroesophageal reflux disease (GERD), hip fracture, osteoarthritis, and osteoporosis. She also has a history of insomnia and bipolar disorder.

Further, Mrs. B reports that 2 months ago, after watching a television program about mental health, she began taking ginkgo biloba, 60 mg/d by mouth for “memory,” and kava kava, 100 mg by mouth 3 times a day for “anxiety.” She did not tell her physician or pharmacist that she began using these supplements because she believes that “natural supplements wouldn’t affect her prescription medications.”

In addition to naproxen, gingko biloba, and kava kava, Mrs. B takes the following medications orally: atorvastatin, 80 mg/d; aspirin, 325 mg/d; omeprazole, 20 mg twice daily; lithium, 300 mg twice daily; trazodone, 50 mg nightly; diphenhydramine, 50 mg nightly; calcium, 500 mg/d; vitamin D, 400 IU/d; and a daily multivitamin.

Mrs. B’s blood pressure is 132/74 mm Hg (at goal for her age) and her laboratory workup is unremarkable, except for the following results: serum creatinine level of 1.1 mg/dL, blood urea nitrogen/serum creatinine ratio of 40, and creatinine clearance rate of approximately 85 mL/min. An electrocardiogram shows normal sinus rhythm with a QTc of 489 ms. A lithium serum concentration level, drawn randomly, is 1.6 mEq/mL, suggesting lithium toxicity.

Although there is no consensus definition of polypharmacy, the most commonly referenced is concurrent use of ≥5 medications.¹ During the last 2 decades, the percentage of adults who report receiving polypharmacy has markedly increased, from 8.2% to 15%.² Geriatric patients, defined as those age >65, typically receive ≥5 prescription medications.² Polypharmacy is associated with increased¹:

• mortality
• adverse drug reactions
• falls
• length of hospital stay
• readmission rates.

Older adults are particularly vulnerable to the negative outcomes associated with polypharmacy because both increasing age and number of medications received are positively correlated with the risk of adverse events.³ However, the use of multiple medications may be clinically appropriate and necessary in patients with multiple chronic conditions. Recent research suggests that in addition to prescription medications, over-the-counter (OTC) medications and dietary supplements also pose polypharmacy concerns for geriatric patients.³ Here we discuss the risks of OTC medications and dietary supplements for older patients who may be receiving polypharmacy, and highlight specific agents and interactions to watch for in these individuals based on Mrs. B’s case.

Continue to: Factors that increase the risks of OTC medications

Although older adults account for only 15% of the present population, they purchase 40% of all OTC medications.⁴ These patients may inadvertently use OTC medications containing unnecessary or potentially harmful active ingredients because of unfamiliarity with the specific product, variability among products, or decreased health literacy. According to research presented at a 2010 Institute of Medicine Workshop on Safe Use Initiative and Health Literacy, many patients have a limited understanding of OTC medication indications and therapeutic duplication.⁵ For example, researchers found that almost 70% of patients thought they could take 2 products containing the same ingredient.⁵ Most patients were not able to determine the active ingredients or maximum daily dose of an OTC medication. Patients who were older, had lower literacy, or were African American were more likely to misunderstand medication labeling.⁵ Additional literature suggests that up to 20% of medical admissions can be attributed to adverse effects of OTC medications.⁶

Misconceptions regarding dietary supplements

The use of alternative and complementary medicine also is on the rise among geriatric patients.^7-9 A recent study found that 70% of older adults in the United States consumed at least 1 dietary supplement in the past 30 days, with 29% consuming ≥4 natural products. Women consumed twice as many supplements as men.¹⁰

The perceived safety of natural medicines and dietary supplements is a common and potentially dangerous misconception.¹¹ Because patients typically assume dietary supplements are safe, they often do not report their use to their clinicians, especially if clinicians do not explicitly ask them about supplement use.¹² This is especially concerning because the FDA does not have the authority to review or regulate natural medicines or dietary supplements.^13,14

With no requirements or regulations regarding quality control of these products, the obvious question is: “How do patients know what they’re ingesting?” The uncertainty regarding the true composition of dietary supplements is a cause for concern because federal regulations do not provide a standard way to verify the purity, quality, and safety. As a result, there is a dearth of information regarding drug–dietary supplement interactions and drug–dietary supplement–disease state interactions.^8,15

What to watch for

Table 1^16-22 outlines OTC medication classes and potential medication and/or disease state interactions. Table 2^23-45 outlines potential interactions between select dietary supplements, medications, and disease states. Here we discuss several of these potential interactions based on the medications that Mrs. B was taking.

Continue to: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs). All OTC NSAIDs, except aspirin and salicylates, increase the risk for lithium toxicity by decreasing glomerular filtration rate and promoting lithium reabsorption in the kidneys.¹⁶ Additionally, NSAIDs increase the risk of developing gastric ulcers and may initiate or exacerbate GERD by suppressing gastric prostaglandin synthesis. Gastric prostaglandins facilitate the formation of a protective lipid-layer in the gastrointestinal (GI) tract.^18,46-48 For Mrs. B, the naproxen she was taking resulted in lithium toxicity.

Ginkgo biloba is a plant used most commonly for its reported effect on memory. However, many drug–dietary supplement interactions have been associated with ginkgo biloba that may pose a problem for geriatric patients who receive polypharmacy.⁴⁹ Mrs. B may have experienced decreased effectiveness of omeprazole and increased sedation or orthostatic hypotension with trazodone.

Kava kava is a natural sedative that can worsen cognition, increase the risk of falls, and potentially cause hepatotoxicity.⁵⁰ The sedative effects of kava kava are thought to be a direct result of gamma-aminobutyric acid (GABA) modulation via the blockage of voltage-gated sodium ion channels.⁵¹ In Mrs. B’s case, when used in combination with diphenhydramine and trazodone, kava kava had the potential to further increase her risk of sedation and falls.

Gastroesophageal reflux disease medications. Older adults may be at an increased risk of GERD due to diseases that affect the esophagus and GI tract, such as diabetes, Parkinson’s disease, and Alzheimer’s disease. Medications may also contribute to gastric reflux by loosening the esophageal tone. Nitrates, benzodiazepines, anticholinergics, antidepressants, and lidocaine have been implicated in precipitating or exacerbating GERD.⁵²

Numerous OTC products can be used to treat heartburn. Calcium carbonate supplements are typically recommended as first-line agents to treat occasional heartburn; histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) generally are reserved for patients who experience heartburn more frequently.⁴⁷ Per the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, H2RAs were removed from the “avoid” list for patients with dementia or cognitive impairment due to a lack of strong evidence; however, H2RAs remain on the “avoid” list for patients with delirium.¹⁷ Low-dose H2RAs can be used safely in geriatric patients who have renal impairment. Although PPIs are not listedon the Beers Criteria, they have been associated with an increased risk of dementia, osteoporosis, and infections.^53,54 There is robust evidence to support bone loss and fractures associated with chronic use of PPIs. However, the data linking PPI use and dementia is controversial due to multiple confounders identified in the studies, such as concomitant use of benzodiazepines.⁴⁸ PPIs should be prescribed sparingly and judiciously in geriatric patients, and the need for continued PPI therapy should frequently be reassessed.⁴⁸ Mrs. B’s use of omeprazole, a PPI, may put her at an increased risk for hip fracture compounded by an elevated fall risk associated with other medications she was taking.

Continue to: Trazodone

Trazodone causes sedative effects via anti-alpha 1 activity, which is thought to be responsible for orthostasis and may further increase the risk of falls.⁵¹ Mrs. B’s use of trazodone may have increased her risk of sedation and falls.

Antihistaminergic medications are associated with sedation, confusion, cognitive dysfunction, falls, and delirium in geriatric patients. Medications that act on histamine receptors can be particularly detrimental in the geriatric population because of their decreased clearance, smaller volume of distribution, and decreased tolerance.^17,18

Anticholinergic medications. Although atropine and benztropine are widely recognized as anticholinergic agents, other medications, such as digoxin, paroxetine, and colchicine, also demonstrate anticholinergic activity that can cause problematic central and peripheral effects in geriatric patients.⁵⁵ Central anticholinergic inhibition can lead to reduced cognitive function and impairments in attention and short-term memory. The peripheral effects of anticholinergic medications are similar to those of antihistamines and may include, but are not limited to, dry eyes and mouth via increased inhibition of acetylcholine-mediated muscle contraction of salivary glands.⁵⁵ These effects can be compounded by the use of OTC medications that exhibit anticholinergic activity.

Diphenhydramine causes sedation through its activity on cholinergic and histaminergic receptors. Patients may not be aware that many OTC cough-and-cold combination products (such as NyQuil, Theraflu, etc.) and OTC nighttime analgesic products (such as Tylenol PM, Aleve PM, Motrin PM, etc.) contain diphenhydramine. For a geriatric patient, such as Mrs. B, diphenhydramine may increase the risk of falls and worsen cognition.

Teach patients to disclose everything they take

Polypharmacy can be detrimental to older patients’ health due to the increased risk of toxicity caused by therapeutic duplication, drug–drug interactions, and drug-disease interactions. Most patients are unable to navigate the nuances of medication indications, maximum dosages, and therapeutic duplications. Older adults frequently take OTC medications and have the greatest risk of developing adverse effects from these medications due to decreased renal and hepatic clearance, increased drug sensitivity, and decreased volume of distribution. Dietary supplements pose a unique risk because they are not FDA-regulated and their purity, quality, and content cannot be verified. Educating patients and family members about the importance of reporting all their prescription medications, OTC medications, and dietary supplements to their pharmacists and clinicians is critical in order to identify and mitigate the risks associated with polypharmacy in geriatric patients.

Continue to: CASE

Mrs. B is diagnosed with lithium toxicity due to a drug–drug interaction with naproxen. Her lithium is held, and IV fluids are administered. Her symptoms resolve over the next few days. Mrs. B and her son are taught about the interaction between lithium and NSAIDs, and she is counseled to avoid all OTC NSAIDs other than aspirin. Her clinician recommends taking acetaminophen because it will not interact with her medications and is the recommended OTC treatment for mild or moderate pain in geriatric patients.^17,56

Next, the clinician addresses Mrs. B’s GERD. Although Mrs. B had been taking PPIs twice daily, her physician recommends decreasing the omeprazole frequency to once daily to minimize adverse effects and pill burden. She also decreases Mrs. B’s aspirin from 325 to 81 mg/d because evidence suggests that when used to prevent CAD, lower-dose aspirin is effective as high-dose aspirin and has fewer adverse effects.⁵⁷ Finally, she advises Mrs. B to stop taking ginkgo biloba and kava kava and to always check with her primary care physician or pharmacist before beginning any new medication, dietary supplement, or vitamin.

Mrs. B agrees to first check with her clinicians before following advice from mass media. A follow-up appointment is scheduled for 2 weeks to assess renal function, a lithium serum concentration, and adherence to her simplified medication regimen.

Related Resources

• US Department of Health and Human Services. National Institutes of Health. MedlinePlus. Herbs and supplements. https://medlineplus.gov/druginfo/herb_All.html.
• US Department of Health and Human Services. National Center for Complementary and Integrative Health. https://nccih.nih.gov/.

Drug Brand Names

Atorvastatin • Lipitor
Atropine • Atropen
Benztropine • Cogentin
Clozapine • Clozaril
Clopidogrel • Plavix
Colchicine • Colcrys, Gloperba
Digoxin • Cardoxin, Digitek
Lidocaine • Lidoderm, Xylocaine Viscous
Lithium • Eskalith, Lithobid
Methadone • Methadose
Morphine • Kadian, Morphabond
Paroxetine • Paxil
Trazodone • Desyrel
Warfarin • Coumadin, Jantoven

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH