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Geriatrician advises on use of vitamin D supplementation, lecanemab, and texting for her patients
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Updates in aspirin use, aducanumab, and CKD diagnostic criteria in geriatric medicine
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.