Geriatrics

On examination, the numerous firm, indurated nodules ranged in size from 1 to 4 cm. There was no palpable lymphadenopathy.

Results of a peripheral blood cell count showed the following:

• Hemoglobin 12.5 g/dL (reference range 13.0–17.0)
• Platelet count 154 × 10⁹/L (130–400)
• White blood cell count 5.0 × 10⁹/L (4.0–11.0)
• Neutrophils 1.7 × 10⁹/L (1.5–8.0)
• Lymphocytes 2.2 × 10⁹/L (1.0–4.0)
• Monocytes 1.0 × 10⁹/L (0.2–1.0)
• Eosinophils 0 (0–0.4)
• Basophils 0 (0–0.2)
• Blasts 0.

The findings were consistent with leukemic cells with monocytic differentiation. The infiltrate was unusual because leukemic infiltrates typically demonstrate a high nuclear-to-cytoplasmic ratio, but in this case the malignant cells had moderate amounts of cytoplasm due to the monocytic differentiation. Also, a grenz zone is more typically seen in B-cell lymphomas, and T cells more typically demonstrate epidermotropism.

Bone marrow aspiration was performed and revealed a hypercellular bone marrow with trilineage maturation with only 2% blasts. The fluorescence in situ hybridization testing for myelodysplastic syndrome and acute myeloid leukemia was normal. A diagnosis of aleukemic leukemia cutis was made.

After 2 months of chemotherapy with azacitidine, the nodules were less indurated. Treatment was briefly withdrawn due to the development of acute pneumonia, leading to a rapid progression of cutaneous involvement. Despite restarting chemotherapy, the patient died.

 

 

ALEUKEMIC LEUKEMIA CUTIS

The differential diagnosis of leukemia cutis is diverse and extensive. Patients often present with painless, firm, indurated nodules, papules, and plaques.¹ The lesions can be small, involving a small amount of body surface area, but can also be very large and diffuse.

In our patient’s case, there were no new drugs or exposures to suggest a drug-related eruption, or pruritus or pain to suggest an inflammatory process. The rapid progression of the lesions suggested either an infectious or malignant process. The top 3 conditions in the differential diagnosis, based on his clinical presentation, were cutaneous T-cell lymphoma, cutaneous CD30+ anaplastic large-cell lymphoma, and a drug-induced cutaneous pseudolymphoma.

Skin biopsy is required to differentiate leukemia cutis from the other conditions. On skin biopsy study, leukemia cutis is characterized by infiltration of the skin by leukemic cells and is seen in 10% to 15% of patients with acute myeloid leukemia.² In 5% of cases, leukemia cutis can present without bone marrow or peripheral signs of leukemia, hence the term aleukemic leukemia cutis.³ Cutaneous signs can occur before, after, or simultaneously with systemic leukemia.⁴

In the absence of systemic symptoms, the diagnosis is made when progressive cutaneous symptoms are present. The prognosis for aleukemic leukemia cutis is poor. Prompt diagnosis with skin biopsy is paramount to improve outcomes.

Acknowledgment: We would like to recognize Maanasa Devabhaktuni for her assistance in reporting this case.

On examination, the numerous firm, indurated nodules ranged in size from 1 to 4 cm. There was no palpable lymphadenopathy.

Results of a peripheral blood cell count showed the following:

• Hemoglobin 12.5 g/dL (reference range 13.0–17.0)
• Platelet count 154 × 10⁹/L (130–400)
• White blood cell count 5.0 × 10⁹/L (4.0–11.0)
• Neutrophils 1.7 × 10⁹/L (1.5–8.0)
• Lymphocytes 2.2 × 10⁹/L (1.0–4.0)
• Monocytes 1.0 × 10⁹/L (0.2–1.0)
• Eosinophils 0 (0–0.4)
• Basophils 0 (0–0.2)
• Blasts 0.

The findings were consistent with leukemic cells with monocytic differentiation. The infiltrate was unusual because leukemic infiltrates typically demonstrate a high nuclear-to-cytoplasmic ratio, but in this case the malignant cells had moderate amounts of cytoplasm due to the monocytic differentiation. Also, a grenz zone is more typically seen in B-cell lymphomas, and T cells more typically demonstrate epidermotropism.

Bone marrow aspiration was performed and revealed a hypercellular bone marrow with trilineage maturation with only 2% blasts. The fluorescence in situ hybridization testing for myelodysplastic syndrome and acute myeloid leukemia was normal. A diagnosis of aleukemic leukemia cutis was made.

After 2 months of chemotherapy with azacitidine, the nodules were less indurated. Treatment was briefly withdrawn due to the development of acute pneumonia, leading to a rapid progression of cutaneous involvement. Despite restarting chemotherapy, the patient died.

 

 

ALEUKEMIC LEUKEMIA CUTIS

The differential diagnosis of leukemia cutis is diverse and extensive. Patients often present with painless, firm, indurated nodules, papules, and plaques.¹ The lesions can be small, involving a small amount of body surface area, but can also be very large and diffuse.

In our patient’s case, there were no new drugs or exposures to suggest a drug-related eruption, or pruritus or pain to suggest an inflammatory process. The rapid progression of the lesions suggested either an infectious or malignant process. The top 3 conditions in the differential diagnosis, based on his clinical presentation, were cutaneous T-cell lymphoma, cutaneous CD30+ anaplastic large-cell lymphoma, and a drug-induced cutaneous pseudolymphoma.

Skin biopsy is required to differentiate leukemia cutis from the other conditions. On skin biopsy study, leukemia cutis is characterized by infiltration of the skin by leukemic cells and is seen in 10% to 15% of patients with acute myeloid leukemia.² In 5% of cases, leukemia cutis can present without bone marrow or peripheral signs of leukemia, hence the term aleukemic leukemia cutis.³ Cutaneous signs can occur before, after, or simultaneously with systemic leukemia.⁴

In the absence of systemic symptoms, the diagnosis is made when progressive cutaneous symptoms are present. The prognosis for aleukemic leukemia cutis is poor. Prompt diagnosis with skin biopsy is paramount to improve outcomes.

Acknowledgment: We would like to recognize Maanasa Devabhaktuni for her assistance in reporting this case.

On examination, the numerous firm, indurated nodules ranged in size from 1 to 4 cm. There was no palpable lymphadenopathy.

Results of a peripheral blood cell count showed the following:

• Hemoglobin 12.5 g/dL (reference range 13.0–17.0)
• Platelet count 154 × 10⁹/L (130–400)
• White blood cell count 5.0 × 10⁹/L (4.0–11.0)
• Neutrophils 1.7 × 10⁹/L (1.5–8.0)
• Lymphocytes 2.2 × 10⁹/L (1.0–4.0)
• Monocytes 1.0 × 10⁹/L (0.2–1.0)
• Eosinophils 0 (0–0.4)
• Basophils 0 (0–0.2)
• Blasts 0.

The findings were consistent with leukemic cells with monocytic differentiation. The infiltrate was unusual because leukemic infiltrates typically demonstrate a high nuclear-to-cytoplasmic ratio, but in this case the malignant cells had moderate amounts of cytoplasm due to the monocytic differentiation. Also, a grenz zone is more typically seen in B-cell lymphomas, and T cells more typically demonstrate epidermotropism.

Bone marrow aspiration was performed and revealed a hypercellular bone marrow with trilineage maturation with only 2% blasts. The fluorescence in situ hybridization testing for myelodysplastic syndrome and acute myeloid leukemia was normal. A diagnosis of aleukemic leukemia cutis was made.

After 2 months of chemotherapy with azacitidine, the nodules were less indurated. Treatment was briefly withdrawn due to the development of acute pneumonia, leading to a rapid progression of cutaneous involvement. Despite restarting chemotherapy, the patient died.

 

 

ALEUKEMIC LEUKEMIA CUTIS

The differential diagnosis of leukemia cutis is diverse and extensive. Patients often present with painless, firm, indurated nodules, papules, and plaques.¹ The lesions can be small, involving a small amount of body surface area, but can also be very large and diffuse.

In our patient’s case, there were no new drugs or exposures to suggest a drug-related eruption, or pruritus or pain to suggest an inflammatory process. The rapid progression of the lesions suggested either an infectious or malignant process. The top 3 conditions in the differential diagnosis, based on his clinical presentation, were cutaneous T-cell lymphoma, cutaneous CD30+ anaplastic large-cell lymphoma, and a drug-induced cutaneous pseudolymphoma.

Skin biopsy is required to differentiate leukemia cutis from the other conditions. On skin biopsy study, leukemia cutis is characterized by infiltration of the skin by leukemic cells and is seen in 10% to 15% of patients with acute myeloid leukemia.² In 5% of cases, leukemia cutis can present without bone marrow or peripheral signs of leukemia, hence the term aleukemic leukemia cutis.³ Cutaneous signs can occur before, after, or simultaneously with systemic leukemia.⁴

In the absence of systemic symptoms, the diagnosis is made when progressive cutaneous symptoms are present. The prognosis for aleukemic leukemia cutis is poor. Prompt diagnosis with skin biopsy is paramount to improve outcomes.

Acknowledgment: We would like to recognize Maanasa Devabhaktuni for her assistance in reporting this case.

Study Overview

Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.

Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.

Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.

Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.

The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.

Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.

Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).

Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.

Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.

Commentary

Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.^1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.³ Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.

The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.

This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.

Applications for Clinical Practice

Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.

—Fred Ko, MD, MS

Study Overview

Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.

Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.

Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.

Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.

The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.

Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.

Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).

Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.

Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.

Commentary

Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.^1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.³ Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.

The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.

This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.

Applications for Clinical Practice

Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.

—Fred Ko, MD, MS

Study Overview

Objective. To compare clinical outcomes (mortality, pain, physical restraint use, pressure ulcer, antipsychotic drug use) in long-term care nursing home (NH) residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management.

Design. A retrospective cohort study utilizing nationwide Medicare (Parts A, B, D and hospice) claims data linked with Centers for Medicare & Medicaid Services Minimum Data Set (MDS version 2.0) assessments.

Setting and participants. Long-stay NH residents older than 65 years with advanced dementia (defined as being assigned to Cognitive Performance Scale category 5 or 6 and a diagnosis of dementia or Alzheimer disease) and without a do not hospitalize (DNH) directive before hip fracture were identified by using MDS assessments completed from January 1, 2008 to December 31, 2013. Medicare (Part A – inpatient, or Part B – outpatient) claims data was then used to identify those residents who experienced a hip fracture within 2 years of the full MDS assessment using the International Classification of Diseases, Ninth Revision diagnostic codes. Procedure codes were used to determine whether a resident who experienced hip fracture underwent surgical repair.

Main outcome measures. The main outcome measure was all-cause mortality after hip fracture ascertained by the Medicare Enrollment File through 2013. The secondary outcome measures were documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status in NH residents who survived 6 months after hip fracture. These outcome measures were captured from the first MDS assessment completed between 120 and 240 days following the fracture or Medicare Part D claims. Documented pain was determined using a validated MDS 2.0 nursing assessment pain instrument within 7 days preceding MDS assessment. Physical restraint use was defined by the use of trunk, limb, or chair restraint within 7 days prior to MDS assessment. Pressure ulcer was defined as any stage 2 to 4 pressure ulcer. Antipsychotic drug use of any medication subclass was determined using Medicare Part D claims data and affirmative if drug was administered 180 days after hip fracture. Ambulatory status between 120 and 240 days following the fracture was determined in a subset of NH residents who were ambulatory before the hip fracture. The utilization of comfort-focused care after hip fracture was determined in NH residents who had a Medicare hospice claim or a new DNH directive in the 180 days after hip fracture.

The differences in survival among NH residents with advanced dementia and hip fracture were described by Kaplan-Meier curves. The association between surgical repair and survival was determined using multivariable Cox proportional hazards for all NH residents and stratified by pre-fracture ambulatory status. In those who survived 6 months after hip fracture, the associations between surgical repair and outcomes including documented pain, physical restraint use, pressure ulcers, antipsychotic drug use, and ambulatory status were determined using multivariable logistic regression models. Adjustment for differences in characteristics before hip fracture was performed using inverse probability of treatment weighting (IPTW) models.

Main results. 3083 long-stay NH residents with advanced dementia and hip fracture were included in the study. The cohort’s mean age was 84.2 ± 7.1 years, 79.2% were female (n = 2441), and 28.5% were ambulatory before hip fracture (n = 879). Of these NH residents, 84.8% (n = 2615) underwent surgical repair and 15.2% (n = 468) received nonsurgical management. At 6 months after hip fracture, mortality was 31.5% in the surgical group compared to 53.8% in the nonsurgical group. The greatest mortality difference between groups occurred in the first 30 days after hip fracture (11.5% in surgical group versus 30.6% in nonsurgical group). Surgical repair was associated with a decreased risk of death (Cox proportional hazard ratio) in the unadjusted (hazard ratio [HR], 0.55 [95% confidence interval {CI}, 0.49-0.61), multivariable adjusted (adjusted HR, 0.56 [95% CI, 0.49-0.63]), and IPTW (adjusted HR, 0.88 [95% CI, 0.79-0.98]) models. Similarly, surgically treated NH residents were less likely to die than those managed non-surgically when mortality was stratified by pre-fracture ambulatory status.

Among NH residents who survived 6 months after hip fracture, those who underwent surgical repair compared with those who received nonsurgical management had less documented pain (29.0% versus 30.9%), fewer pressure ulcers (11.2% versus 19.0%), greater physical restraint use (13.0% versus 11.1%), and greater antipsychotic drug use (29.5% versus 20.4%). In the adjusted IPTW models, surgical repair was associated with less pain (adjusted HR, 0.78 [95% CI, 0.61-0.99]) and fewer pressure ulcers (adjusted HR, 0.64 [95% CI, 0.47-0.86]).

Overall, 21.5% of NH residents utilized comfort-focused care within 6 months after hip fracture, with a mean time to utilization of hospice care of 56 ± 49 days. In those who were managed surgically, 19.3% utilized hospice care, as compared with 33.8% in those who did not receive surgical intervention. In NH residents who survived 6 months after hip fracture, only 1.1% in both groups acquired a DNH directive.

Conclusion. In older long-stay NH residents with advanced dementia and hip fracture, surgical repair was associated with lower all-cause mortality, less documented pain, and fewer pressure ulcers compared to nonsurgical management. However, adverse clinical outcomes such as pain, physical restraint use, pressure ulcers, and antipsychotic drug use were common regardless of treatment modality. The high incidence of these adverse outcomes and hazardous interventions, coupled with low utilization of comfort-focused care and DNH directive, highlight an opportunity to improve the quality of care in this vulnerable population.

Commentary

Hip fracture is very common in NH residents, with an overall incident rate of 2.3 per 100 person years and is associated with a high mortality rate of 36.2% by 6 months after fracture.^1,2 Moreover, Neuman and colleagues have recently reported that among NH residents who have some degree of functional independence in locomotion prior to hip fracture, 54% either die or develop new total dependence in locomotion within 6 months of fracture and that severe cognitive impairment is a risk factor highly associated with these adverse outcomes.³ Despite this emerging knowledge, surgical repair of hip fracture remains the mainstay treatment in many NH residents in the hope of alleviating pain and improving mobility, and palliative care is considered only when patients are imminently dying or have deteriorated past the point of meaningful recovery. In cases of NH residents with advanced dementia whose life expectancy is limited and whose care goals may favor maintaining comfort, the health care proxies are frequently challenged with a difficult choice of either pursuing or foregoing surgical management—a complex medical decision to be made in the absence of sufficient evidence in this uniquely frail patient population.

The study reported by Berry and colleagues provides an important and timely investigation in examining associations of adverse clinical outcomes (mortality, pain, pressure ulcer) and hazardous interventions (physical restraint and antipsychotic drug use) in long-stay NH residents with advanced dementia and hip fracture who underwent surgical repair or nonsurgical management. The authors reported a 6-month mortality rate of 31.5% in NH residents who underwent surgical repair, an event rate similar to that reported by Neuman and colleagues. While surgical repair after hip fracture was associated with a decreased risk of death compared to nonsurgical management, high incidences of pain (29.0% to 30.9%) and pressure ulcers (11.2% to 19.0%), and frequent physical restraint use (11.1% to 13.0%) and antipsychotic drug use (20.4% to 29.5%) were noted in NH residents who survived 6 months after fracture regardless of treatment modality. These findings are consistent with the high rate of post-hip fracture functional disability previously reported by Neuman and colleagues, and highlight the trajectory of decline, frequent distressing symptoms, and prevalent use of pharmacologic and nonpharmacologic restraints in long-stay NH residents after hip fracture. Taken together, the low utilization of comfort-focused care (21.5%) and DNH directive (1.1%) in NH residents who survived 6 months suggest a missed opportunity to integrate palliative care in a patient population that stands to benefit from this intervention.

This study is the first to report the associations between hip fracture surgery and a reduction in adverse outcomes such as pain and pressure ulcer that commonly affect vulnerable NH residents with advanced dementia. This study was well designed and leveraged strengths of Medicare claims data linked with MDS assessments to capture outcome measures including pain, pressure ulcer, and restraint use that would otherwise be difficult to ascertain. However, as in all retrospective cohort design, there were limitations in this study. For instance, secondary outcomes were determined from a single time point (ie, first MDS assessment completed between 120 to 240 days following hip fracture) and thus data capture may be incomplete. Additionally, other conditions important to complex decision making in the care of frail older adults including postoperative complications (eg, delirium, infections, cardiac complications) and in-hospital mortality were not examined. Despite these limitations, this study has enhanced our understanding of the clinical course of long-term care NH residents with advanced dementia who endured hip fracture.

Applications for Clinical Practice

Patients’ goals of care should guide medical decision making in the management of hip fracture in NH residents with advanced dementia. The increased survival benefit of surgical repair of hip fracture in this patient population should be considered in the medical decision-making process if life-prolongation is preferred. However, palliative and hospice care need to be an important facet of discussion given the high rates of mortality, pain, pressure ulcer, and restraint use in this vulnerable subset of older adults.

—Fred Ko, MD, MS

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

[email protected]

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

In elderly patients with osteoarthritis, long-term opioid use is highly prevalent and varies substantially by state, suggest the results of a large, observational cohort study.

sdominick/iStock/Getty Images

Long term opioid use prior to total joint replacement (TJR) varied somewhat by access to primary care providers, but not by access to rheumatologists, according to authors of the study, led by Rishi J Desai, MS, PhD, of the department of medicine at Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

“These findings suggest that geographically targeted dissemination strategies for safe opioid prescribing guidelines may be required to address the high use observed in certain states,” said Dr. Desai and his colleagues in a report on the study published in Arthritis & Rheumatology.

This study by Dr. Desai and his colleagues looked at long-term use of opioids, which was defined as at least 90 days of use in the year prior to TJR. They analyzed a total of 358,121 Medicare enrollees with advanced osteoarthritis, with a mean age of 74 years.

Geographic areas in the South tended to have higher proportions of long-term opioid users, while the Northeast and Midwest had lower proportions, according to investigators.

Long-term use of opioids ranged from a low of 8.9% in Minnesota to 26.4% in Alabama, they reported. Beyond Alabama, the top 10 states included West Virginia, Georgia, Kentucky, Louisiana, Oklahoma, North Carolina, Virginia, Indiana, and Mississippi, with proportions of long-term opioid users ranging from 17% to 25%, the report shows.

Only modest associations were seen between provider density and opioid use, investigators said. There was a 1.4% mean difference (95% confidence interval, 0.8%-2.0%) in long-term opioid users between primary care service areas (PCSAs) with the highest concentrations of primary care providers versus those with the lowest, and there was just a 0.6% mean difference (95% CI, –0.1% to 1.3%) between PCSAs with the highest concentrations of rheumatologists and those with the lowest.

Among long-term opioid users, almost 20% were using an average daily dose of 50 or more morphine milligram equivalents, a range that potentially imparts a high risk of opioid-related harms, according to investigators.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Desai reported disclosures related to Merck and Vertex. Co-authors provided disclosures related to a number of pharmaceutical companies.

SOURCE: Desai RJ et al. Arthritis Rheumatol. 2019. doi: 10.1002/art.40834.

Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.

In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). About 57% of prescriptions were for specific psychiatric indications, 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.

Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).

Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.

“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”

The authors reported no conflicts of interest.

[email protected]

SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.

Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.

In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). About 57% of prescriptions were for specific psychiatric indications, 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.

Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).

Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.

“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”

The authors reported no conflicts of interest.

[email protected]

SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.

Almost a quarter of an elderly U.S. population who were prescribed an antidepressant potentially received an overprescription, according to William V. Bobo, MD, MPH, of the Mayo Clinic in Jacksonville, Fla., and his associates.

In a study published in Pharmacology Research & Perspectives, the authors drew data from the Rochester Epidemiology Project and included 3,199 incident antidepressant prescriptions from adults aged at least 65 years who lived in Olmsted County, Minn., from 2005 to 2012. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed medication (40%), followed by trazodone/nefazodone (20%), tricyclic antidepressants (16%), and mirtazapine (12%). About 57% of prescriptions were for specific psychiatric indications, 22% were for nonspecific symptoms, and 21% were for general medical diagnoses, Dr. Bobo and his associates reported.

Potential antidepressant overprescribing occurred in 24% of all prescriptions; SSRIs were most commonly overprescribed, accounting for 74% of all overprescriptions, followed by mirtazapine (19%). Overprescription was most common when antidepressants were prescribed for nonspecific psychiatric symptoms (18%), compared with specific psychiatric indications (3.5%) and general medical diagnoses (2.5%).

Other factors associated with antidepressant overprescription included living in a nursing home, having a higher number of comorbid medical conditions and outpatient prescribers, taking more concomitant medications, more commonly using urgent or acute care in the year prior to index prescription, and being prescribed antidepressants via telephone, email, or patient portal.

“Potential antidepressant overprescribing in a large cohort of elderly patients mainly involved the use of newer antidepressants for nonspecific psychiatric symptoms and indications,” the investigators wrote. “However, the majority of incident antidepressant starts did not represent potential overprescribing. When overprescribing occurred, it was associated with factors representing higher multimorbidity, clinical complexity, and severity – and with antidepressant prescribing that did not involve face-to-face interaction of patients with prescribers.”

The authors reported no conflicts of interest.

[email protected]

SOURCE: Bobo WV et al. Pharmacol Res Perspect. 2019 Jan 24. doi: 10.1002/prp2.461.

CHICAGO – The first prospective randomized trial support for the efficacy of LDL-lowering therapy for primary cardiovascular prevention in patients age 75 and older has been provided by the Japanese EWTOPIA 75 trial.

Bruce Jancin/MDedge News

Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.

There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.

The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.

“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.

Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.

The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.

The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.

Bruce Jancin/MDedge News

Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.

She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.

“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.

“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.

Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.

“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.

As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.

Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
 

[email protected]

SOURCE: Ouchi Y. AHA Late Breaker 02.

CHICAGO – The first prospective randomized trial support for the efficacy of LDL-lowering therapy for primary cardiovascular prevention in patients age 75 and older has been provided by the Japanese EWTOPIA 75 trial.

Bruce Jancin/MDedge News

Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.

There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.

The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.

“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.

Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.

The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.

The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.

Bruce Jancin/MDedge News

Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.

She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.

“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.

“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.

Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.

“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.

As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.

Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
 

[email protected]

SOURCE: Ouchi Y. AHA Late Breaker 02.

CHICAGO – The first prospective randomized trial support for the efficacy of LDL-lowering therapy for primary cardiovascular prevention in patients age 75 and older has been provided by the Japanese EWTOPIA 75 trial.

Bruce Jancin/MDedge News

Ezetimibe (Zetia) at 10 mg/day reduced the risk of the primary endpoint, a composite of atherosclerotic cardiovascular events, by 34% compared with a dietary counseling control group over the course of 5 years of followup. Yasuyoshi Ouchi, MD, PhD, reported the findings of the 3,796-patient study at the American Heart Association scientific sessions.

There was also a 40% relative risk reduction for cardiac events in the ezetimibe group. The 22% reduction in cerebrovascular events, however, didn’t achieve statistical significance, and there was no between-group difference in all-cause mortality, said Dr. Ouchi, principal investigator in EWTOPIA 75 and professor emeritus of geriatric medicine at the University of Tokyo.

The landmark randomized clinical trials of lipid-lowering for primary cardiovascular prevention included too few elderly participants to permit assessment of its merits and possible harms in that population. This has left a major evidence gap at a time when in many parts of the world, including the United States, Europe, and Japan, the population over age 75 is growing explosively.

“Along with this population change, the number of patients age 75 and older with hypercholesterolemia has dramatically increased,” Dr. Ouchi continued.

Eligibility for EWTOPIA was restricted to patients who were at least 75 years old, had an LDL of at least 140 mg/dL, no history of CAD, and had at least one high-risk factor, such as diabetes or hypertension. Their mean age at enrollment was 80.7 years. Seventy-four percent of them were women, reflecting the significantly longer life expectancy of Japanese women compared to men.

The study design was open-label with no placebo arm. Dr. Ouchi argued that this was appropriate, given that the components of the primary composite endpoint were “entirely objective”: fatal and nonfatal MI, fatal and nonfatal stroke, sudden cardiac death, and coronary revascularization.

The mean LDL in the ezetimibe group dropped from 162 mg/dL at baseline to 120 mg/dL at 5 years, versus 131 mg/dL in the control group.

Bruce Jancin/MDedge News

Discussant Jennifer G. Robinson, MD, said that for a decade she has tried without success to get backing for a primary prevention statin trial in elderly U.S. patients, so congratulations to the Japanese investigators are in order.

She expressed doubts as to the generalizability of the EWTOPIA results to non-Japanese populations, however.

“Frankly, I was very surprised to see the large effect size. EWTOPIA had far more effect than we expected based on other trials of LDL-lowering agents to date,” said Dr. Robinson, professor of epidemiology and medicine and director of the Prevention Intervention Center at the University of Iowa, Iowa City.

“It’s a little better performance than we expected from that magnitude of LDL lowering, which was quite modest,” she added.

Among the possible explanations she cited for the greater magnitude of reduction in major vascular events seen in EWTOPIA as compared, for example, to the IMPROVE-IT trial, which also utilized ezetimibe, are genetic differences in the Japanese population. It’s known that the Japanese have different genetic polymorphisms of Niemann-Pick C1 Like 1 (NPC1L1), which is what ezetimibe binds to in order to inhibit small intestinal enterocyte uptake and absorption of cholesterol. Or it might just be that older adults, regardless of their ethnicity, have a more robust response to LDL lowering than the younger ones who’ve been the focus of previous trials.

“I think the LDL lowering from ezetimibe was very effective in Japanese older adults without cardiovascular disease, and I think that’s a very appropriate therapy for primary prevention moving forward in that population,” Dr. Robinson said.

As for herself, she’s awaiting confirmation in other populations. She’s particularly eager to see the outcome of the ongoing double-blind, randomized STAREE trial of atorvastatin (Lipitor) at 40 mg/day or placebo for primary prevention in 18,000 Australians age 70 and up. Results are expected in 2022.

Dr. Ouchi reported having no financial conflicts regarding the EWTOPIA study, funded by the Japanese government.
 

[email protected]

SOURCE: Ouchi Y. AHA Late Breaker 02.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

[email protected]

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

[email protected]

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.

Among people of the same age, the degree of frailty influences the association between Alzheimer’s disease pathology and Alzheimer’s dementia, according to research published online ahead of print Jan. 17 in Lancet Neurology. Data suggest that frailty reduces the threshold for Alzheimer’s disease pathology to cause cognitive decline. Frailty also may contribute to other mechanisms that cause dementia, such as inflammation and immunosenescence, said the investigators.

“While more research is needed, given that frailty is potentially reversible, it is possible that helping people to maintain function and independence in later life could reduce both dementia risk and the severity of debilitating symptoms common in this disease,” said Professor Kenneth Rockwood, MD, of the Nova Scotia Health Authority and Dalhousie University in Halifax, N.S., in a press release.
 

More susceptible to dementia?

The presence of amyloid plaques and neurofibrillary tangles is not a sufficient condition for the clinical expression of dementia. Some patients with a high degree of Alzheimer’s disease pathology have no apparent cognitive decline. Other factors therefore may modify the relationship between pathology and dementia.

Most people who develop Alzheimer’s disease dementia are older than 65 years, and many of these patients are frail. Frailty is understood as a decreased physiologic reserve and an increased risk for adverse health outcomes. Dr. Rockwood and his colleagues hypothesized that frailty moderates the clinical expression of dementia in relation to Alzheimer’s disease pathology.

To test their hypothesis, the investigators performed a cross-sectional analysis of data from the Rush Memory and Aging Project, which collects clinical and pathologic data from adults older than 59 years without dementia at baseline who live in Illinois. Since 1997, participants have undergone annual clinical and neuropsychological evaluations, and the cohort has been followed for 21 years. For their analysis, Dr. Rockwood and his colleagues included participants without dementia or with Alzheimer’s dementia at their last clinical assessment. Eligible participants had died, and complete autopsy data were available for them.

The researchers measured Alzheimer’s disease pathology using a summary measure of neurofibrillary tangles and neuritic and diffuse plaques. Clinical diagnoses of Alzheimer’s dementia were based on clinician consensus. Dr. Rockwood and his colleagues retrospectively created a 41-item frailty index from variables (e.g., symptoms, signs, comorbidities, and function) that were obtained at each clinical evaluation.

Logistic regression and moderation modeling allowed the investigators to evaluate relationships between Alzheimer’s disease pathology, frailty, and Alzheimer’s dementia. Dr. Rockwood and hus colleagues adjusted all analyses for age, sex, and education.

In all, 456 participants were included in the analysis. The sample’s mean age at death was 89.7 years, and 69% of participants were women. At participants’ last clinical assessment, 242 (53%) had possible or probable Alzheimer’s dementia.

The sample’s mean frailty index was 0.42. The median frailty index was 0.41, a value similar to the threshold commonly used to distinguish between moderate and severe frailty. People with high frailty index scores (i.e., 0.41 or greater) were older, had lower Mini-Mental State Examination scores, were more likely to have a diagnosis of dementia, and had a higher Braak stage than those with moderate or low frailty index scores.
 

Significant interaction between frailty and Alzheimer’s disease

After the investigators adjusted for age, sex, and education, frailty (odds ratio, 1.76) and Alzheimer’s disease pathology (OR, 4.81) were independently associated with Alzheimer’s dementia. When the investigators added frailty to the model for the relationship between Alzheimer’s disease pathology and Alzheimer’s dementia, the model fit improved. They found a significant interaction between frailty and Alzheimer’s disease pathology (OR, 0.73). People with a low amount of frailty were better able to tolerate Alzheimer’s disease pathology, and people with higher amounts of frailty were more likely to have more Alzheimer’s disease pathology and clinical dementia.

One of the study’s limitations is that it is a secondary analysis, according to Dr. Rockwood and his colleagues. In addition, frailty was measured close to participants’ time of death, and the measurements may thus reflect terminal decline. Participant deaths resulting from causes other than those related to dementia might have confounded the results. Finally, the sample came entirely from people living in retirement homes in Illinois, which might have introduced bias. Future research should use a population-based sample, said the authors.

Frailty could be a basis for risk stratification and could inform the management and treatment of older adults, said Dr. Rockwood and his colleagues. The study results have “the potential to improve our understanding of disease expression, explain failures in pharmacologic treatment, and aid in the development of more appropriate therapeutic targets, approaches, and measurements of success,” they concluded.

The study had no source of funding. The authors reported receiving fees and grants from DGI Clinical, GlaxoSmithKline, Pfizer, and Sanofi. Authors also received support from governmental bodies such as the National Institutes of Health and the Canadian Institutes of Health Research.

[email protected]

SOURCE: Wallace LMK et al. Lancet Neurol. 2019;18:177-84.

Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Decreased time in deep, dreamless sleep is associated with increasing Alzheimer’s disease pathology. Also today, physician groups are pushing back on Part B of the drug reimbursement proposal, dabigatran matches aspirin for second stroke prevention, and reassurance for pregnancy in atopic dermatitis.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Children in military families face unique challenges that other children do not face. Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Children in military families face unique challenges that other children do not face. Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Children in military families face unique challenges that other children do not face. Knee pathologies predict accelerated knee osteoarthritis, patients with a poor-prognosis cancer have a higher risk of suicide in the first year, and Nuedexta is mainly being prescribed for dementia and Parkinson’s.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify