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Vascular Risk: What’s Really Important?
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
Antiviral receives breakthrough designation for CMV
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need. 
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to maribavir (SHP620) as a treatment for cytomegalovirus (CMV) infection and disease in transplant recipients who are resistant or refractory to prior therapy.
Maribavir, an antiviral therapy that belongs to a class of drugs called benzimidazole ribosides, is being evaluated in patients who have CMV infection after undergoing hematopoietic stem cell transplant or solid organ transplant.
The drug inhibits the CMV UL97 protein kinase and is thought to affect several critical processes in CMV replication, including viral DNA synthesis, viral gene expression, encapsidation, and egress of mature capsids from the nucleus.
The FDA granted maribavir breakthrough designation based on data from two phase 2 studies. For one of these studies (NCT00223925), data are not yet available.
The other study (NCT01611974) was presented at IDWeek 2016. This study included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant.
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Sixty-seven percent (80/120) of patients met this endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
The incidence of treatment-emergent adverse events (AEs) was 78% (n=93) overall, 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA approves denosumab for MM patients
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA®) for use in patients with multiple myeloma (MM).
The drug was previously approved to prevent skeletal-related events in patients with bone metastases from solid tumors.
Now, denosumab is FDA-approved to prevent skeletal-related events in MM patients as well.
Denosumab is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function, and survival of osteoclasts—thereby inhibiting osteoclast-mediated bone destruction.
The FDA’s approval of denosumab in MM is based on data from the phase 3 '482 study, which were presented at the 2017 ASCO Annual Meeting last June.
In this trial, researchers compared denosumab to zoledronic acid for the prevention of skeletal-related events in 1718 adults with newly diagnosed MM and bone disease.
Patients were randomized to receive either subcutaneous denosumab at 120 mg and intravenous placebo every 4 weeks (n=859) or intravenous zoledronic acid at 4 mg (adjusted for renal function) and subcutaneous placebo every 4 weeks (n=859).
Denosumab proved non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). The hazard ratio (HR) was 0.98 (95% CI: 0.85, 1.14; P=0.01).
Denosumab was not superior to zoledronic acid in delaying the time to a first skeletal-related event or delaying the time to first-and-subsequent skeletal-related events.
Overall survival was comparable between the treatment arms. The HR was 0.90 (95% CI: 0.70, 1.16; P=0.41).
The median difference in progression-free survival favored denosumab by 10.7 months (HR=0.82, 95% CI: 0.68-0.99; descriptive P=0.036). The median progression-free survival was 46.1 months for denosumab and 35.4 months for zoledronic acid.
The most common adverse events in patients who received denosumab were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%) and headache (11%).
The most common adverse event resulting in discontinuation of denosumab was osteonecrosis of the jaw.
In the primary treatment phase of the study, osteonecrosis of the jaw was confirmed in 4.1% of patients in the denosumab arm (median exposure of 16 months; range, 1-50) and 2.8% of those in the zoledronic acid arm (median 15 months; range, 1-45 months).
Rituximab tackles relapse of severe, difficult-to-treat pemphigus
, based on data from a case series of 11 patients.
“We found that treatment with rituximab alone, even at a low dose, not only prevented relapse but also maintained complete remission with a better benefit-to-risk ratio than treatment with corticosteroids,” Julia Sanchez, MD, of Reims (France) University Hospital and her colleagues reported in a research letter in JAMA Dermatology.
The study population consisted of patients diagnosed with pemphigus at a single center from Jan. 1, 2014, to Dec. 31, 2014, and treated with at least one cycle of rituximab for corticosteroid dependence, corticosteroid resistance, or adverse events. All the patients were in remission at the time of the first maintenance dose of rituximab.
All patients received a 1-g rituximab infusion every 6 months for 24-67 months; some patients changed to a once-yearly dose after 18 months. Although 5 patients experienced grade 3 or 4 adverse events (1 patient had sepsis; 2, diabetes; 1, hypertension; and 2, endocrine disorders) between the initial therapy cycle and the first rituximab maintenance infusion, no adverse events were reported by any of the 11 patients during the maintenance therapy period.
All 11 patients remained in remission after their last follow-up visit (an average of 78 months after the first cycle), at which point 10 patients had discontinued the therapy.
“A progressive decrease in serum anti-desmoglein autoantibody levels to less than 14 U/mL occurred in all cases along with clinical complete remission even after maintenance therapy cessation,” Dr. Sanchez and her associates noted.
Future research should address questions including the optimal dose and dosing frequency of rituximab, as well as the cost-effectiveness of the treatment and criteria for treatment withdrawal, they said.
The researchers had no relevant financial conflicts disclosures.
SOURCE: JAMA Dermatol. 2017 Jan 3. doi: 10.1001/jamadermatol.2017.5176.
, based on data from a case series of 11 patients.
“We found that treatment with rituximab alone, even at a low dose, not only prevented relapse but also maintained complete remission with a better benefit-to-risk ratio than treatment with corticosteroids,” Julia Sanchez, MD, of Reims (France) University Hospital and her colleagues reported in a research letter in JAMA Dermatology.
The study population consisted of patients diagnosed with pemphigus at a single center from Jan. 1, 2014, to Dec. 31, 2014, and treated with at least one cycle of rituximab for corticosteroid dependence, corticosteroid resistance, or adverse events. All the patients were in remission at the time of the first maintenance dose of rituximab.
All patients received a 1-g rituximab infusion every 6 months for 24-67 months; some patients changed to a once-yearly dose after 18 months. Although 5 patients experienced grade 3 or 4 adverse events (1 patient had sepsis; 2, diabetes; 1, hypertension; and 2, endocrine disorders) between the initial therapy cycle and the first rituximab maintenance infusion, no adverse events were reported by any of the 11 patients during the maintenance therapy period.
All 11 patients remained in remission after their last follow-up visit (an average of 78 months after the first cycle), at which point 10 patients had discontinued the therapy.
“A progressive decrease in serum anti-desmoglein autoantibody levels to less than 14 U/mL occurred in all cases along with clinical complete remission even after maintenance therapy cessation,” Dr. Sanchez and her associates noted.
Future research should address questions including the optimal dose and dosing frequency of rituximab, as well as the cost-effectiveness of the treatment and criteria for treatment withdrawal, they said.
The researchers had no relevant financial conflicts disclosures.
SOURCE: JAMA Dermatol. 2017 Jan 3. doi: 10.1001/jamadermatol.2017.5176.
, based on data from a case series of 11 patients.
“We found that treatment with rituximab alone, even at a low dose, not only prevented relapse but also maintained complete remission with a better benefit-to-risk ratio than treatment with corticosteroids,” Julia Sanchez, MD, of Reims (France) University Hospital and her colleagues reported in a research letter in JAMA Dermatology.
The study population consisted of patients diagnosed with pemphigus at a single center from Jan. 1, 2014, to Dec. 31, 2014, and treated with at least one cycle of rituximab for corticosteroid dependence, corticosteroid resistance, or adverse events. All the patients were in remission at the time of the first maintenance dose of rituximab.
All patients received a 1-g rituximab infusion every 6 months for 24-67 months; some patients changed to a once-yearly dose after 18 months. Although 5 patients experienced grade 3 or 4 adverse events (1 patient had sepsis; 2, diabetes; 1, hypertension; and 2, endocrine disorders) between the initial therapy cycle and the first rituximab maintenance infusion, no adverse events were reported by any of the 11 patients during the maintenance therapy period.
All 11 patients remained in remission after their last follow-up visit (an average of 78 months after the first cycle), at which point 10 patients had discontinued the therapy.
“A progressive decrease in serum anti-desmoglein autoantibody levels to less than 14 U/mL occurred in all cases along with clinical complete remission even after maintenance therapy cessation,” Dr. Sanchez and her associates noted.
Future research should address questions including the optimal dose and dosing frequency of rituximab, as well as the cost-effectiveness of the treatment and criteria for treatment withdrawal, they said.
The researchers had no relevant financial conflicts disclosures.
SOURCE: JAMA Dermatol. 2017 Jan 3. doi: 10.1001/jamadermatol.2017.5176.
FROM JAMA DERMATOLOGY
Key clinical point: Treatment with rituximab prevented relapse and maintained remission in 11 patients with severe, difficult-to-treat pemphigus.
Major finding: All 11 patients treated with a 1-g dose of rituximab given every 6 months maintained remission at an average of 78 months after the first cycle.
Data source: The data come from a single-center, retrospective case series of 11 adults.
Disclosures: The researchers had no relevant financial disclosures.
Source: JAMA Dermatol. 2017 Jan 3. doi: 10.1001/jamadermatol.2017.5176.
FDA cites manufacturer of autologous stem cells for regulatory, manufacturing missteps
for manufacturing processes that may compromise its safety and for failing to toe the regulatory line in marketing.
American CryoStem received an FDA warning letter Jan. 3 demanding that the company comply with best-manufacturing processes and obtain an investigational new drug application if it wishes to continue marketing ATCELL for its currently advertised clinical indications and administration routes. These include intravenous, intrathecal, or aerosol inhalation of the product for anoxic brain injury, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis.
“Please be advised that, to lawfully market a drug that is a biological product, a valid biologics license must be in effect,” noted the letter. “Such licenses are issued only after a showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations. ATCELL is not the subject of an approved biologics license application nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Food, Drug, and Cosmetic Act and the Public Health Service Act.”
FDA inspectors conducted a site inspection of American CryoStem in Eatontown, N.J., last summer, during which they “documented evidence of significant deviations from current good manufacturing practice.” The agency then provided the company a chance to respond to these issues. The new warning letter discussed each complaint, noting that some were inadequately addressed, and demanded that the company take action within 15 working days or face potential legal process, including seizure and/or injunction.
American CryoStem is one of the first companies to experience increased scrutiny under FDA’s new commitment to regulate the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.
The new policy is designed to support the potential of cellular rejuvenation medicine, while protecting patients from “unscrupulous actors” who might endanger public health with untested products, according to FDA Commissioner Scott Gottlieb, MD. As enthusiasm for stem cell treatments surges, so are reports of adverse events. The New England Journal of Medicine recently reported on three patients with age-related macular degeneration who were blinded by intravitreal injection of autologous adipose-derived stem cells (N Engl J Med. 2017;376:1047-53).
Under the new policy, cell- and tissue-based products could be exempt from FDA premarket review only if they are removed from and implanted back into the same patient in their original form, or if the products are “minimally manipulated.” ATCELL fulfills neither qualification, the FDA warning letter said.
“You process adipose tissue ... to isolate cellular components of adipose tissue, commonly referred to as stromal vascular fraction [SVF]. Such processing is more than minimal manipulation because [it alters] the original relevant characteristics of the [tissue] relating to its utility for reconstruction, repair, or replacement. Then you process the SVF by expanding it in cell culture to manufacture ATCELL. Such expansion also is more than minimal manipulation because it alters the original relevant characteristics of the tissue.”
Furthermore, the letter noted, at least one of the components used in the clonal expansion process is investigational and not intended for human use. The manufacturer of that component, which was not named, “indicates the following: ‘Unless otherwise stated in our catalog or other company documentation accompanying the product(s), our products are intended for research use only and are not to be used for any other purpose, which includes but is not limited to, unauthorized commercial uses, in vitro diagnostic uses, ex vivo or in vivo therapeutic uses or any type of consumption or application to human and animals.”
The FDA also took exception with several equipment and lab safety issues. ATCELL was being created in areas that had no clean space designation – a serious concern, the letter said.
“American CryoStem’s unvalidated processes, inadequately controlled environment, lack of control of components used in production, and lack of sufficient and validated product testing ... pose a significant risk that ATCELL may be contaminated with microorganisms or have other serious product quality defects ... Because the product is administered to humans by various higher risk routes of administration, including intravenously, intrathecally, and by aerosol inhalation, if contaminated, its use could cause a range of adverse events, from infections to death.”
FDA also expressed concerns over a lack of consistent quality control testing of each batch and questioned whether the company’s method of shipping ATCELL to clinicians had been adequately validated.
Finally, the agency raised concerns that ATCELL, while it is labeled as being for research purposes only, may harm patients indirectly by preventing them from seeking timely treatment with proven therapies.
“ATCELL is intended to treat a variety of serious or life-threatening diseases or conditions, all of which are non-homologous uses,” the warning letter noted. “Such uses raise potential significant safety concerns because there is less basis on which to predict the product’s behavior in the recipient, and use of these unapproved products may cause users to delay or discontinue medical treatments that have been found safe and effective.”
SOURCE: FDA warning letter
for manufacturing processes that may compromise its safety and for failing to toe the regulatory line in marketing.
American CryoStem received an FDA warning letter Jan. 3 demanding that the company comply with best-manufacturing processes and obtain an investigational new drug application if it wishes to continue marketing ATCELL for its currently advertised clinical indications and administration routes. These include intravenous, intrathecal, or aerosol inhalation of the product for anoxic brain injury, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis.
“Please be advised that, to lawfully market a drug that is a biological product, a valid biologics license must be in effect,” noted the letter. “Such licenses are issued only after a showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations. ATCELL is not the subject of an approved biologics license application nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Food, Drug, and Cosmetic Act and the Public Health Service Act.”
FDA inspectors conducted a site inspection of American CryoStem in Eatontown, N.J., last summer, during which they “documented evidence of significant deviations from current good manufacturing practice.” The agency then provided the company a chance to respond to these issues. The new warning letter discussed each complaint, noting that some were inadequately addressed, and demanded that the company take action within 15 working days or face potential legal process, including seizure and/or injunction.
American CryoStem is one of the first companies to experience increased scrutiny under FDA’s new commitment to regulate the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.
The new policy is designed to support the potential of cellular rejuvenation medicine, while protecting patients from “unscrupulous actors” who might endanger public health with untested products, according to FDA Commissioner Scott Gottlieb, MD. As enthusiasm for stem cell treatments surges, so are reports of adverse events. The New England Journal of Medicine recently reported on three patients with age-related macular degeneration who were blinded by intravitreal injection of autologous adipose-derived stem cells (N Engl J Med. 2017;376:1047-53).
Under the new policy, cell- and tissue-based products could be exempt from FDA premarket review only if they are removed from and implanted back into the same patient in their original form, or if the products are “minimally manipulated.” ATCELL fulfills neither qualification, the FDA warning letter said.
“You process adipose tissue ... to isolate cellular components of adipose tissue, commonly referred to as stromal vascular fraction [SVF]. Such processing is more than minimal manipulation because [it alters] the original relevant characteristics of the [tissue] relating to its utility for reconstruction, repair, or replacement. Then you process the SVF by expanding it in cell culture to manufacture ATCELL. Such expansion also is more than minimal manipulation because it alters the original relevant characteristics of the tissue.”
Furthermore, the letter noted, at least one of the components used in the clonal expansion process is investigational and not intended for human use. The manufacturer of that component, which was not named, “indicates the following: ‘Unless otherwise stated in our catalog or other company documentation accompanying the product(s), our products are intended for research use only and are not to be used for any other purpose, which includes but is not limited to, unauthorized commercial uses, in vitro diagnostic uses, ex vivo or in vivo therapeutic uses or any type of consumption or application to human and animals.”
The FDA also took exception with several equipment and lab safety issues. ATCELL was being created in areas that had no clean space designation – a serious concern, the letter said.
“American CryoStem’s unvalidated processes, inadequately controlled environment, lack of control of components used in production, and lack of sufficient and validated product testing ... pose a significant risk that ATCELL may be contaminated with microorganisms or have other serious product quality defects ... Because the product is administered to humans by various higher risk routes of administration, including intravenously, intrathecally, and by aerosol inhalation, if contaminated, its use could cause a range of adverse events, from infections to death.”
FDA also expressed concerns over a lack of consistent quality control testing of each batch and questioned whether the company’s method of shipping ATCELL to clinicians had been adequately validated.
Finally, the agency raised concerns that ATCELL, while it is labeled as being for research purposes only, may harm patients indirectly by preventing them from seeking timely treatment with proven therapies.
“ATCELL is intended to treat a variety of serious or life-threatening diseases or conditions, all of which are non-homologous uses,” the warning letter noted. “Such uses raise potential significant safety concerns because there is less basis on which to predict the product’s behavior in the recipient, and use of these unapproved products may cause users to delay or discontinue medical treatments that have been found safe and effective.”
SOURCE: FDA warning letter
for manufacturing processes that may compromise its safety and for failing to toe the regulatory line in marketing.
American CryoStem received an FDA warning letter Jan. 3 demanding that the company comply with best-manufacturing processes and obtain an investigational new drug application if it wishes to continue marketing ATCELL for its currently advertised clinical indications and administration routes. These include intravenous, intrathecal, or aerosol inhalation of the product for anoxic brain injury, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis.
“Please be advised that, to lawfully market a drug that is a biological product, a valid biologics license must be in effect,” noted the letter. “Such licenses are issued only after a showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations. ATCELL is not the subject of an approved biologics license application nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Food, Drug, and Cosmetic Act and the Public Health Service Act.”
FDA inspectors conducted a site inspection of American CryoStem in Eatontown, N.J., last summer, during which they “documented evidence of significant deviations from current good manufacturing practice.” The agency then provided the company a chance to respond to these issues. The new warning letter discussed each complaint, noting that some were inadequately addressed, and demanded that the company take action within 15 working days or face potential legal process, including seizure and/or injunction.
American CryoStem is one of the first companies to experience increased scrutiny under FDA’s new commitment to regulate the rapid growth and development of regenerative medicine products, which include novel cellular therapies, with the aim of ensuring their safety and effectiveness.
The new policy is designed to support the potential of cellular rejuvenation medicine, while protecting patients from “unscrupulous actors” who might endanger public health with untested products, according to FDA Commissioner Scott Gottlieb, MD. As enthusiasm for stem cell treatments surges, so are reports of adverse events. The New England Journal of Medicine recently reported on three patients with age-related macular degeneration who were blinded by intravitreal injection of autologous adipose-derived stem cells (N Engl J Med. 2017;376:1047-53).
Under the new policy, cell- and tissue-based products could be exempt from FDA premarket review only if they are removed from and implanted back into the same patient in their original form, or if the products are “minimally manipulated.” ATCELL fulfills neither qualification, the FDA warning letter said.
“You process adipose tissue ... to isolate cellular components of adipose tissue, commonly referred to as stromal vascular fraction [SVF]. Such processing is more than minimal manipulation because [it alters] the original relevant characteristics of the [tissue] relating to its utility for reconstruction, repair, or replacement. Then you process the SVF by expanding it in cell culture to manufacture ATCELL. Such expansion also is more than minimal manipulation because it alters the original relevant characteristics of the tissue.”
Furthermore, the letter noted, at least one of the components used in the clonal expansion process is investigational and not intended for human use. The manufacturer of that component, which was not named, “indicates the following: ‘Unless otherwise stated in our catalog or other company documentation accompanying the product(s), our products are intended for research use only and are not to be used for any other purpose, which includes but is not limited to, unauthorized commercial uses, in vitro diagnostic uses, ex vivo or in vivo therapeutic uses or any type of consumption or application to human and animals.”
The FDA also took exception with several equipment and lab safety issues. ATCELL was being created in areas that had no clean space designation – a serious concern, the letter said.
“American CryoStem’s unvalidated processes, inadequately controlled environment, lack of control of components used in production, and lack of sufficient and validated product testing ... pose a significant risk that ATCELL may be contaminated with microorganisms or have other serious product quality defects ... Because the product is administered to humans by various higher risk routes of administration, including intravenously, intrathecally, and by aerosol inhalation, if contaminated, its use could cause a range of adverse events, from infections to death.”
FDA also expressed concerns over a lack of consistent quality control testing of each batch and questioned whether the company’s method of shipping ATCELL to clinicians had been adequately validated.
Finally, the agency raised concerns that ATCELL, while it is labeled as being for research purposes only, may harm patients indirectly by preventing them from seeking timely treatment with proven therapies.
“ATCELL is intended to treat a variety of serious or life-threatening diseases or conditions, all of which are non-homologous uses,” the warning letter noted. “Such uses raise potential significant safety concerns because there is less basis on which to predict the product’s behavior in the recipient, and use of these unapproved products may cause users to delay or discontinue medical treatments that have been found safe and effective.”
SOURCE: FDA warning letter
Very preterm birth is linked to reduced risk of eczema
according to data from a meta-analysis of 18 studies.
Previous research suggests that low birth weight is protective against the development of atopic dermatitis, said Tingting Zhu, PhD, of West China Second University Hospital, Chengdu, and colleagues.
Preterm birth (before 37 completed weeks’ gestation) was divided into subgroups of extremely preterm (less than 28 weeks’ gestation), very preterm (28 weeks’ to less than 32 weeks’ gestation), and moderate/late preterm (32 weeks’ gestation to less than 37 weeks’ gestation).
In an analysis based on gestational age, children had a significantly reduced risk of eczema if they were very preterm (relative risk, 0.77; 95% confidence interval, 0.70-0.84, P less than .01; adjusted RR, 0.73; 95% CI, 0.64-0.82; P less than 0.01), compared with children born full term. The association between eczema and preterm birth was no longer significant among children born moderately preterm, Dr. Zhu and associates reported.
The reasons for the impact of very preterm birth on eczema are unclear, but maturation of the stratum corneum at 29-37 weeks’ gestational age could play a role, the researchers noted. Also, limited microflora in very preterm infants could affect acquiring immune tolerance and lead to reduced risk of eczema. The study was limited by several factors, including variations in gestational age and inconsistent assessments of eczema among the studies.
However, the large sample size lends strength to the results, and further studies are needed to explore how the environment, nutrition, immune system development, and skin barrier function impact the risk of eczema in very preterm infants, Dr. Zhu and associates said.
The researchers had no relevant financial disclosures. The researchers had no financial conflicts to disclose. The study was funded in part by the National Science Foundation of China, the Ministry of Health of China, and various other grants.
SOURCE: Zhu T et al. J Amer Dermatol. 2018. doi: 10.1016/j.jaad.2017.12.015.
according to data from a meta-analysis of 18 studies.
Previous research suggests that low birth weight is protective against the development of atopic dermatitis, said Tingting Zhu, PhD, of West China Second University Hospital, Chengdu, and colleagues.
Preterm birth (before 37 completed weeks’ gestation) was divided into subgroups of extremely preterm (less than 28 weeks’ gestation), very preterm (28 weeks’ to less than 32 weeks’ gestation), and moderate/late preterm (32 weeks’ gestation to less than 37 weeks’ gestation).
In an analysis based on gestational age, children had a significantly reduced risk of eczema if they were very preterm (relative risk, 0.77; 95% confidence interval, 0.70-0.84, P less than .01; adjusted RR, 0.73; 95% CI, 0.64-0.82; P less than 0.01), compared with children born full term. The association between eczema and preterm birth was no longer significant among children born moderately preterm, Dr. Zhu and associates reported.
The reasons for the impact of very preterm birth on eczema are unclear, but maturation of the stratum corneum at 29-37 weeks’ gestational age could play a role, the researchers noted. Also, limited microflora in very preterm infants could affect acquiring immune tolerance and lead to reduced risk of eczema. The study was limited by several factors, including variations in gestational age and inconsistent assessments of eczema among the studies.
However, the large sample size lends strength to the results, and further studies are needed to explore how the environment, nutrition, immune system development, and skin barrier function impact the risk of eczema in very preterm infants, Dr. Zhu and associates said.
The researchers had no relevant financial disclosures. The researchers had no financial conflicts to disclose. The study was funded in part by the National Science Foundation of China, the Ministry of Health of China, and various other grants.
SOURCE: Zhu T et al. J Amer Dermatol. 2018. doi: 10.1016/j.jaad.2017.12.015.
according to data from a meta-analysis of 18 studies.
Previous research suggests that low birth weight is protective against the development of atopic dermatitis, said Tingting Zhu, PhD, of West China Second University Hospital, Chengdu, and colleagues.
Preterm birth (before 37 completed weeks’ gestation) was divided into subgroups of extremely preterm (less than 28 weeks’ gestation), very preterm (28 weeks’ to less than 32 weeks’ gestation), and moderate/late preterm (32 weeks’ gestation to less than 37 weeks’ gestation).
In an analysis based on gestational age, children had a significantly reduced risk of eczema if they were very preterm (relative risk, 0.77; 95% confidence interval, 0.70-0.84, P less than .01; adjusted RR, 0.73; 95% CI, 0.64-0.82; P less than 0.01), compared with children born full term. The association between eczema and preterm birth was no longer significant among children born moderately preterm, Dr. Zhu and associates reported.
The reasons for the impact of very preterm birth on eczema are unclear, but maturation of the stratum corneum at 29-37 weeks’ gestational age could play a role, the researchers noted. Also, limited microflora in very preterm infants could affect acquiring immune tolerance and lead to reduced risk of eczema. The study was limited by several factors, including variations in gestational age and inconsistent assessments of eczema among the studies.
However, the large sample size lends strength to the results, and further studies are needed to explore how the environment, nutrition, immune system development, and skin barrier function impact the risk of eczema in very preterm infants, Dr. Zhu and associates said.
The researchers had no relevant financial disclosures. The researchers had no financial conflicts to disclose. The study was funded in part by the National Science Foundation of China, the Ministry of Health of China, and various other grants.
SOURCE: Zhu T et al. J Amer Dermatol. 2018. doi: 10.1016/j.jaad.2017.12.015.
FROM JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point: Very preterm birth was associated with a significantly reduced risk of eczema, compared with full-term birth, but no difference in risk appeared between moderate preterm and full-term birth.
Major finding: Children had a significantly reduced risk of eczema if they were very preterm (RR, 0.77; 95% CI, 0.70-0.84; P less than .01; aRR 0.73, 95% CI, 0.64-0.82; P less than .01), compared with children born full term.
Data source: The data come from a meta-analysis of 18 studies.
Disclosures: The researchers had no financial conflicts to disclose. The study was funded in part by the National Science Foundation of China, the Ministry of Health of China, and various other grants.
Source: Zhu T et al. J Amer Dermatol. 2018. doi: 10.1016/j.jaad.2017.12.015.
The price of protection
It’s very likely that you have at least one or two female patients who play lacrosse. The sport has been reported to be the fastest-growing high school sport in the United States. (“Lacrosse is Actually America’s Fastest-Growing Sport,” by John Templon, BuzzFeed News, June 30, 2014). When I played in college, most of my teammates were products of prep schools in the Northeast or one of the few local hotbeds in Baltimore, Long Island, or the Finger Lakes Region of New York. But pickings were slim, and there was room for walk-ons like me looking to learn a new sport and stay in shape for football. Now hundreds of high schools in all parts of the country offer the sport for both boys and girls.
With growing awareness of the long-term effects of repeated head trauma, there has been a call from some parents and organizers of women’s lacrosse to require helmets on all players (“As Concussion Worries Rise, Girls’ Lacrosse Turns to Headgear,” by Bill Pennington, The New York Times, Nov 23, 2017). To those of us who have committed our professional lives to the health of children, the inclusion of helmets to the standard equipment for a female lacrosse player sounds like a good idea.
However, the proposed mandate has its critics, including several college coaches. Karen Corbett, women’s lacrosse coach at the University of Pennsylvania, has said that, players “will start to lead with their head because they feel protected, and that causes more injuries. We’ll become a more physical sport and a very different sport than we are today.”
Although I’m afraid that there are few data to support the validity of Dr. Hanley’s prediction, any observer of college hockey over the last 3 or 4 decades will tell you that he was unfortunately correct. There have been certainly fewer lacerations and eye injuries since face masks were introduced, but the game has become far more violent, and head, neck, and spine injuries have become more frequent. I think part of the problem is that game officials have been duped by the same false assumption as the players that more protection would make the game safer, and enforcement of the rules has not kept up with the technological changes.
There will always be injuries in any sport, but before we as physicians lend our support to a proposed change in protective equipment, we should step back and look at the broader picture. While the loss of an eye for an individual player is a tragedy, did we put several dozen more players at greater risk for spinal injury in college hockey with more protective gear? If adding headgear protects female lacrosse players from concussions, what might be the result if play becomes more physical? Protection can come with a price.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
It’s very likely that you have at least one or two female patients who play lacrosse. The sport has been reported to be the fastest-growing high school sport in the United States. (“Lacrosse is Actually America’s Fastest-Growing Sport,” by John Templon, BuzzFeed News, June 30, 2014). When I played in college, most of my teammates were products of prep schools in the Northeast or one of the few local hotbeds in Baltimore, Long Island, or the Finger Lakes Region of New York. But pickings were slim, and there was room for walk-ons like me looking to learn a new sport and stay in shape for football. Now hundreds of high schools in all parts of the country offer the sport for both boys and girls.
With growing awareness of the long-term effects of repeated head trauma, there has been a call from some parents and organizers of women’s lacrosse to require helmets on all players (“As Concussion Worries Rise, Girls’ Lacrosse Turns to Headgear,” by Bill Pennington, The New York Times, Nov 23, 2017). To those of us who have committed our professional lives to the health of children, the inclusion of helmets to the standard equipment for a female lacrosse player sounds like a good idea.
However, the proposed mandate has its critics, including several college coaches. Karen Corbett, women’s lacrosse coach at the University of Pennsylvania, has said that, players “will start to lead with their head because they feel protected, and that causes more injuries. We’ll become a more physical sport and a very different sport than we are today.”
Although I’m afraid that there are few data to support the validity of Dr. Hanley’s prediction, any observer of college hockey over the last 3 or 4 decades will tell you that he was unfortunately correct. There have been certainly fewer lacerations and eye injuries since face masks were introduced, but the game has become far more violent, and head, neck, and spine injuries have become more frequent. I think part of the problem is that game officials have been duped by the same false assumption as the players that more protection would make the game safer, and enforcement of the rules has not kept up with the technological changes.
There will always be injuries in any sport, but before we as physicians lend our support to a proposed change in protective equipment, we should step back and look at the broader picture. While the loss of an eye for an individual player is a tragedy, did we put several dozen more players at greater risk for spinal injury in college hockey with more protective gear? If adding headgear protects female lacrosse players from concussions, what might be the result if play becomes more physical? Protection can come with a price.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
It’s very likely that you have at least one or two female patients who play lacrosse. The sport has been reported to be the fastest-growing high school sport in the United States. (“Lacrosse is Actually America’s Fastest-Growing Sport,” by John Templon, BuzzFeed News, June 30, 2014). When I played in college, most of my teammates were products of prep schools in the Northeast or one of the few local hotbeds in Baltimore, Long Island, or the Finger Lakes Region of New York. But pickings were slim, and there was room for walk-ons like me looking to learn a new sport and stay in shape for football. Now hundreds of high schools in all parts of the country offer the sport for both boys and girls.
With growing awareness of the long-term effects of repeated head trauma, there has been a call from some parents and organizers of women’s lacrosse to require helmets on all players (“As Concussion Worries Rise, Girls’ Lacrosse Turns to Headgear,” by Bill Pennington, The New York Times, Nov 23, 2017). To those of us who have committed our professional lives to the health of children, the inclusion of helmets to the standard equipment for a female lacrosse player sounds like a good idea.
However, the proposed mandate has its critics, including several college coaches. Karen Corbett, women’s lacrosse coach at the University of Pennsylvania, has said that, players “will start to lead with their head because they feel protected, and that causes more injuries. We’ll become a more physical sport and a very different sport than we are today.”
Although I’m afraid that there are few data to support the validity of Dr. Hanley’s prediction, any observer of college hockey over the last 3 or 4 decades will tell you that he was unfortunately correct. There have been certainly fewer lacerations and eye injuries since face masks were introduced, but the game has become far more violent, and head, neck, and spine injuries have become more frequent. I think part of the problem is that game officials have been duped by the same false assumption as the players that more protection would make the game safer, and enforcement of the rules has not kept up with the technological changes.
There will always be injuries in any sport, but before we as physicians lend our support to a proposed change in protective equipment, we should step back and look at the broader picture. While the loss of an eye for an individual player is a tragedy, did we put several dozen more players at greater risk for spinal injury in college hockey with more protective gear? If adding headgear protects female lacrosse players from concussions, what might be the result if play becomes more physical? Protection can come with a price.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Early Hip Fracture Surgery Is Associated with Lower 30-Day Mortality
Study Overview
Objective. To determine the association between wait times for hip fracture surgery and outcomes after surgery and to identify the optimal time window for conducting hip fracture surgery.
Design. Observational cohort study.
Setting and participants. The study was conducted using population-based health administrative databases in Ontario, Canada. The databases collected information on health care services, physician and hospital information, and demographic characteristics in Ontario. The investigators used the databases to identify adults undergoing hip fracture surgery between April 2009 and March 2014. Excluded were adults who are non-Ontario residents, those with elective hospital admissions, those with prior hip fractures, and patients without hospital arrival time data. Other exclusion criteria include age younger than 45 years, those with delay in surgery longer than 10 days, surgery performed by a nonorthopedic surgeon, and those at hospitals with fewer than 5 hip fracture surgeries during the study period.
The primary independent variable was wait time for surgery, calculated from time from emergency department arrival until surgery and rounded in hours. Other covariates included in the analysis were patient characteristics including age, sex and comorbid conditions using the Deyo-Charlson comorbidity index, the Johns Hopkins Collapsed Aggregated Diagnosis Groups, and other validated algorithms. In addition, other conditions associated with hip fracture were included—osteomyelitis, bone cancer, other fractures, history of total hip arthroplasty, and multiple trauma. Additional covariates included median neighborhood household income quintile as a proxy for socioeconomic status, patient’s discharge disposition, and rural status. Characteristics of the procedure including procedure type, duration and timing (working vs. after hours) were assessed. Surgeon- and hospital-related factors included years since orthopedic certification as a proxy for surgeon experience and number of hip fracture procedures performed in the year preceding the event for surgeon and hospital. Other hospital characteristics included academic or community-based hospital, hospital size, and hospital’s capacity for performing nonelective surgery.
Main outcome measures. The main outcome measure was mortality within 30 days of being admitted for hip fracture surgery. Other secondary outcomes included mortality at 90 and 365 days after admission, medical complications within 30, 90, and 365 days, and a composite of mortality and any complications at these timeframes. Complications included myocardial infarction, deep vein thrombosis, pulmonary embolism and pneumonia. Statistical analysis include modeling for the probability of complications according to the time elapsed from emergency department arrival to surgery using risk adjusted spline analyses. The association between surgical wait time and mortality was graphically represented to visualize an inflection point when complications begin to rise. The area under the receiver operating characteristic curve was calculated at time thresholds around the area of inflection and the time producing the maximum area under the curve was selected as the threshold to classify patients
as receiving early or delayed surgery. Early and delayed patients were matched using propensity score with 1:1 matching without replacement. Outcomes were compared between early and delayed groups after matching and absolute risk differences were calculated using generalized estimating equations.
Main results. A total of 42,230 adults were included, with a mean age of 80.1 (SD 10.7) years; 70.5% were women. The average time from arrival to emergency room to surgery was 38.8 (SD 28.8) hours. The spline models identified an area of inflection at 24 hours when the risk of complications begins to rise. The investigators used 24 hours as a time point to classify patients into early or delayed surgery group. 33.6% of patients received early surgery and 66.4% had delayed surgery. Propensity score matching yielded a sample of 13,731 in each group. Patients with delayed surgery compared with early surgery had higher 30-day mortality (6.5% vs. 5.8%, absolute risk difference 0.79%), rate of pulmonary embolism (1.2% vs. 0.7%, absolute risk difference 0.51%), rate of myocardial infarction (1.2% vs. 0.8%, absolute risk difference 0.39%), and rate of pneumonia (4.6% vs. 3.7%, absolute risk difference 0.95%). For the composite outcome, 12.1% vs. 10.1% had mortality or complications in the delayed group and the early group respectively with an absolute difference of 2.16%. Outcomes at 90 days and 365 days were similar and remained significant. In subgroups of patients without comorbidity and those receiving surgery within 36 hours the results remained similar.
Conclusion. Early hip fracture surgery, defined as within 24 hours after arrival to emergency room, is associated with lower mortality and complications when compared to delayed surgery.
Commentary
Hip fracture affects predominantly older adults and leads to potential devastating consequences. Older adults who experience hip fracture have increased risk of functional decline, institutionalization, and death [1]. As hip fracture care often include surgical repair, many studies have examined the impact of timing of surgery on hip fracture outcomes, as the timing of surgery is a potentially modifiable factor that could impact patient outcomes [2]. Prior smaller cohort studies have demonstrated that delayed surgery may impact outcomes but the reasons for the delay, such as medical complexity, may also play a role in increasing the risk of adverse outcomes [3]. The current study adds to the previous literature by examining a large population-based cohort, thereby allowing for analysis that takes into account medical comorbidities using matching methods and sensitivity analyses that examined a sample without comorbidities. The study also employs a different approach to defining early vs. delayed surgery by using analytical methods to determine when risk of complications begins to rise. The results indicate that early surgery is associated with better outcomes at 30 days and beyond and that delaying surgery beyond 24 hours is associated with poorer patient outcomes.
Patients with hip fracture require care from multiple disciplines and care across multiple settings. These care components may also have an impact on patient outcomes, particularly outcomes at 90 and 365 days; some examples include anesthesia care during hip fracture surgery [4], pain control, early mobilization, and delirium prevention [1,5]. A limitation of utilizing administrative databases is that some of these potentially important factors that may affect outcome may not be included and thus cannot be controlled for. It is conceivable that early surgery may be associated with care characteristics that may also be favorable to outcomes. Another limitation is that it is still difficult to tease out the effect of medical complexity at the
time of hip fracture presentation, which may impact both timing of surgery and patient outcomes, despite sensitivity analyses that limit the sample to those who had surgery within 36 hours and also those without medical comorbidities according to the administrative data, and adjusting for antiplatelet or anticoagulant medications. It is also important to note that a randomized controlled trial may further elucidate the causal relationship between timing of surgery and patient outcomes. Despite the limitations of the study, the results make a strong case for limiting surgical wait time to within 24 hours from the time when the patient arrives in the emergency room.
Applications for Clinical Practice
Similar to how hospitals organize their care for patients with acute myocardial infarction for early reperfusion, and for patients with acute ischemic stroke with early thombolytic therapy, hip fracture care may need to be organized and coordinated in order to reduce surgical wait time to within 24 hours. Timely assessments by an orthopedic surgeon, anesthesiologist, and medical consultants to prepare patients for surgery and making available operating room and staff for hip fracture patients are necessary steps to reach the goal of reducing surgical wait time.
—William W. Hung, MD, MPH
1. Hung WW, Egol KA, Zuckerman JD, Siu AL. Hip fracture management: tailoring care for the older patient. JAMA 2012;307:2185–94.
2. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA 2004;291:1738–43.
3. Vidán MT, Sánchez E, Gracia Y, et al. Causes and effects of surgical delay in patients with hip fracture: a cohort study. Ann Intern Med 2011;155:226–33.
4. Neuman MD, Silber JH, Elkassabany NM, et al. Comparative effectiveness of regional versus general anesthesia for hip fracture surgery in adults. Anesthesiology 2012;117: 72–92.
5. Grigoryan KV, Javedan H, Rudolph JL. Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and meta-analysis. J Orthop Trauma 2014;28:e49–55.
Study Overview
Objective. To determine the association between wait times for hip fracture surgery and outcomes after surgery and to identify the optimal time window for conducting hip fracture surgery.
Design. Observational cohort study.
Setting and participants. The study was conducted using population-based health administrative databases in Ontario, Canada. The databases collected information on health care services, physician and hospital information, and demographic characteristics in Ontario. The investigators used the databases to identify adults undergoing hip fracture surgery between April 2009 and March 2014. Excluded were adults who are non-Ontario residents, those with elective hospital admissions, those with prior hip fractures, and patients without hospital arrival time data. Other exclusion criteria include age younger than 45 years, those with delay in surgery longer than 10 days, surgery performed by a nonorthopedic surgeon, and those at hospitals with fewer than 5 hip fracture surgeries during the study period.
The primary independent variable was wait time for surgery, calculated from time from emergency department arrival until surgery and rounded in hours. Other covariates included in the analysis were patient characteristics including age, sex and comorbid conditions using the Deyo-Charlson comorbidity index, the Johns Hopkins Collapsed Aggregated Diagnosis Groups, and other validated algorithms. In addition, other conditions associated with hip fracture were included—osteomyelitis, bone cancer, other fractures, history of total hip arthroplasty, and multiple trauma. Additional covariates included median neighborhood household income quintile as a proxy for socioeconomic status, patient’s discharge disposition, and rural status. Characteristics of the procedure including procedure type, duration and timing (working vs. after hours) were assessed. Surgeon- and hospital-related factors included years since orthopedic certification as a proxy for surgeon experience and number of hip fracture procedures performed in the year preceding the event for surgeon and hospital. Other hospital characteristics included academic or community-based hospital, hospital size, and hospital’s capacity for performing nonelective surgery.
Main outcome measures. The main outcome measure was mortality within 30 days of being admitted for hip fracture surgery. Other secondary outcomes included mortality at 90 and 365 days after admission, medical complications within 30, 90, and 365 days, and a composite of mortality and any complications at these timeframes. Complications included myocardial infarction, deep vein thrombosis, pulmonary embolism and pneumonia. Statistical analysis include modeling for the probability of complications according to the time elapsed from emergency department arrival to surgery using risk adjusted spline analyses. The association between surgical wait time and mortality was graphically represented to visualize an inflection point when complications begin to rise. The area under the receiver operating characteristic curve was calculated at time thresholds around the area of inflection and the time producing the maximum area under the curve was selected as the threshold to classify patients
as receiving early or delayed surgery. Early and delayed patients were matched using propensity score with 1:1 matching without replacement. Outcomes were compared between early and delayed groups after matching and absolute risk differences were calculated using generalized estimating equations.
Main results. A total of 42,230 adults were included, with a mean age of 80.1 (SD 10.7) years; 70.5% were women. The average time from arrival to emergency room to surgery was 38.8 (SD 28.8) hours. The spline models identified an area of inflection at 24 hours when the risk of complications begins to rise. The investigators used 24 hours as a time point to classify patients into early or delayed surgery group. 33.6% of patients received early surgery and 66.4% had delayed surgery. Propensity score matching yielded a sample of 13,731 in each group. Patients with delayed surgery compared with early surgery had higher 30-day mortality (6.5% vs. 5.8%, absolute risk difference 0.79%), rate of pulmonary embolism (1.2% vs. 0.7%, absolute risk difference 0.51%), rate of myocardial infarction (1.2% vs. 0.8%, absolute risk difference 0.39%), and rate of pneumonia (4.6% vs. 3.7%, absolute risk difference 0.95%). For the composite outcome, 12.1% vs. 10.1% had mortality or complications in the delayed group and the early group respectively with an absolute difference of 2.16%. Outcomes at 90 days and 365 days were similar and remained significant. In subgroups of patients without comorbidity and those receiving surgery within 36 hours the results remained similar.
Conclusion. Early hip fracture surgery, defined as within 24 hours after arrival to emergency room, is associated with lower mortality and complications when compared to delayed surgery.
Commentary
Hip fracture affects predominantly older adults and leads to potential devastating consequences. Older adults who experience hip fracture have increased risk of functional decline, institutionalization, and death [1]. As hip fracture care often include surgical repair, many studies have examined the impact of timing of surgery on hip fracture outcomes, as the timing of surgery is a potentially modifiable factor that could impact patient outcomes [2]. Prior smaller cohort studies have demonstrated that delayed surgery may impact outcomes but the reasons for the delay, such as medical complexity, may also play a role in increasing the risk of adverse outcomes [3]. The current study adds to the previous literature by examining a large population-based cohort, thereby allowing for analysis that takes into account medical comorbidities using matching methods and sensitivity analyses that examined a sample without comorbidities. The study also employs a different approach to defining early vs. delayed surgery by using analytical methods to determine when risk of complications begins to rise. The results indicate that early surgery is associated with better outcomes at 30 days and beyond and that delaying surgery beyond 24 hours is associated with poorer patient outcomes.
Patients with hip fracture require care from multiple disciplines and care across multiple settings. These care components may also have an impact on patient outcomes, particularly outcomes at 90 and 365 days; some examples include anesthesia care during hip fracture surgery [4], pain control, early mobilization, and delirium prevention [1,5]. A limitation of utilizing administrative databases is that some of these potentially important factors that may affect outcome may not be included and thus cannot be controlled for. It is conceivable that early surgery may be associated with care characteristics that may also be favorable to outcomes. Another limitation is that it is still difficult to tease out the effect of medical complexity at the
time of hip fracture presentation, which may impact both timing of surgery and patient outcomes, despite sensitivity analyses that limit the sample to those who had surgery within 36 hours and also those without medical comorbidities according to the administrative data, and adjusting for antiplatelet or anticoagulant medications. It is also important to note that a randomized controlled trial may further elucidate the causal relationship between timing of surgery and patient outcomes. Despite the limitations of the study, the results make a strong case for limiting surgical wait time to within 24 hours from the time when the patient arrives in the emergency room.
Applications for Clinical Practice
Similar to how hospitals organize their care for patients with acute myocardial infarction for early reperfusion, and for patients with acute ischemic stroke with early thombolytic therapy, hip fracture care may need to be organized and coordinated in order to reduce surgical wait time to within 24 hours. Timely assessments by an orthopedic surgeon, anesthesiologist, and medical consultants to prepare patients for surgery and making available operating room and staff for hip fracture patients are necessary steps to reach the goal of reducing surgical wait time.
—William W. Hung, MD, MPH
Study Overview
Objective. To determine the association between wait times for hip fracture surgery and outcomes after surgery and to identify the optimal time window for conducting hip fracture surgery.
Design. Observational cohort study.
Setting and participants. The study was conducted using population-based health administrative databases in Ontario, Canada. The databases collected information on health care services, physician and hospital information, and demographic characteristics in Ontario. The investigators used the databases to identify adults undergoing hip fracture surgery between April 2009 and March 2014. Excluded were adults who are non-Ontario residents, those with elective hospital admissions, those with prior hip fractures, and patients without hospital arrival time data. Other exclusion criteria include age younger than 45 years, those with delay in surgery longer than 10 days, surgery performed by a nonorthopedic surgeon, and those at hospitals with fewer than 5 hip fracture surgeries during the study period.
The primary independent variable was wait time for surgery, calculated from time from emergency department arrival until surgery and rounded in hours. Other covariates included in the analysis were patient characteristics including age, sex and comorbid conditions using the Deyo-Charlson comorbidity index, the Johns Hopkins Collapsed Aggregated Diagnosis Groups, and other validated algorithms. In addition, other conditions associated with hip fracture were included—osteomyelitis, bone cancer, other fractures, history of total hip arthroplasty, and multiple trauma. Additional covariates included median neighborhood household income quintile as a proxy for socioeconomic status, patient’s discharge disposition, and rural status. Characteristics of the procedure including procedure type, duration and timing (working vs. after hours) were assessed. Surgeon- and hospital-related factors included years since orthopedic certification as a proxy for surgeon experience and number of hip fracture procedures performed in the year preceding the event for surgeon and hospital. Other hospital characteristics included academic or community-based hospital, hospital size, and hospital’s capacity for performing nonelective surgery.
Main outcome measures. The main outcome measure was mortality within 30 days of being admitted for hip fracture surgery. Other secondary outcomes included mortality at 90 and 365 days after admission, medical complications within 30, 90, and 365 days, and a composite of mortality and any complications at these timeframes. Complications included myocardial infarction, deep vein thrombosis, pulmonary embolism and pneumonia. Statistical analysis include modeling for the probability of complications according to the time elapsed from emergency department arrival to surgery using risk adjusted spline analyses. The association between surgical wait time and mortality was graphically represented to visualize an inflection point when complications begin to rise. The area under the receiver operating characteristic curve was calculated at time thresholds around the area of inflection and the time producing the maximum area under the curve was selected as the threshold to classify patients
as receiving early or delayed surgery. Early and delayed patients were matched using propensity score with 1:1 matching without replacement. Outcomes were compared between early and delayed groups after matching and absolute risk differences were calculated using generalized estimating equations.
Main results. A total of 42,230 adults were included, with a mean age of 80.1 (SD 10.7) years; 70.5% were women. The average time from arrival to emergency room to surgery was 38.8 (SD 28.8) hours. The spline models identified an area of inflection at 24 hours when the risk of complications begins to rise. The investigators used 24 hours as a time point to classify patients into early or delayed surgery group. 33.6% of patients received early surgery and 66.4% had delayed surgery. Propensity score matching yielded a sample of 13,731 in each group. Patients with delayed surgery compared with early surgery had higher 30-day mortality (6.5% vs. 5.8%, absolute risk difference 0.79%), rate of pulmonary embolism (1.2% vs. 0.7%, absolute risk difference 0.51%), rate of myocardial infarction (1.2% vs. 0.8%, absolute risk difference 0.39%), and rate of pneumonia (4.6% vs. 3.7%, absolute risk difference 0.95%). For the composite outcome, 12.1% vs. 10.1% had mortality or complications in the delayed group and the early group respectively with an absolute difference of 2.16%. Outcomes at 90 days and 365 days were similar and remained significant. In subgroups of patients without comorbidity and those receiving surgery within 36 hours the results remained similar.
Conclusion. Early hip fracture surgery, defined as within 24 hours after arrival to emergency room, is associated with lower mortality and complications when compared to delayed surgery.
Commentary
Hip fracture affects predominantly older adults and leads to potential devastating consequences. Older adults who experience hip fracture have increased risk of functional decline, institutionalization, and death [1]. As hip fracture care often include surgical repair, many studies have examined the impact of timing of surgery on hip fracture outcomes, as the timing of surgery is a potentially modifiable factor that could impact patient outcomes [2]. Prior smaller cohort studies have demonstrated that delayed surgery may impact outcomes but the reasons for the delay, such as medical complexity, may also play a role in increasing the risk of adverse outcomes [3]. The current study adds to the previous literature by examining a large population-based cohort, thereby allowing for analysis that takes into account medical comorbidities using matching methods and sensitivity analyses that examined a sample without comorbidities. The study also employs a different approach to defining early vs. delayed surgery by using analytical methods to determine when risk of complications begins to rise. The results indicate that early surgery is associated with better outcomes at 30 days and beyond and that delaying surgery beyond 24 hours is associated with poorer patient outcomes.
Patients with hip fracture require care from multiple disciplines and care across multiple settings. These care components may also have an impact on patient outcomes, particularly outcomes at 90 and 365 days; some examples include anesthesia care during hip fracture surgery [4], pain control, early mobilization, and delirium prevention [1,5]. A limitation of utilizing administrative databases is that some of these potentially important factors that may affect outcome may not be included and thus cannot be controlled for. It is conceivable that early surgery may be associated with care characteristics that may also be favorable to outcomes. Another limitation is that it is still difficult to tease out the effect of medical complexity at the
time of hip fracture presentation, which may impact both timing of surgery and patient outcomes, despite sensitivity analyses that limit the sample to those who had surgery within 36 hours and also those without medical comorbidities according to the administrative data, and adjusting for antiplatelet or anticoagulant medications. It is also important to note that a randomized controlled trial may further elucidate the causal relationship between timing of surgery and patient outcomes. Despite the limitations of the study, the results make a strong case for limiting surgical wait time to within 24 hours from the time when the patient arrives in the emergency room.
Applications for Clinical Practice
Similar to how hospitals organize their care for patients with acute myocardial infarction for early reperfusion, and for patients with acute ischemic stroke with early thombolytic therapy, hip fracture care may need to be organized and coordinated in order to reduce surgical wait time to within 24 hours. Timely assessments by an orthopedic surgeon, anesthesiologist, and medical consultants to prepare patients for surgery and making available operating room and staff for hip fracture patients are necessary steps to reach the goal of reducing surgical wait time.
—William W. Hung, MD, MPH
1. Hung WW, Egol KA, Zuckerman JD, Siu AL. Hip fracture management: tailoring care for the older patient. JAMA 2012;307:2185–94.
2. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA 2004;291:1738–43.
3. Vidán MT, Sánchez E, Gracia Y, et al. Causes and effects of surgical delay in patients with hip fracture: a cohort study. Ann Intern Med 2011;155:226–33.
4. Neuman MD, Silber JH, Elkassabany NM, et al. Comparative effectiveness of regional versus general anesthesia for hip fracture surgery in adults. Anesthesiology 2012;117: 72–92.
5. Grigoryan KV, Javedan H, Rudolph JL. Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and meta-analysis. J Orthop Trauma 2014;28:e49–55.
1. Hung WW, Egol KA, Zuckerman JD, Siu AL. Hip fracture management: tailoring care for the older patient. JAMA 2012;307:2185–94.
2. Orosz GM, Magaziner J, Hannan EL, et al. Association of timing of surgery for hip fracture and patient outcomes. JAMA 2004;291:1738–43.
3. Vidán MT, Sánchez E, Gracia Y, et al. Causes and effects of surgical delay in patients with hip fracture: a cohort study. Ann Intern Med 2011;155:226–33.
4. Neuman MD, Silber JH, Elkassabany NM, et al. Comparative effectiveness of regional versus general anesthesia for hip fracture surgery in adults. Anesthesiology 2012;117: 72–92.
5. Grigoryan KV, Javedan H, Rudolph JL. Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and meta-analysis. J Orthop Trauma 2014;28:e49–55.
Low caffeine in blood could be marker of early Parkinson’s
Low serum caffeine and caffeine metabolite levels after an overnight fast may be a sensitive way to detect the presence of Parkinson’s disease, according to the results of a new case-control study.
Levels of caffeine and its metabolites were also lower in Parkinson’s disease (PD) patients who had motor dysfunction, compared with those without motor dysfunction, but no differences in serum levels of caffeine metabolites could be detected between patients with mild to more severe stages of PD, reported Motoki Fujimaki, MD, of Juntendo University, Tokyo, and colleagues. The report was published online Jan. 3 in Neurology.
To test that idea, Dr. Fujimaki and associates recruited 31 healthy controls (18 women) and 108 patients with PD but no dementia (50 women). The control group’s mean caffeine intake of 115.81 mg/day (standard deviation, 69.22) was similar to PD patients’ intake of 107.50 mg/day (SD, 67.27).
Serum caffeine levels measured after an overnight fast showed that a cutoff of 33.04 pmol/10 mcL identified PD with an area under the curve (AUC) of 0.78 (sensitivity 76.9%, specificity 74.2%). Inclusion of the primary caffeine metabolites theophylline, theobromine, and paraxanthine improved the AUC to 0.87. When the researchers included all 11 measurable metabolites, the AUC jumped to 0.98.
Genetic analyses found no significant differences in the frequencies of caffeine metabolism–associated genetic variants between PD patients and controls.
The study was limited by the fact that it was conducted at a single university hospital, and the patient population did not include many severe cases. The algorithm should also be studied in other PD patient populations.
The study was funded by grants from several Japanese government agencies. Some of the authors have financial relationships with the pharmaceutical industry.
SOURCE: Fujimaki M et al. Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004888
A key question is what is causing the decrease in serum concentration found in patients with Parkinson’s disease? Nearly all of the patients were receiving treatment, which could have affected serum levels.
The researchers addressed this by looking for an association between serum caffeine metabolite levels and levodopa equivalent doses, and they found none.
Still, the validity of the study depends on whether caffeine metabolism may be affected by treatment. To demonstrate the utility of caffeine metabolites unequivocally, a future study will have to reproduce these results in patients with untreated PD or subjects at high risk of PD, such as those with prodromal signs of PD.
David G. Munoz, MD, is in the department of laboratory medicine and pathobiology at the University of Toronto. Shinsuke Fujioka, MD is in the department of neurology at Fukuoka (Japan) University. Dr. Munoz and Dr. Fujioka reported having no financial disclosures. Their comments are derived from an editorial accompanying the study by Dr. Fujimaki and colleagues (Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004898).
A key question is what is causing the decrease in serum concentration found in patients with Parkinson’s disease? Nearly all of the patients were receiving treatment, which could have affected serum levels.
The researchers addressed this by looking for an association between serum caffeine metabolite levels and levodopa equivalent doses, and they found none.
Still, the validity of the study depends on whether caffeine metabolism may be affected by treatment. To demonstrate the utility of caffeine metabolites unequivocally, a future study will have to reproduce these results in patients with untreated PD or subjects at high risk of PD, such as those with prodromal signs of PD.
David G. Munoz, MD, is in the department of laboratory medicine and pathobiology at the University of Toronto. Shinsuke Fujioka, MD is in the department of neurology at Fukuoka (Japan) University. Dr. Munoz and Dr. Fujioka reported having no financial disclosures. Their comments are derived from an editorial accompanying the study by Dr. Fujimaki and colleagues (Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004898).
A key question is what is causing the decrease in serum concentration found in patients with Parkinson’s disease? Nearly all of the patients were receiving treatment, which could have affected serum levels.
The researchers addressed this by looking for an association between serum caffeine metabolite levels and levodopa equivalent doses, and they found none.
Still, the validity of the study depends on whether caffeine metabolism may be affected by treatment. To demonstrate the utility of caffeine metabolites unequivocally, a future study will have to reproduce these results in patients with untreated PD or subjects at high risk of PD, such as those with prodromal signs of PD.
David G. Munoz, MD, is in the department of laboratory medicine and pathobiology at the University of Toronto. Shinsuke Fujioka, MD is in the department of neurology at Fukuoka (Japan) University. Dr. Munoz and Dr. Fujioka reported having no financial disclosures. Their comments are derived from an editorial accompanying the study by Dr. Fujimaki and colleagues (Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004898).
Low serum caffeine and caffeine metabolite levels after an overnight fast may be a sensitive way to detect the presence of Parkinson’s disease, according to the results of a new case-control study.
Levels of caffeine and its metabolites were also lower in Parkinson’s disease (PD) patients who had motor dysfunction, compared with those without motor dysfunction, but no differences in serum levels of caffeine metabolites could be detected between patients with mild to more severe stages of PD, reported Motoki Fujimaki, MD, of Juntendo University, Tokyo, and colleagues. The report was published online Jan. 3 in Neurology.
To test that idea, Dr. Fujimaki and associates recruited 31 healthy controls (18 women) and 108 patients with PD but no dementia (50 women). The control group’s mean caffeine intake of 115.81 mg/day (standard deviation, 69.22) was similar to PD patients’ intake of 107.50 mg/day (SD, 67.27).
Serum caffeine levels measured after an overnight fast showed that a cutoff of 33.04 pmol/10 mcL identified PD with an area under the curve (AUC) of 0.78 (sensitivity 76.9%, specificity 74.2%). Inclusion of the primary caffeine metabolites theophylline, theobromine, and paraxanthine improved the AUC to 0.87. When the researchers included all 11 measurable metabolites, the AUC jumped to 0.98.
Genetic analyses found no significant differences in the frequencies of caffeine metabolism–associated genetic variants between PD patients and controls.
The study was limited by the fact that it was conducted at a single university hospital, and the patient population did not include many severe cases. The algorithm should also be studied in other PD patient populations.
The study was funded by grants from several Japanese government agencies. Some of the authors have financial relationships with the pharmaceutical industry.
SOURCE: Fujimaki M et al. Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004888
Low serum caffeine and caffeine metabolite levels after an overnight fast may be a sensitive way to detect the presence of Parkinson’s disease, according to the results of a new case-control study.
Levels of caffeine and its metabolites were also lower in Parkinson’s disease (PD) patients who had motor dysfunction, compared with those without motor dysfunction, but no differences in serum levels of caffeine metabolites could be detected between patients with mild to more severe stages of PD, reported Motoki Fujimaki, MD, of Juntendo University, Tokyo, and colleagues. The report was published online Jan. 3 in Neurology.
To test that idea, Dr. Fujimaki and associates recruited 31 healthy controls (18 women) and 108 patients with PD but no dementia (50 women). The control group’s mean caffeine intake of 115.81 mg/day (standard deviation, 69.22) was similar to PD patients’ intake of 107.50 mg/day (SD, 67.27).
Serum caffeine levels measured after an overnight fast showed that a cutoff of 33.04 pmol/10 mcL identified PD with an area under the curve (AUC) of 0.78 (sensitivity 76.9%, specificity 74.2%). Inclusion of the primary caffeine metabolites theophylline, theobromine, and paraxanthine improved the AUC to 0.87. When the researchers included all 11 measurable metabolites, the AUC jumped to 0.98.
Genetic analyses found no significant differences in the frequencies of caffeine metabolism–associated genetic variants between PD patients and controls.
The study was limited by the fact that it was conducted at a single university hospital, and the patient population did not include many severe cases. The algorithm should also be studied in other PD patient populations.
The study was funded by grants from several Japanese government agencies. Some of the authors have financial relationships with the pharmaceutical industry.
SOURCE: Fujimaki M et al. Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004888
FROM NEUROLOGY
Key clinical point:
Major finding: Combining serum levels of caffeine and nine related metabolites identified individuals with PD with an AUC of 0.98.
Data source: Analysis of 108 Parkinson’s patients and 31 healthy controls.
Disclosures: The study was funded by grants from several Japanese government agencies. Some of the authors have financial relationships with the pharmaceutical industry.
Source: Fujimaki M et al., Neurology. 2018 Jan 3. doi: 10.1212/WNL.0000000000004888
Improving Strength and Balance for Long-Term Care Residents At Risk for Falling: Suggestions for Practice
From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada
Abstract
- Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
- Methods: Review of positive trials included in systematic reviews.
- Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
- Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.
Key words: long-term care; nursing homes; falls reduction; exercise.
Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.
Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.
Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).
A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].
Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.
Methods
To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.
We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].
Results
We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].
A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search. 
Type of Exercise
Balance Exercises
There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.
Strength Exercises
Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure) 
Frequency, Time of Sessions, Duration of Program
In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).
Intensity
For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].
Delivery of Intervention
Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].
Discussion
There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.
Balance Training
Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.
Strength Training
Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].
Implementing Exercise Programs in LTC
Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.
Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.
Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.
Modifications for Physical Impairments
Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].
Modifications for Cognitive Impairments
More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].
Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48]. 
Standing versus Seated Exercises
Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.
Resident-Centered Exercise for Falls Prevention
Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.
There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.
Multifactorial Falls Prevention Programs
While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].
Conclusion and Suggestions for Clinical Practice
We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.
Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.
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From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada
Abstract
- Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
- Methods: Review of positive trials included in systematic reviews.
- Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
- Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.
Key words: long-term care; nursing homes; falls reduction; exercise.
Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.
Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.
Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).
A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].
Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.
Methods
To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.
We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].
Results
We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].
A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.
Type of Exercise
Balance Exercises
There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.
Strength Exercises
Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure)
Frequency, Time of Sessions, Duration of Program
In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).
Intensity
For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].
Delivery of Intervention
Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].
Discussion
There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.
Balance Training
Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.
Strength Training
Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].
Implementing Exercise Programs in LTC
Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.
Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.
Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.
Modifications for Physical Impairments
Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].
Modifications for Cognitive Impairments
More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].
Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].
Standing versus Seated Exercises
Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.
Resident-Centered Exercise for Falls Prevention
Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.
There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.
Multifactorial Falls Prevention Programs
While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].
Conclusion and Suggestions for Clinical Practice
We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.
Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.
From the Geriatric Education and Research in Aging Sciences Centre, McMaster University Hamilton, ON (Dr. McArthur) and the University of Waterloo and Research Institute for Aging, Waterloo, ON (Dr. Giangregorio), Canada
Abstract
- Objective: To synthesize the available literature on exercise and falls reduction interventions in long-term care (LTC) and provide practical information for clinicians and other decision makers.
- Methods: Review of positive trials included in systematic reviews.
- Results: Falls are a major concern for residents, families, clinicians, and decision-makers in LTC. Exercise is recommended as part of a multifactorial falls prevention program for residents in LTC. Strength and balance exercises should be incorporated into the multifactorial falls prevention program. They should be challenging and progressed as the residents’ abilities improve. Evidence suggests that exercises should be completed 2 to 3 times per week for a period longer than 6 months. Exercise programs in LTC should be resident-centered and should consider residents’ potential physical and cognitive impairments. Exercises in standing should be prioritized where appropriate.
- Conclusion: Appropriately challenging and progressive strength and balance exercises should be included in a multifactorial falls prevention program for residents in LTC.
Key words: long-term care; nursing homes; falls reduction; exercise.
Falls are common in long-term care (LTC) homes: the estimated falls rate is 1.5 falls per bed per year, which is 3 times greater than that for older adults living in the community [1]. Falls can have significant consequences for residents in LTC, including functional disability, fractures, pain, reduced quality of life, and death [1–6]. Indeed, 25% of residents who are hospitalized after a fall die within 1 year [3]. Consequently, falls prevention programs are important to help in reducing falls and averting the associated negative consequences.
Exercise may address the circumstances and physical deconditioning that often contribute to falls in LTC residents. Weight shifting [7], walking, and transferring [8–10], are common activities that precede falls, suggesting that balance, gait, and functional mobility training may be possible targets for prevention. Additionally, it is estimated that LTC residents spend three quarters of their waking time in sedentary activities [11,12] and have a high prevalence of sarcopenia [13–16]. Challenging balance training and resistance exercise are well-known intervention for reducing falls [17] and improving muscle strength for community-dwelling older adults [18]. However, evidence around balance and strength training for preventing falls in LTC is mixed [17,19,20], and careful planning and modification of exercises is necessary to meet the needs of LTC residents.
Residents in LTC are often medically complex, with multiple comorbidities [21] that can affect their ability to meaningfully participate in exercise. In Canada, 56.3% of residents have a diagnosis of Alzheimer’s or other dementias, 25.0% have diabetes, 14.4% have chronic obstructive pulmonary disease, and 21.2% have experienced a stroke [21]. Residents also often have significant functional impairments. For example, 97% of residents require assistance with basic activities of daily living [21]. Therefore, the lack of effect of exercise as a single falls prevention strategy observed in previous studies may be because the often complex, multimorbid LTC population likely requires a multifactorial approach to fall prevention [17]. Additionally, organizational aspects of LTC homes (eg, specific funds dedicated to employing exercise professionals and to support exercise programming) can affect residents’ engagement in exercise [22,23]. Subsequently, prescribing exercises in the LTC context must consider both resident characteristics and organizational features of the LTC home (eg, professionals available to support exercise programming).
A comprehensive exercise prescription describes the elements of an appropriate exercise program to facilitate implementation of that program. The exercise prescription should include a description of the type (eg, balance, strength) and intensity of exercises (eg, subjective or objective measurement of how hard the resident is working) included in the program [24]. The prescription should also include a description of the dose of exercise: frequency of exercise participation (eg, 2 days per week), duration of individual exercise sessions (eg, 30-minute sessions), and duration of exercise program (eg, 12-week program) [24]. Lastly, the prescription should describe the setting of the exercise program (eg, group or individual basis) and the professional delivering the program (eg, physiotherapist, fitness instructor) [24].
Therefore, the objectives of this article are to (1) synthesize studies demonstrating a positive effect of exercise on reducing falls for residents in LTC; (2) provide an overview of the principles of balance and strength training to guide clinicians in designing appropriate exercise prescription; and (3) make suggestions for clinical practice regarding an appropriate strength and balance exercise protocol by considering the influence of the LTC context.
Methods
To provide clinicians and other policy-makers with a description of which balance and strength exercises may be effective for preventing falls, we synthesized trials that demonstrated a positive effect on reducing falls or falls risk for residents in LTC. Studies were identified through a database search for systematic reviews in PubMed, Ovid, and Google Scholar using the keywords falls, long-term care, nursing homes, exercise, strength, balance, and systematic reviews. Our purpose was to provide practical information on what works to prevent falls through balance and strength training for residents in LTC rather than to evaluate the available evidence. Therefore, only positive trials from systematic reviews were discussed, as we wanted to present exercises that seem to have a positive effect on decreasing falls. Positive trials were defined as those included in identified systematic reviews with a risk or rate ratio and confidence intervals below 1.0.
We first provide an overview of the conclusions of the systematic reviews found in our search. Next, for each positive trial we describe the following elements of the exercise component of the intervention: frequency, time of sessions, length of program, intensity, type of exercise including a description of the specific exercises performed, whether the intervention was delivered in a group or on an individual basis, the professional delivering the intervention, and any other features of the intervention aside from the exercise component. We used the ProFaNE taxonomy definitions [25] to identify and describe each element of the exercise interventions. Frequency is the number of times per week that residents engage in sessions, time of sessions is the amount allocated to each exercise session, duration of program is how long the resident participates in the exercise program, and intensity is the subjective or objective report of how hard the resident is working [25]. The types of exercises described were those targeting balance defined as “...the efficient transfer of bodyweight from one part of the body to another or challenges specific aspects of the balance systems (eg, vestibular system)” [25], and strength defined as “...contracting the muscles against a resistance to ‘overload’ and bring about a training effect in the muscular system” [25]. Strength could be either an external resistance (eg, dumbbell) or using body weight against gravity (eg, squat) [25].
Results
We found 3 systematic reviews that include exercise programs to reduce falls in LTC homes [17,19,20]. Overall, evidence suggests that exercise should be included as part of a multifactorial falls prevention program for residents in LTC. There is limited evidence that exercise as a single intervention prevents falls, and some trials, albeit underpowered, even demonstrate an increased risk of falling in the exercise group compared to control [19]. With regards to specific exercise programs, the Cochrane review found that gait, balance, and functional training decrease the rate of falls but not the risk of falling [26–28], and the 2013 review by Silva et al [20] concluded that combined exercise programs (ie, multiple types of exercise) that include balance tasks, are completed frequently (2–3 times per week), and over a long term (greater than 6 months) were most effective at preventing falls [20].
A more recent systematic review and meta-analysis [17] also concluded that there was no evidence that exercise as a single intervention can prevent falls for residents in LTC. Table 1 provides a description of the exercise component of the seven positive trials [29–35] that were included in the 3 systematic reviews we identified in our search.
Type of Exercise
Balance Exercises
There were 4 positive trials that included balance exercises in their intervention [31,33–35]. Trials that had a positive effect on reducing falls and included balance training employed mostly dynamic balance exercises in standing (Table 1). However, only 2 of the 7 trials provided a detailed description of their balance exercises (Table 1) [26,34]. Jensen et al [30] and Dyer et al [31] did not include a description of the balance training performed but stated that balance was part of the multicomponent exercise program. Becker et al [36] stated that participants performed standing balance exercises, while Schnelle et al [39] and Huang et al [32] did not include balance training in their trial.
Strength Exercises
Of the 7 positive trials included in this review, 6 included strength exercises [29–32,34,35]. The strength activities used in trials where exercise had a positive effect on decreasing falls included functional activities [29,31] and progressive resistance training [31,36] (Table 1). Functional activities are those that replicate what a resident might be required to do in their everyday life, such as performing sit-to-stands out of a chair (Figure)
Frequency, Time of Sessions, Duration of Program
In our description of positive trials, exercise was performed on 2 to 3 days per week for 20 to 75 minutes per session, for periods ranging from 4 to 52 weeks (Table 1).
Intensity
For the trials including balance exercises, one trial described the intensity as resident-specific [37] and another as individualized [33]. Two studies did not describe the intensity of their balance exercises [31,34]. The intensity of strength exercises included in the positive trials was individualized for one of the trial [29]. Two trials had participants complete 2 to 3 sets of 10 repetitions [32,35], with one indicating an intensity of 12–13 or “somewhat difficult” on the Borg Rating of Perceived Exertion Scale [32] and the other using a 10-rep max [35]. Two studies described their strength exercises as progressive [31,37], and one at a moderate to high intensity [30]. Lord et al prescribed 30 repetitions of each strength exercise [34].
Delivery of Intervention
Exercise was delivered in a group setting for 4 of the trials [31,32,34,36], individually for 2 of the trials [26,29], and the setting was not described for one of the trials (Table 1) [30]. Finally, only 3 of the 7 articles reported the professional delivering the intervention: one was research staff [29], one was geriatric nurses [32], and one was exercise assistants supported by a physiotherapist [31].
Discussion
There is limited evidence to support the use of strength and balance exercise as a single intervention to prevent falls in LTC. However, exercise should be included as part of a multifactorial falls prevention program. Trials that had a positive effect on decreasing falls training used dynamic balance exercises in standing, functional training, and progressive resistance training on 2 to 3 days per week, for 20 to 75 minutes per session, over 4 to 52 weeks. The intensity of balance exercises was individualized, and strength exercises were described as somewhat difficult or performed at a moderate to high intensity. Exercise was performed in a group or individually, and was delivered by research staff, geriatric nurses, exercise assistants supervised by physiotherapists, or more frequently, it was not reported who delivered the intervention.
Balance Training
Our work suggests that standing, dynamic balance exercises may be best to decrease falls. Example balance exercises include reducing the base of support (eg, standing with feet together instead of apart, or tandem with one foot in front), moving the center of gravity and control body position while standing (eg, reaching, weight shifting, stepping up or down), and standing without using arms for support or reducing reliance on the upper limbs for support (eg, use one hand on a handrail instead of two, or two fingers instead of the whole hand) [17]. It is well established that balance training programs, especially those including challenging exercises, can prevent falls in community-dwelling older adults [17]. However, the relationship is not as clear in LTC.
Strength Training
Reduced muscle strength has been identified as an important risk factor for falls [38]. There are also many psychological and metabolic benefits to strength training [39]. To induce change in muscular strength, resistance exercises need to be challenging and progressive. Our work suggests that strength training that is effective at decreasing falls is functional and progressive, and is completed at a moderate to high intensity. A resident should be able to do a strength exercise for one to two sets of 6 to 8 repetitions before being fatigued [40]. Once the resident can complete two sets of 13 to 15 repetitions easily the exercise should be progressed. Residents who are particularly deconditioned may need to begin with lower intensity strength exercises (eg, only do one set, with a lower resistance and progress to a higher resistance) [40]. Residents should perform resistance exercises for all major muscle groups [40]. Progression could include increasing the number of sets (eg, increase from one to two sets), the resistance (eg, holding dumbbells while squatting), or the intensity of the exercise (eg, squat lower or faster) [41].
Implementing Exercise Programs in LTC
Implementation of exercise programs into LTC homes should consider the dose of exercise (eg, time and frequency of sessions, duration of program), if they are delivered in a group or individual setting, and who is delivering them. First, trials included in this paper suggest that strength and balance exercises to prevent falls were delivered 2 to 3 times per week, for 20 to 75 minutes per session, over 4 to 52 weeks. Second, previous work has established that exercise programs delivered on 2 to 3 days per week over a period of more than 6 months are most effective at reducing falls in LTC [20]. Finally, a recent task force report from an international group of clinician researchers in LTC recommends twice weekly exercise sessions lasting 35 to 45 minutes each [40]. Therefore, strength and balance exercises to prevent falls in LTC should be delivered at least twice per week, for at least 20 minutes, for greater than 6 weeks’ duration.
Whether exercise should be performed in a group or individual setting remains unclear. Two of the 6 positive trials in this paper were completed individually, while 3 were in a group. The aforementioned task force also recommended that every resident who does not have contraindications to exercise must have an individualized exercise program as part of their health care plan [40]. However, whether the exercise program is provided on an individual basis or in a group setting was not delineated. Indeed, there are currently no recommendations concerning prioritizing group or individual exercise programs. Therefore, exercise programs being implemented into LTC homes should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings.
Finally, which professionals should deliver the exercise program is also uncertain. Only 3 of the positive trials in this paper described the professional delivering the intervention, with one being research staff, one geriatric nurses, and one exercise assistants supported by a physiotherapist. We suggest that professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC.
Modifications for Physical Impairments
Residents in LTC often have complex health needs, with multiple comorbidities (eg, stroke, Parkinson’s disease, multiple sclerosis) [21]. Modifications of strength and balance exercises may be required to accommodate for physical impairments (eg, hemiplegia, drop foot, freezing gait). For example, if a resident has hemiplegia and cannot fully activate the muscles of one arm, one can do resistance exercises with a dumbbell on the functioning side and active assisted range of motion (ie, the exercise provider assists the resident to achieve full range of motion against gravity) on the hemiparetic side. A resident with Parkinson’s disease who has freezing gait may need visual or rhythmical verbal cues to be able to accomplish standing balance tasks such as altered walking patterns (eg, wide or narrow stepping) [42].
Modifications for Cognitive Impairments
More than 80% of residents in LTC have some degree of cognitive impairment [21]. Cognitive impairment may be the result of stroke, depression, traumatic injuries, medications, and degenerative diseases such as Parkinson’s and Alzheimer’s disease [43]. A common misconception is that residents with cognitive impairment cannot benefit from exercise because they cannot learn new skills and have difficulty following directions. On the contrary, evidence suggests that exercise can improve functional mobility for residents with cognitive impairment [44,45].
Residents with cognitive impairment may require a different approach to facilitate participation in the desired exercises because of difficulty following multi-step directions, responsive behaviors, or increased distractibility [46]. Clear communication is key in improving the quality of interaction for residents with cognitive impairment. The Alzheimer Society of Ontario suggests 10 strategies for communicating with people with dementia [47], and we have provided suggestions of how to apply these communication strategies to the exercise context in LTC (Table 2). Other suggestions for engaging residents with cognitive impairment in strength and balance training include making the exercises functional (eg, ask them to pick something up of the floor to perform a squat, or reach a point on the wall to do calf raises) and playful (eg, toss a ball back and forth or sing a song about rowing to promote weight shifting) [48].
Standing versus Seated Exercises
Residents may not be able to participate in standing exercises for several reasons: perhaps the resident cannot stand or has severe balance impairments and a high falls risk; the resident may have poor insight into which exercises are safe to perform in standing versus sitting; or there may be limited supervision of a large group exercise class where the risk of falls is a concern. If balance impairments are a concern, where the risk of injury or falling while completing exercises in standing outweighs the benefit of doing the exercises, then seated exercises are appropriate. However, when residents are able, we recommend encouraging some or all exercises in standing, to facilitate carry over of strength gains into functional tasks such as being able to rise from a chair and walking. A recent study, comparing standing versus seated exercises for community dwelling older adults, saw greater functional gains for those who completed the standing exercises [49]. Therefore, strength and balance exercises should be performed in standing, where appropriate.
Resident-Centered Exercise for Falls Prevention
Putting the resident at the center of falls prevention is important. Previous work has found that older adults have expressed a strong preference for care that transcends traditional biomedical care and that values efficiency, consistency, and hierarchical decision making [50]. On the contrary, resident-centered care emphasizes well-being and quality of life as defined by the resident, values giving residents greater control over the nature of services they receive, and respects their rights to be involved in every day decision making [51,52]. Indeed, residents may choose to engage in risky behaviors that increase their risk of falls but also increases their quality of life. Previous work has found disconnects between residents’ perceived frailty and the potential ability of protective devices to prevent adverse events, such as falls and fractures [53]. Additionally, one study identified that older residents feared being labelled, so instead hid impairments and chose to refuse assistance and assistive devices [54]. For example, a resident with impaired balance and gait may choose to walk independently when they have been deemed as requiring a gait aid (eg, rollator walker). However, they may value walking without a gait aid and accept the increased risk of falling. Therefore, it is essential to find the delicate balance between respecting a resident’s right to make their own decisions and preventing adverse events, such as falls [52]. An example of this would be respecting a resident’s right to refuse to attend exercise programming even though the team may think they can benefit from strength and balance training.
There is limited evidence around falls prevention and resident-centered care. A recent systematic review [55] revealed that resident-centered care may increase falls rates [56,57]. However, the authors of the review attributed the increase in falls to differences in frailty between the control and intervention group [56], and to environmental factors (eg, slippery flooring material, lack of handrails) [57]. Additionally, these trials did not include an exercise program as part of the resident-centered care program. On the other hand, resident-centered care has been associated with reduction of boredom, helplessness, and depression [58,59]. Most studies included in the review were quasi-experimental, which significantly limits the evidence quality [55]. At this point in time, the evidence suggests that resident-centered care is important for mood and quality of life but may have a negative or no effect on reducing falls.
Multifactorial Falls Prevention Programs
While there are mixed results about the effect of exercise as a single intervention for reducing falls for residents in LTC, the literature clearly supports exercise as part of a multifactorial falls prevention program [17,20,60–62]. A 2015 umbrella review [62] of meta-analyses of randomized controlled trials of falls prevention interventions in LTC concluded that multifactorial interventions were the most effective at preventing falls in LTC. Additionally, recently developed recommendations for fracture prevention in LTC [61] suggest that balance, strength, and functional training should be included for residents who are not at high risk of fracture, while for those at high risk, exercise should be provided as part of a multifactorial falls prevention intervention. Clinicians must therefore incorporate elements aside from exercise into their falls prevention strategies. Interventions that have shown positive effects on reducing falls when delivered as part of multifactorial interventions include: staff and resident education [31,35,37], environmental modifications [31,35], supply/repair/provision of assistive devices [30], falls problem-solving conferences [30], urinary incontinence management [29], medication review [30], optician review [31], and cognitive behavioral therapy [32].
Conclusion and Suggestions for Clinical Practice
We suggest incorporating strength and balance exercises as part of a multifactorial falls prevention program for residents in LTC. Balance exercises should be challenging and dynamic (eg, weight shifting). Strength exercises should be of a moderate to high intensity (eg, can complete one to sets of 6 to 8 repetitions) and need to be progressed as the residents’ abilities improve. Residents should participate in strength and balance training on 2 to 3 days per week, for 30- to 45-minute sessions, for at least 6 months. Exercises in standing should be prioritized where appropriate. Exercise could be delivered in a group or individual format, but should consider the residents’ preferences, the social benefits of group exercise, and the feasibility of individualizing exercises for the complex needs of residents in LTC in large group settings. Professionals delivering an exercise program should be trained in exercise planning, delivery, and progression, be familiar with the principles of balance and strength training, and have training in working with older adults in LTC. Exercise programs in LTC should be resident-centered and consider residents’ potential physical and cognitive impairments.
Funding/support: Dr. Giangregorio was supported by grants from the Canadian Frailty Network and Canadian Institutes of Health Research.
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41. American College of Sports Medicine. Progression models in resistance training for healthy adults. Med Sci Sport Exerc 2009;41:687–708.
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43. Patterson C, Feightner J, Garcia A, MacKnight C. General risk factors for dementia: A systematic evidence review. Alzheimer Dement 2007;3:341–7.
44. Roach KE, Tappen RM, Kirk-Sanchez N, et al. A randomized controlled trial of an activity specific exercise program for individuals with alzheimer disease in long-term care settings. J Geriatr Phys Ther 2011;34:50–6.
45. Christofoletti G, Oliani MM, Gobbi S, et al. A controlled clinical trial on the effects of motor intervention on balance and cognition in institutionalized elderly patients with dementia. Clin Rehabil 2008;22:618–26.
46. van Alphen HJM, Hortobágyi T, van Heuvelen MJG. Barriers, motivators, and facilitators of physical activity in dementia patients: A systematic review. Arch Gerontol Geriatr 2016;66:109–18.
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48. Roach KE, Tappen RM, Kirk-Sanchez N, et al. A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings. J Geriatr Phys Ther 2011;34:50–6.
49. Brach JS, Perera S, Gilmore S, et al. Effectiveness of a timing and coordination group exercise program to improve mobility in community-dwelling older adults. JAMA Intern Med August 2017.
50. Rosher RB, Robinson S. Impact of the Eden alternative on family satisfaction. J Am Med Dir Assoc 2005;6:189–93.
51. Crandall LG, White DL, Schuldheis S, Talerico KA. Initiating person-centered care practices in long-term care facilities. J Gerontol Nurs 2007;33:47–56.
52. Sims-Gould J, McKay HA, Feldman F, et al. Autonomy, choice, patient-centered care, and hip protectors: the experience of residents and staff in long-term care. J Appl Gerontol 2014;33:690–709.
53. Robinovitch SN, Cronin T. Perception of postural limits in elderly nursing home and day care participants. J Gerontol A Biol Sci Med Sci 1999;54:B124-30.
54. Perkins MM, Ball MM, Whittington FJ, Hollingsworth C. Relational autonomy in assisted living: a focus on diverse care settings for older adults. J Aging Stud 2012;26:214–25.
55. Brownie S, Nancarrow S. Effects of person-centered care on residents and staff in aged-care facilities: a systematic review. Clin Interv Aging 2013;8:1–10.
56. Coleman MT, Looney S, O’Brien J, et al. The Eden Alternative: findings after 1 year of implementation. J Gerontol A Biol Sci Med Sci 2002;57:M422–7.
57. Chenoweth L, King MT, Jeon Y-H, et al. Caring for Aged Dementia Care Resident Study (CADRES) of personcentred care, dementia-care mapping, and usual care in dementia: a cluster-randomised trial. Lancet Neurol 2009;8: 317–25.
58. Bergman-Evans B. Beyond the basics. Effects of the Eden Alternative model on quality of life issues. J Gerontol Nurs 2004;30:27–34.
59. Robinson SB, Rosher RB. Tangling with the barriers to culture change: creating a resident-centered nursing home environment. J Gerontol Nurs 2006;32:19–25.
60. Cameron ID, Gillespie LD, Robertson MC, et al. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev 2012;12.
61. Papaioannou A, Santesso N, Morin SN, et al. Recommendations for preventing fracture in long-term care. Can Med Assoc J 2015;187:1135–44.
62. Stubbs B, Denkinger MD, Brefka S, Dallmeier D. What works to prevent falls in older adults dwelling in long term care facilities and hospitals? An umbrella review of meta-analyses of randomised controlled trials. Maturitas 2015;81:335–42.
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37. Jensen J, Lundin-Olsson L, Nyberg L, Gustafson Y. Fall and injury prevention in older people living in residential care facilities. A cluster randomized trial. Ann Intern Med 2002;136:733–41.
38. Moreland JD, Richardson JA, Goldsmith CH, Clase CM. Muscle weakness and falls in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 2004;52: 1121–9.
39. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al. Exercise and physical activity for older adults. Med Sci Sport Exerc 2009;41:1510–30.
40. de Souto Barreto P, Morley JE, Chodzko-Zajko W, et al. Recommendations on physical activity and exercise for older adults living in long-term care facilities: a taskforce report. J Am Med Dir Assoc 2016;17:381–92.
41. American College of Sports Medicine. Progression models in resistance training for healthy adults. Med Sci Sport Exerc 2009;41:687–708.
42. Fietzek UM, Schroeteler FE, Ziegler K, et al. Randomized cross-over trial to investigate the efficacy of a two-week physiotherapy programme with repetitive exercises of cueing to reduce the severity of freezing of gait in patients with Parkinson’s disease. Clin Rehabil 2014;28:902–11.
43. Patterson C, Feightner J, Garcia A, MacKnight C. General risk factors for dementia: A systematic evidence review. Alzheimer Dement 2007;3:341–7.
44. Roach KE, Tappen RM, Kirk-Sanchez N, et al. A randomized controlled trial of an activity specific exercise program for individuals with alzheimer disease in long-term care settings. J Geriatr Phys Ther 2011;34:50–6.
45. Christofoletti G, Oliani MM, Gobbi S, et al. A controlled clinical trial on the effects of motor intervention on balance and cognition in institutionalized elderly patients with dementia. Clin Rehabil 2008;22:618–26.
46. van Alphen HJM, Hortobágyi T, van Heuvelen MJG. Barriers, motivators, and facilitators of physical activity in dementia patients: A systematic review. Arch Gerontol Geriatr 2016;66:109–18.
47. Alzheimer Society of Ontario. Rethink Dementia. Accessed 18 Sep 2017 at http://rethinkdementia.ca/.
48. Roach KE, Tappen RM, Kirk-Sanchez N, et al. A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings. J Geriatr Phys Ther 2011;34:50–6.
49. Brach JS, Perera S, Gilmore S, et al. Effectiveness of a timing and coordination group exercise program to improve mobility in community-dwelling older adults. JAMA Intern Med August 2017.
50. Rosher RB, Robinson S. Impact of the Eden alternative on family satisfaction. J Am Med Dir Assoc 2005;6:189–93.
51. Crandall LG, White DL, Schuldheis S, Talerico KA. Initiating person-centered care practices in long-term care facilities. J Gerontol Nurs 2007;33:47–56.
52. Sims-Gould J, McKay HA, Feldman F, et al. Autonomy, choice, patient-centered care, and hip protectors: the experience of residents and staff in long-term care. J Appl Gerontol 2014;33:690–709.
53. Robinovitch SN, Cronin T. Perception of postural limits in elderly nursing home and day care participants. J Gerontol A Biol Sci Med Sci 1999;54:B124-30.
54. Perkins MM, Ball MM, Whittington FJ, Hollingsworth C. Relational autonomy in assisted living: a focus on diverse care settings for older adults. J Aging Stud 2012;26:214–25.
55. Brownie S, Nancarrow S. Effects of person-centered care on residents and staff in aged-care facilities: a systematic review. Clin Interv Aging 2013;8:1–10.
56. Coleman MT, Looney S, O’Brien J, et al. The Eden Alternative: findings after 1 year of implementation. J Gerontol A Biol Sci Med Sci 2002;57:M422–7.
57. Chenoweth L, King MT, Jeon Y-H, et al. Caring for Aged Dementia Care Resident Study (CADRES) of personcentred care, dementia-care mapping, and usual care in dementia: a cluster-randomised trial. Lancet Neurol 2009;8: 317–25.
58. Bergman-Evans B. Beyond the basics. Effects of the Eden Alternative model on quality of life issues. J Gerontol Nurs 2004;30:27–34.
59. Robinson SB, Rosher RB. Tangling with the barriers to culture change: creating a resident-centered nursing home environment. J Gerontol Nurs 2006;32:19–25.
60. Cameron ID, Gillespie LD, Robertson MC, et al. Interventions for preventing falls in older people in care facilities and hospitals. Cochrane Database Syst Rev 2012;12.
61. Papaioannou A, Santesso N, Morin SN, et al. Recommendations for preventing fracture in long-term care. Can Med Assoc J 2015;187:1135–44.
62. Stubbs B, Denkinger MD, Brefka S, Dallmeier D. What works to prevent falls in older adults dwelling in long term care facilities and hospitals? An umbrella review of meta-analyses of randomised controlled trials. Maturitas 2015;81:335–42.