Geriatrics

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

In the wake of Biogen and Eisai’s Oct. 22 announcement about plans to apply to the Food and Drug Administration next year for the regulatory approval of the investigational monoclonal antibody aducanumab as a treatment for Alzheimer’s disease, we spoke with Paul Aisen, MD, the founding director of the Alzheimer’s Therapy Research Institute at the University of Southern California, Los Angeles, for his views on the news. He has been a consultant for Biogen and is a member of the aducanumab steering committee.

Q: What was your first reaction when you heard about the plan to submit an application for aducanumab to the FDA?

A: My initial reaction is that this provides terrific support for the amyloid hypothesis, and is consistent with the early aducanumab studies showing significant reductions in brain amyloid with resulting clinical improvement.

My next thought was that these data are going to be very, very challenging to analyze because both of these trials were stopped early, and one was clearly negative. We really need to scrutinize the data, but even at this point I would say this strongly supports targeting amyloid. The scrutiny will begin in detail at the Clinical Trials in Alzheimer’s Disease conference in December, when Biogen will likely release detailed data. A lot of people will analyze it, and I think that’s great. It’s beneficial to bring different perspectives.

We have had a terribly frustrating series of disappointments in the field. After the futility analysis of aducanumab and the multiple failures of BACE [beta-secretase] inhibitors, many were convinced we were barking up the wrong tree. I think these results, although complicated, should resurrect the enthusiasm for targeting amyloid.
 

Q: What is different about aducanumab from other antibodies tested – and rejected – in Alzheimer’s drug development?

A: There are lots of antibodies that have been tested in clinical trials. They all differ in terms of their affinity for amyloid beta. Some target monomers of the protein. Some target dimers. Some target fibrils. Some tie up amyloid and some reduce it. Aducanumab directly attacks brain plaques, reducing the plaque load in the brain. It carries a liability of amyloid-related imaging abnormalities [ARIA], but it also allows us to assess the impact that removing plaques might have on downstream events, including biomarkers. Overall, these data show that aducanumab did remove brain plaques and that removing them had a beneficial effect on cognition and function, and also a favorable effect on downstream biomarkers.

But again, we must be cautious because this is a complex data set taken from a post hoc analysis of two different terminated trials.
 

Q: We see some statistically significant differences in cognitive and functional outcomes. What would that mean for patients on an everyday basis?

A: Well, everyone is different, so that’s hard to say. A 25% slowing of functional decline on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) might mean that, at the end of a year, there’s not a significant change in memory, or that there’s better social function. If both trials had been completed and if people had 18 months of high-dose aducanumab, the slowing of functional decline on the CDR-SB might in fact be greater than reported. Again, we’re having to draw conclusions from interrupted trials.
 

Q: This suggestion you make of a potentially continuous slowing of decline – are you suggesting that aducanumab might slow decline to the point of stopping it altogether? If an elderly patient has little or no progression until death would that, in effect, be considered a “cure?”

A: I don’t think it is possible to cure AD once the disease is clinically evident. These are studies of people with early AD, late mild cognitive impairment, and mild dementia. At that stage, there’s already a loss of synapses that won’t come back, and these studies don’t suggest that aducanumab can cure that. But what if people took it earlier, when the brain is still functioning normally? Some of us have argued for many years that earlier intervention is the way to go. And since we can now identify people [with brain plaques] before they become symptomatic, there is the possibility that if we removed them, we could stop progression.

Q: Are there any plans to study aducanumab as a preventive agent?

A: A grant has been awarded for this, but it was put on hold after the futility analysis. I don’t know when or if that will go forward.

(Editor’s note: The National Institutes of Health previously awarded Banner Health a $32 million, 5-year grant to examine this. The 2-year prevention study of aducanumab is aimed at cognitively unimpaired 65- to 80-year-old patients with PET-confirmed amyloid brain plaques. It was to be a multicenter, double-blind, placebo-controlled trial using Alzheimer’s biomarker endpoints as primary outcomes, along with cognitive and clinical changes, safety, and tolerability. The study was put on hold after Biogen discontinued the aducanumab development program in March. Investigators are considering whether to resurrect plans considering the new data. The study is intended to be a public-private partnership, with additional unspecified funding from Biogen plus $10 million from philanthropic sources. It has three intended goals: To find an approved prevention therapy as early as 2023, ahead of the National Plan to Address Alzheimer’s Disease’s goal of an effective prevention strategy by 2025; to advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical Alzheimer’s stages when some treatments may have their greatest benefit; and to help make it possible to conduct prevention trials in at-risk persons even before they have extensive amyloid plaques, when some treatments may have their greatest benefit.)
 

Q: It seems like rolling this out to an enormous population of patients is going to be difficult, if not impossible. Are people really going to be able to commit to what could be a lifetime of monthly intravenous infusions of a medicine that could be expensive, as therapeutic antibodies generally are?

A: I would say, nothing about this disease is easy. It’s devastating and horrible. And if someone is diagnosed at this stage, I would think that individual would embrace any opportunity to treat it. My hope is that we will be able to prescreen people with an effective blood test for amyloid that would be part of a regular testing protocol once they reach a certain age. Those with positive results would be referred for more testing, including amyloid brain imaging.

The flu season is underway in the United States, and an Advisory Committee on Immunization Practices’ work group is set to assess vaccines for older adults, according to data presented at a meeting of the Centers for Disease Control and Prevention’s ACIP.

copyright Wavebreakmedia/Thinkstock

Lynette Brammer of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD) presented a surveillance update of the flu season in the United States so far. Overall, the influenza A(H3N2) viruses are predominant, although dominance varies in different regions of the country, and it is too soon to predict what strain will dominate later in the season.

“While two of the four vaccine components were updated for the Southern Hemisphere, the components selected for the 2019-2020 Northern Hemisphere vaccine, at this time, look appropriate for the season,” she said.

In other flu news, Lisa Groskopf, MD, of the NCIRD discussed the influenza work group’s plans for a meta-analysis to assess the relative benefit of different vaccines for older adults, in light of the growing variety of products available.

Currently, no preferential recommendations have been made for a specific vaccine for a particular age group. “There’s a dearth of data comparing these vaccines to one another,” said Dr. Groskopf. She added that, because vaccine effectiveness varies by season, the generalizability of effectiveness data is another challenge.

The work group’s systematic review and meta-analysis is designed to compare the high-dose inactivated influenza vaccine (HD-IIV), the adjuvanted inactivated influenza vaccine (aIIV), and the recombinant influenza vaccine (RIV). The study will include adults aged 65 years and older who receive trivalent or quadrivalent HD-IIV, aIIV, or RIV, compared with those who receive another influenza vaccine, a noninfluenza control vaccine, placebo, or no vaccine. The outcomes will include data on safety and effectiveness of the vaccines, Dr. Groskopf said.

In addition to safety and effectiveness, manufacturers such as Sanofi Pasteur continue to collect data on the success of available vaccines and develop new ones. Lee-Jah Chang, MD, of Sanofi Pasteur presented results of a noninferiority study of the company’s investigational high-dose quadrivalent influenza vaccine (QIV-HD; including two prevailing B viruses) versus the high-dose trivalent influenza vaccine (TID-HD). The study was conducted at 35 sites in the United States and included 2,670 adults aged 65 years and older.

Overall, the reactogenicity profile for patients given QIV-HD was similar to that of TID-HD, and approximately 5% of patients in the QIV group reported an immediate adverse event, Dr. Chang said. However, no related deaths or related adverse events of special interest occurred in any of the study groups.

Sanofi plans to pursue licensure of the QIV-HD vaccine, with a Center for Biologics Evaluation and Research action date of Nov. 4, 2019, said Dr. Chang. If the vaccine is licensed, it should be available for purchase by health care providers in the first quarter of 2020.

The ACIP members had no financial conflicts to disclose.

The flu season is underway in the United States, and an Advisory Committee on Immunization Practices’ work group is set to assess vaccines for older adults, according to data presented at a meeting of the Centers for Disease Control and Prevention’s ACIP.

copyright Wavebreakmedia/Thinkstock

Lynette Brammer of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD) presented a surveillance update of the flu season in the United States so far. Overall, the influenza A(H3N2) viruses are predominant, although dominance varies in different regions of the country, and it is too soon to predict what strain will dominate later in the season.

“While two of the four vaccine components were updated for the Southern Hemisphere, the components selected for the 2019-2020 Northern Hemisphere vaccine, at this time, look appropriate for the season,” she said.

In other flu news, Lisa Groskopf, MD, of the NCIRD discussed the influenza work group’s plans for a meta-analysis to assess the relative benefit of different vaccines for older adults, in light of the growing variety of products available.

Currently, no preferential recommendations have been made for a specific vaccine for a particular age group. “There’s a dearth of data comparing these vaccines to one another,” said Dr. Groskopf. She added that, because vaccine effectiveness varies by season, the generalizability of effectiveness data is another challenge.

The work group’s systematic review and meta-analysis is designed to compare the high-dose inactivated influenza vaccine (HD-IIV), the adjuvanted inactivated influenza vaccine (aIIV), and the recombinant influenza vaccine (RIV). The study will include adults aged 65 years and older who receive trivalent or quadrivalent HD-IIV, aIIV, or RIV, compared with those who receive another influenza vaccine, a noninfluenza control vaccine, placebo, or no vaccine. The outcomes will include data on safety and effectiveness of the vaccines, Dr. Groskopf said.

In addition to safety and effectiveness, manufacturers such as Sanofi Pasteur continue to collect data on the success of available vaccines and develop new ones. Lee-Jah Chang, MD, of Sanofi Pasteur presented results of a noninferiority study of the company’s investigational high-dose quadrivalent influenza vaccine (QIV-HD; including two prevailing B viruses) versus the high-dose trivalent influenza vaccine (TID-HD). The study was conducted at 35 sites in the United States and included 2,670 adults aged 65 years and older.

Overall, the reactogenicity profile for patients given QIV-HD was similar to that of TID-HD, and approximately 5% of patients in the QIV group reported an immediate adverse event, Dr. Chang said. However, no related deaths or related adverse events of special interest occurred in any of the study groups.

Sanofi plans to pursue licensure of the QIV-HD vaccine, with a Center for Biologics Evaluation and Research action date of Nov. 4, 2019, said Dr. Chang. If the vaccine is licensed, it should be available for purchase by health care providers in the first quarter of 2020.

The ACIP members had no financial conflicts to disclose.

The flu season is underway in the United States, and an Advisory Committee on Immunization Practices’ work group is set to assess vaccines for older adults, according to data presented at a meeting of the Centers for Disease Control and Prevention’s ACIP.

copyright Wavebreakmedia/Thinkstock

Lynette Brammer of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD) presented a surveillance update of the flu season in the United States so far. Overall, the influenza A(H3N2) viruses are predominant, although dominance varies in different regions of the country, and it is too soon to predict what strain will dominate later in the season.

“While two of the four vaccine components were updated for the Southern Hemisphere, the components selected for the 2019-2020 Northern Hemisphere vaccine, at this time, look appropriate for the season,” she said.

In other flu news, Lisa Groskopf, MD, of the NCIRD discussed the influenza work group’s plans for a meta-analysis to assess the relative benefit of different vaccines for older adults, in light of the growing variety of products available.

Currently, no preferential recommendations have been made for a specific vaccine for a particular age group. “There’s a dearth of data comparing these vaccines to one another,” said Dr. Groskopf. She added that, because vaccine effectiveness varies by season, the generalizability of effectiveness data is another challenge.

The work group’s systematic review and meta-analysis is designed to compare the high-dose inactivated influenza vaccine (HD-IIV), the adjuvanted inactivated influenza vaccine (aIIV), and the recombinant influenza vaccine (RIV). The study will include adults aged 65 years and older who receive trivalent or quadrivalent HD-IIV, aIIV, or RIV, compared with those who receive another influenza vaccine, a noninfluenza control vaccine, placebo, or no vaccine. The outcomes will include data on safety and effectiveness of the vaccines, Dr. Groskopf said.

In addition to safety and effectiveness, manufacturers such as Sanofi Pasteur continue to collect data on the success of available vaccines and develop new ones. Lee-Jah Chang, MD, of Sanofi Pasteur presented results of a noninferiority study of the company’s investigational high-dose quadrivalent influenza vaccine (QIV-HD; including two prevailing B viruses) versus the high-dose trivalent influenza vaccine (TID-HD). The study was conducted at 35 sites in the United States and included 2,670 adults aged 65 years and older.

Overall, the reactogenicity profile for patients given QIV-HD was similar to that of TID-HD, and approximately 5% of patients in the QIV group reported an immediate adverse event, Dr. Chang said. However, no related deaths or related adverse events of special interest occurred in any of the study groups.

Sanofi plans to pursue licensure of the QIV-HD vaccine, with a Center for Biologics Evaluation and Research action date of Nov. 4, 2019, said Dr. Chang. If the vaccine is licensed, it should be available for purchase by health care providers in the first quarter of 2020.

The ACIP members had no financial conflicts to disclose.

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

msullivan@mdedge.com

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

msullivan@mdedge.com

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

msullivan@mdedge.com

ID Week, the annual meeting of the Infectious Disease Society of America, provided valuable insights into past season’s endemic influenza burden and the effectiveness of prevention strategies. Each year, there are from 9million to 49 million influenza cases in the United States, 140,000-960,000 hospitalized cases, and 12,000-70,000 deaths directly attributable to influenza infection. The burden disproportionately falls on infants and adults 65 years of age and older; 11,000-48,000 children are hospitalized, and as many as several hundred children may die from influenza and related complications. School age children (aged 5-19 years) and adults (aged 30-39 years) are a major part of the transmission cycle. Influenza vaccine underlies the prevention strategy for limiting the burden of disease in U.S. populations. ID Week provided new insights into critical questions about influenza vaccines.

spukkato/Getty Images

1. What is the effectiveness of influenza vaccine against severe disease (hospitalization) in children? Does it vary by age? By type or subtype?

Angela P. Campbell, MD, MPH, of the Centers for Disease Control and Prevention, and associates presented data on influenza vaccine effectiveness from the New Vaccine Surveillance Network in children for the 2016-2017 and 2017-2018 season (ID Week session 99; Abstract 899). During both 2016-2017 and 2017-2018, H3N2 was the dominant virus and influenza B represented about one-third of cases, and H1N1 was a greater percentage of cases in 2017-2018. Influenza positivity among children younger than 18 years of age admitted to hospital with respiratory disease was 14% among unvaccinated and 8% among vaccinated children; effectiveness again hospitalization was 50%. Vaccine effectiveness (VE) was not statistically different between children younger than 8 years of age and those older that 8 years but did differ by vaccine type. VE was 76% against H1N1 disease, 59% again B disease, and only 33% against H3N2 disease.

Clearly, vaccination with influenza vaccine prevents serious respiratory disease. However, the impact of vaccine will vary by season and by which influenza stains are circulating in the community. The authors concluded that further understanding of the lower VE against H3N2 disease is needed.

2. Does the priming dose of influenza vaccine improve vaccine effectiveness?

Current recommendations call for a two-dose series for influenza vaccine in children aged 6 months through 8 years who have not had prior influenza vaccine. The recommendation is based on evidence demonstrating higher antibody responses in children receiving two doses, compared with a single dose. Using data from the U.S. Influenza Vaccine Effectiveness Network, Jessie R. Chung, MPH, of the CDC, and associates compared VE in children younger than 2 years receiving two doses in the first year of flu immunization (fully immunized), compared with those who received only one dose (partially immunized) (ID Week session 99; Abstract 900). VE was 53% for fully immunized and 23% for partially immunized children. Receipt of a single dose did not provide statistically significant protection against influenza. Surprisingly (to me), of 5,355 children aged 6 months to less than 2 years with no prior influenza vaccine, 1,870 (35%) received only one dose in the season.

The data strongly support the current recommendations for a priming dose, especially in young children, in the first season of influenza vaccine and warrants increased efforts to increase the update of second doses during the season. Hopefully we can do better in 2019!

3. Should we wait to vaccinate with influenza vaccine?

Some evidence suggests that waning immunity to influenza vaccine, primarily in those aged 65 years and older, may explain increased disease activity toward the end of influenza season. Other explanations include increasing viral diversity throughout the season, resulting in reduced effectiveness. Do such concerns warrant delaying immunization? The onset and peak of influenza season varies by year; in October 2019, 3% of tests performed on patients with respiratory illness were influenza positive. The trade-offs for delaying immunization until October are the unpredictability of onset of influenza season, the requirement for two doses in infants, the need for 2 weeks to achieve peak antibody concentrations, and the potential that fewer individuals will be vaccinated. Kathy Neuzil, MD, MPH, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, reviewed recent modeling (for adults aged 65 years and older) and reported that delaying vaccine programs until October is associated with greater burden of hospitalization if 14% fewer individuals (who would be vaccinated in August/September) are vaccinated (ID Week; Session 940).

In response to these concerns, the CDC recommendations for 2019 are that, in children aged 6 months through 8 years who need two doses, start early so that you can achieve both doses before influenza season (MMWR 2019 Aug 23;68[3]:1-21).In older children and adults, who need only a single dose, early vaccination (August and early September) may lead to reduced protection late in the influenza season?

4. How can we optimize vaccine impact?

Vaccine impact refers to the affect on a population level and not at an individual level. Meagan C. Fitzpatrick, PhD, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, evaluated the benefits of our moderately effective influenza vaccines (VE 40%-60%) to the population beyond those who are vaccinated. Her conclusions were that even a modestly effective vaccine prevents 21 million cases of influenza, 129,000 hospitalizations, and 62,000 deaths. And that two-thirds of the deaths prevented are from herd benefit (or indirect effects). Although both coverage and vaccine effectiveness are important, she reported that population impact was most sensitive to coverage, compared with vaccine effectiveness. Dr. Fitzpatrick found that targeting school-age children 6-19 years of age and adults 30-39 years of age maximizes the public health benefits (herd effects) of influenza vaccine. In 2018 season, influenza coverage was 63% for at least one dose in children aged 6 months through 17 years and 45% in adults aged 18 years and older; in the two target age groups 5-17 and 30-39 years, coverage was 59% and approximately 35%, respectively (ID Week; Session 939).

Clearly, even our modestly effective influenza vaccines have significant public health benefit in protecting the U.S. populations from serious disease and death. Efforts to increase vaccine uptake in school-age children, both those with and without comorbidity, and the 30- to 39-year-old adult cohort would likely further reduce the burden of serious disease from influenza.

In summary, despite a vaccine that is only moderately effective, there is clear evidence to support current recommendations of universal immunization beginning at 6 months of age. Optimizing the impact of the flu vaccine requires increasing coverage, including two doses for those less than 8 years of age being immunized for the first time. Delaying until October 1 is a good idea only if the same number of individuals will receive influenza vaccine, otherwise the hypothetical benefit is lost.
 

Dr. Pelton is professor of pediatrics and epidemiology at Boston University schools of medicine and public health and is senior attending physician, Boston Medical Center. Dr. Pelton has investigator-initiated research awards to Boston Medical Center from Pfizer and Merck Vaccines. He also received honorarium as an advisory board member, participation in symposium and consultation from Seqirus and Merck Vaccine, Pfizer, and Sanofi Pasteur. Email him at pdnews@mdedge.com.

ID Week, the annual meeting of the Infectious Disease Society of America, provided valuable insights into past season’s endemic influenza burden and the effectiveness of prevention strategies. Each year, there are from 9million to 49 million influenza cases in the United States, 140,000-960,000 hospitalized cases, and 12,000-70,000 deaths directly attributable to influenza infection. The burden disproportionately falls on infants and adults 65 years of age and older; 11,000-48,000 children are hospitalized, and as many as several hundred children may die from influenza and related complications. School age children (aged 5-19 years) and adults (aged 30-39 years) are a major part of the transmission cycle. Influenza vaccine underlies the prevention strategy for limiting the burden of disease in U.S. populations. ID Week provided new insights into critical questions about influenza vaccines.

spukkato/Getty Images

1. What is the effectiveness of influenza vaccine against severe disease (hospitalization) in children? Does it vary by age? By type or subtype?

Angela P. Campbell, MD, MPH, of the Centers for Disease Control and Prevention, and associates presented data on influenza vaccine effectiveness from the New Vaccine Surveillance Network in children for the 2016-2017 and 2017-2018 season (ID Week session 99; Abstract 899). During both 2016-2017 and 2017-2018, H3N2 was the dominant virus and influenza B represented about one-third of cases, and H1N1 was a greater percentage of cases in 2017-2018. Influenza positivity among children younger than 18 years of age admitted to hospital with respiratory disease was 14% among unvaccinated and 8% among vaccinated children; effectiveness again hospitalization was 50%. Vaccine effectiveness (VE) was not statistically different between children younger than 8 years of age and those older that 8 years but did differ by vaccine type. VE was 76% against H1N1 disease, 59% again B disease, and only 33% against H3N2 disease.

Clearly, vaccination with influenza vaccine prevents serious respiratory disease. However, the impact of vaccine will vary by season and by which influenza stains are circulating in the community. The authors concluded that further understanding of the lower VE against H3N2 disease is needed.

2. Does the priming dose of influenza vaccine improve vaccine effectiveness?

Current recommendations call for a two-dose series for influenza vaccine in children aged 6 months through 8 years who have not had prior influenza vaccine. The recommendation is based on evidence demonstrating higher antibody responses in children receiving two doses, compared with a single dose. Using data from the U.S. Influenza Vaccine Effectiveness Network, Jessie R. Chung, MPH, of the CDC, and associates compared VE in children younger than 2 years receiving two doses in the first year of flu immunization (fully immunized), compared with those who received only one dose (partially immunized) (ID Week session 99; Abstract 900). VE was 53% for fully immunized and 23% for partially immunized children. Receipt of a single dose did not provide statistically significant protection against influenza. Surprisingly (to me), of 5,355 children aged 6 months to less than 2 years with no prior influenza vaccine, 1,870 (35%) received only one dose in the season.

The data strongly support the current recommendations for a priming dose, especially in young children, in the first season of influenza vaccine and warrants increased efforts to increase the update of second doses during the season. Hopefully we can do better in 2019!

3. Should we wait to vaccinate with influenza vaccine?

Some evidence suggests that waning immunity to influenza vaccine, primarily in those aged 65 years and older, may explain increased disease activity toward the end of influenza season. Other explanations include increasing viral diversity throughout the season, resulting in reduced effectiveness. Do such concerns warrant delaying immunization? The onset and peak of influenza season varies by year; in October 2019, 3% of tests performed on patients with respiratory illness were influenza positive. The trade-offs for delaying immunization until October are the unpredictability of onset of influenza season, the requirement for two doses in infants, the need for 2 weeks to achieve peak antibody concentrations, and the potential that fewer individuals will be vaccinated. Kathy Neuzil, MD, MPH, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, reviewed recent modeling (for adults aged 65 years and older) and reported that delaying vaccine programs until October is associated with greater burden of hospitalization if 14% fewer individuals (who would be vaccinated in August/September) are vaccinated (ID Week; Session 940).

In response to these concerns, the CDC recommendations for 2019 are that, in children aged 6 months through 8 years who need two doses, start early so that you can achieve both doses before influenza season (MMWR 2019 Aug 23;68[3]:1-21).In older children and adults, who need only a single dose, early vaccination (August and early September) may lead to reduced protection late in the influenza season?

4. How can we optimize vaccine impact?

Vaccine impact refers to the affect on a population level and not at an individual level. Meagan C. Fitzpatrick, PhD, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, evaluated the benefits of our moderately effective influenza vaccines (VE 40%-60%) to the population beyond those who are vaccinated. Her conclusions were that even a modestly effective vaccine prevents 21 million cases of influenza, 129,000 hospitalizations, and 62,000 deaths. And that two-thirds of the deaths prevented are from herd benefit (or indirect effects). Although both coverage and vaccine effectiveness are important, she reported that population impact was most sensitive to coverage, compared with vaccine effectiveness. Dr. Fitzpatrick found that targeting school-age children 6-19 years of age and adults 30-39 years of age maximizes the public health benefits (herd effects) of influenza vaccine. In 2018 season, influenza coverage was 63% for at least one dose in children aged 6 months through 17 years and 45% in adults aged 18 years and older; in the two target age groups 5-17 and 30-39 years, coverage was 59% and approximately 35%, respectively (ID Week; Session 939).

Clearly, even our modestly effective influenza vaccines have significant public health benefit in protecting the U.S. populations from serious disease and death. Efforts to increase vaccine uptake in school-age children, both those with and without comorbidity, and the 30- to 39-year-old adult cohort would likely further reduce the burden of serious disease from influenza.

In summary, despite a vaccine that is only moderately effective, there is clear evidence to support current recommendations of universal immunization beginning at 6 months of age. Optimizing the impact of the flu vaccine requires increasing coverage, including two doses for those less than 8 years of age being immunized for the first time. Delaying until October 1 is a good idea only if the same number of individuals will receive influenza vaccine, otherwise the hypothetical benefit is lost.
 

Dr. Pelton is professor of pediatrics and epidemiology at Boston University schools of medicine and public health and is senior attending physician, Boston Medical Center. Dr. Pelton has investigator-initiated research awards to Boston Medical Center from Pfizer and Merck Vaccines. He also received honorarium as an advisory board member, participation in symposium and consultation from Seqirus and Merck Vaccine, Pfizer, and Sanofi Pasteur. Email him at pdnews@mdedge.com.

ID Week, the annual meeting of the Infectious Disease Society of America, provided valuable insights into past season’s endemic influenza burden and the effectiveness of prevention strategies. Each year, there are from 9million to 49 million influenza cases in the United States, 140,000-960,000 hospitalized cases, and 12,000-70,000 deaths directly attributable to influenza infection. The burden disproportionately falls on infants and adults 65 years of age and older; 11,000-48,000 children are hospitalized, and as many as several hundred children may die from influenza and related complications. School age children (aged 5-19 years) and adults (aged 30-39 years) are a major part of the transmission cycle. Influenza vaccine underlies the prevention strategy for limiting the burden of disease in U.S. populations. ID Week provided new insights into critical questions about influenza vaccines.

spukkato/Getty Images

1. What is the effectiveness of influenza vaccine against severe disease (hospitalization) in children? Does it vary by age? By type or subtype?

Angela P. Campbell, MD, MPH, of the Centers for Disease Control and Prevention, and associates presented data on influenza vaccine effectiveness from the New Vaccine Surveillance Network in children for the 2016-2017 and 2017-2018 season (ID Week session 99; Abstract 899). During both 2016-2017 and 2017-2018, H3N2 was the dominant virus and influenza B represented about one-third of cases, and H1N1 was a greater percentage of cases in 2017-2018. Influenza positivity among children younger than 18 years of age admitted to hospital with respiratory disease was 14% among unvaccinated and 8% among vaccinated children; effectiveness again hospitalization was 50%. Vaccine effectiveness (VE) was not statistically different between children younger than 8 years of age and those older that 8 years but did differ by vaccine type. VE was 76% against H1N1 disease, 59% again B disease, and only 33% against H3N2 disease.

Clearly, vaccination with influenza vaccine prevents serious respiratory disease. However, the impact of vaccine will vary by season and by which influenza stains are circulating in the community. The authors concluded that further understanding of the lower VE against H3N2 disease is needed.

2. Does the priming dose of influenza vaccine improve vaccine effectiveness?

Current recommendations call for a two-dose series for influenza vaccine in children aged 6 months through 8 years who have not had prior influenza vaccine. The recommendation is based on evidence demonstrating higher antibody responses in children receiving two doses, compared with a single dose. Using data from the U.S. Influenza Vaccine Effectiveness Network, Jessie R. Chung, MPH, of the CDC, and associates compared VE in children younger than 2 years receiving two doses in the first year of flu immunization (fully immunized), compared with those who received only one dose (partially immunized) (ID Week session 99; Abstract 900). VE was 53% for fully immunized and 23% for partially immunized children. Receipt of a single dose did not provide statistically significant protection against influenza. Surprisingly (to me), of 5,355 children aged 6 months to less than 2 years with no prior influenza vaccine, 1,870 (35%) received only one dose in the season.

The data strongly support the current recommendations for a priming dose, especially in young children, in the first season of influenza vaccine and warrants increased efforts to increase the update of second doses during the season. Hopefully we can do better in 2019!

3. Should we wait to vaccinate with influenza vaccine?

Some evidence suggests that waning immunity to influenza vaccine, primarily in those aged 65 years and older, may explain increased disease activity toward the end of influenza season. Other explanations include increasing viral diversity throughout the season, resulting in reduced effectiveness. Do such concerns warrant delaying immunization? The onset and peak of influenza season varies by year; in October 2019, 3% of tests performed on patients with respiratory illness were influenza positive. The trade-offs for delaying immunization until October are the unpredictability of onset of influenza season, the requirement for two doses in infants, the need for 2 weeks to achieve peak antibody concentrations, and the potential that fewer individuals will be vaccinated. Kathy Neuzil, MD, MPH, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, reviewed recent modeling (for adults aged 65 years and older) and reported that delaying vaccine programs until October is associated with greater burden of hospitalization if 14% fewer individuals (who would be vaccinated in August/September) are vaccinated (ID Week; Session 940).

In response to these concerns, the CDC recommendations for 2019 are that, in children aged 6 months through 8 years who need two doses, start early so that you can achieve both doses before influenza season (MMWR 2019 Aug 23;68[3]:1-21).In older children and adults, who need only a single dose, early vaccination (August and early September) may lead to reduced protection late in the influenza season?

4. How can we optimize vaccine impact?

Vaccine impact refers to the affect on a population level and not at an individual level. Meagan C. Fitzpatrick, PhD, from the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, evaluated the benefits of our moderately effective influenza vaccines (VE 40%-60%) to the population beyond those who are vaccinated. Her conclusions were that even a modestly effective vaccine prevents 21 million cases of influenza, 129,000 hospitalizations, and 62,000 deaths. And that two-thirds of the deaths prevented are from herd benefit (or indirect effects). Although both coverage and vaccine effectiveness are important, she reported that population impact was most sensitive to coverage, compared with vaccine effectiveness. Dr. Fitzpatrick found that targeting school-age children 6-19 years of age and adults 30-39 years of age maximizes the public health benefits (herd effects) of influenza vaccine. In 2018 season, influenza coverage was 63% for at least one dose in children aged 6 months through 17 years and 45% in adults aged 18 years and older; in the two target age groups 5-17 and 30-39 years, coverage was 59% and approximately 35%, respectively (ID Week; Session 939).

Clearly, even our modestly effective influenza vaccines have significant public health benefit in protecting the U.S. populations from serious disease and death. Efforts to increase vaccine uptake in school-age children, both those with and without comorbidity, and the 30- to 39-year-old adult cohort would likely further reduce the burden of serious disease from influenza.

In summary, despite a vaccine that is only moderately effective, there is clear evidence to support current recommendations of universal immunization beginning at 6 months of age. Optimizing the impact of the flu vaccine requires increasing coverage, including two doses for those less than 8 years of age being immunized for the first time. Delaying until October 1 is a good idea only if the same number of individuals will receive influenza vaccine, otherwise the hypothetical benefit is lost.
 

Dr. Pelton is professor of pediatrics and epidemiology at Boston University schools of medicine and public health and is senior attending physician, Boston Medical Center. Dr. Pelton has investigator-initiated research awards to Boston Medical Center from Pfizer and Merck Vaccines. He also received honorarium as an advisory board member, participation in symposium and consultation from Seqirus and Merck Vaccine, Pfizer, and Sanofi Pasteur. Email him at pdnews@mdedge.com.

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

rfranki@mdedge.com

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

rfranki@mdedge.com

Almost all of Medicare’s 58 million enrollees had a blood pressure screening in 2017, and just under 90% saw a physician during the year, according to new data released by the Centers for Medicare & Medicaid Services.

The latest edition of Medicare Beneficiaries at a Glance takes a look at some of the services provided in 2017, and BP checks were high on the list, with 96% of enrollees getting screened. BP was also prominent on another list featured in the Medicare snapshot for 2017, as hypertension was the most common chronic condition among beneficiaries with a prevalence of 58%, the CMS said.

A second glance at the report shows that 41% of enrollees had high cholesterol that year, making it the next-most common chronic condition, with arthritis third at 33%, the CMS said. Diabetes was fourth and heart disease was fifth, but rounding gives them the same prevalence of 27%.

rfranki@mdedge.com

CASE

Ronald W^a is a 74-year old man with an extensive medical history: diabetes, hypertension, heart failure, atrial fibrillation, pancreatitis, hyperlipidemia, gout, depression, generalized anxiety, obstructive sleep apnea, and benign prostatic hypertrophy. He arrives at the emergency department (ED) of the hospital by nonemergent ambulance from home for evaluation of lethargy and confusion over the past week.

In the ED, Mr. W is afebrile, normotensive, and oxygenating on room air. Mucous membranes are dry. On physical examination, he appears pale, fatigued, and modestly confused but is able to state his name and birthday, although not the location or date.

Laboratory testing reveals: blood glucose, 107 mg/dL; serum creatinine, 2.3 mg/dL; sodium, 127 mEq/L; and hemoglobin level and hematocrit, within normal limits. Urinalysis is negative. Renal ultrasonography is unremarkable, without evidence of urinary tract obstruction.

Mr. W is admitted to the general medical unit with hyponatremia. The pharmacy admission specialist begins reconciliation of the long list of the patient’s home medications.

Overprescribing: Often, more is not better

Some experts consider prescribing medication to be the most common form of medical intervention; beyond that, polypharmacy—often defined as the use of more medications than are medically necessary (see the next section on terminology)—is recognized as an increasingly serious problem in many medical specialties.¹ Here are specifics about the extent of, and harm caused by, the problem^2,3:

• The US General Accounting Office reports that inappropriate polypharmacy is associated with significant morbidity and mortality.² Research has established a strong relationship between polypharmacy and harmful clinical consequences,³ to which the older patient population is most susceptible.  
• Polypharmacy is also recognized as an expensive practice; the US Center for Medicare and Medicaid Services estimates that polypharmacy cost US health insurers more than $50 billion annually.²
• Worldwide, with more and more people older than 65 years, polypharmacy is becoming more prevalent, and a growing concern, in older adults; approximately 50% of them take ≥ 1 medications that are medically unnecessary.³

Despite many programs to help with deprescribing, drug–drug interactions and the so-called prescribing cascade (ie, when signs and symptoms of an adverse drug effect are misdiagnosed as a new medical condition) continue to affect patients, leading to comorbidities. It is important, therefore, for physicians to be aware of commonly used tools to prevent polypharmacy and its consequences.

What is “polypharmacy” understood to mean?

Despite the compelling association of polypharmacy with the presence of multiple morbidities in the older patient population, there is no consensus on its definition:

• Starting with the dictionary, “polypharmacy” derives from 2 words in Ancient Greek: poly, “more than one,” and “pharmakon, “drug.”³
• The definition can vary based on the number of drugs a patient has been prescribed, their safety, and the appropriateness of their use.¹
• Another definition is the use of more medications than are medically necessary; such a grouping includes agents that are not indicated, are ineffective, or constitute a therapeutic duplication. Although this definition is more clinically relevant than the others, it is premised on undertaking a clinical review of a medication regimen.³
• A numerical definition is the most commonly reported category, a number that varies from study to study—from ≥ 2 to ≥ 11 medications. When applied to health care settings, accepted definitions are ≥ 5 medications at hospital discharge and ≥ 10 during a hospital stay.⁴ Numerical definitions of polypharmacy do not ascertain the clinical appropriateness of therapy nor the process of rationalizing those medications.¹

^aA composite, hypothetical patient, based on the authors' clinical experience.

Continue to: Appropriateness

Appropriateness

Polypharmacy is classified as appropriate or inappropriate:

• Appropriate polypharmacy is the optimization of medications for patients with complex or multiple conditions, when the use of medicine is in agreement with best evidence.
• Inappropriate polypharmacy can increase the risk of adverse drug effects and drug–drug interactions and can be characterized by medication underuse and duplication.⁴

There are subdefinitions of “appropriateness,” but these are beyond the scope of this article.

What variables contribute to polypharmacy?

Polypharmacy is not only medically unnecessary; it also causes significant morbidity and mortality and is expensive.

Multimorbidity is common in the older population. The presence of multiple chronic conditions increases the complexity of therapeutic management for health professionals and patients; such complexity can have a harmful impact on health outcomes. Combinations of medications to treat chronic diseases automatically push many patients into polypharmacy. Few treatment guidelines provide recommendations on when to stop medications.

Consequences of polypharmacy, some of which are masked as syndromes in the older patient, include delirium and dementia, urinary incontinence, dizziness, falls, adverse drug reactions, increased length of hospital stay, readmission soon after discharge, and death.^3-5 Relatively high rates of drug consumption and other variables (eg, decreased renal and hepatic function, decreased total body water and lean body mass, cognitive impairment, age-related decline in vision and hearing, frequency of chronic diseases and medical comorbidities, communication barriers, prescribing cascades, and health care delivery involving multiple prescribers) can contribute to an increased prevalence of medication-associated morbidity and mortality as the result of polypharmacy.

In a descriptive study⁶ that examined these variables, researchers explored whether general practitioners experience barriers to medication review in multimorbid patients with polypharmacy. They concluded that the primary barriers were (1) lack of communication and teamwork with specialists and (2) the challenge of handling polypharmacy in a culture that encourages adding medications and inhibits conversations about medication withdrawal.⁶

Continue to: Reducing consequences of polypharmacy

 

 

Reducing consequences of polypharmacy

Collaborative medication review

Interventions to help physicians reduce polypharmacy include reviewing medications with older patients at every office visit and during transitions of care into and out of the hospital or other care facility. A 2016 Cochrane review of 5 randomized trials of inpatient medication reviews led by pharmacists, physicians, and other health care professionals showed a 36% reduction in ED visits 30 days to 1 year after discharge.⁷

Consequences of polypharmacy can be masked as syndromes in older patients—eg, delirium, urinary incontinence, dizziness.

Patients can collaborate in this effort by bringing all medications to each appointment or upon hospital admission—not just a list but the actual supply, to ensure that a correct medication list is compiled and a thorough review conducted.⁸ Explicitly ask open-ended questions of the patient about over-the-counter medications, herbal products, and other home remedies that have not been prescribed; many patients may have trouble with recall or are uncertain what fits the definition of a nonprescription medication.^8,9

Compare the medication list with the patient’s current problem list; consider removing medications that do not have a pertinent indication. (Physicians can help in this regard when prescribing by making note in the medical record of the indication for each medication they prescribe.)

Evaluate the patient’s signs and symptoms as a possible drug-related adverse effect, thus making an effort to minimize the chance of a prescribing cascade.⁹

Use Beers criteria,¹⁰ which list potentially inappropriate medications to be avoided in older adults. The criteria serve as a filter when considering starting a new medication and aiding in the review process.⁸

Continue to: The NO TEARS tool...

The NO TEARS tool¹¹ can be useful for simplifying the medication review process. Components of this tool are:

• Need and indication: Does the patient still require each of his medications? Was long-term treatment anticipated?
• Open questions: Ask the patient for his views about his medications; for example, “Do you think the drugs you take work?”
• Tests and monitoring: Are any of the patient’s conditions undertreated, based on laboratory and clinical findings?
• Evidence and guidelines: Has the base of evidence been updated for each of the patient’s medications since they were started?
• Adverse events: Is the patient experiencing adverse effects of medication? Have possible adverse drug interactions been noted?
• Risk reduction or prevention: Does the patient face risks of treatment (eg, loss of appetite, urinary incontinence) that can be reduced by optimizing the medication plan?
• Simplification and switches: Can treatment be simplified while maintaining effectiveness?

There are strategies to promote patient advocacy, as well. Encourage patients to use a holistic approach by asking you, their other physicians, and their pharmacist about how their condition is being treated:

• What other treatment options exist, including nonpharmacotherapeutic options?
• What are the possible benefits and harms of medical therapy?
• Under what circumstances would discontinuing a medication be appropriate?¹²

CASE

Medication reconciliation identifies > 20 medications that had been prescribed for the patient to take at home (TABLE 1). A clinical pharmacist then performs a home medication review as part of routine patient care upon transition of care into the hospital.

Identifying polypharmacy

Implementing polypharmacy identification tools is a necessary first step in the process of mitigating the risk of multiple concurrent medications (TABLE 2^2,10,12-18). In addition to tools that are used to identify polypharmacy, there are steps that physicians and pharmacists can take to decrease the risk of polypharmacy.

Get patients to collaborate on deprescribing by having them bring all medications to appointments and hospital admissions—the actual supply, not just a list.

For example, in a longitudinal, time-series cohort study measuring polypharmacy events, a pharmacist intervention was used as the means to decrease polypharmacy.¹⁹ Pharmacists intervened twice (each intervention separated by 1 year) to identify and manage 5 categories of high-risk drugs in patients whose care was provided by a managed care plan.¹⁹ During that time, pharmacists provided drug therapy reviews, education to physicians and patients about drug safety, and information for physicians on ways to correct problems with polypharmacy.¹⁹

Continue to: Over the course of the 2 interventions...

Over the course of the 2 interventions, the overall rate of polypharmacy events decreased 67% after the first intervention and 39% after the second. The practice of having pharmacists spearhead this task was shown to reduce the cost and number of prescriptions in patients at risk for polypharmacy. (In fact, some general practitioners report that they deem multidisciplinary decision-making with pharmacists a necessary component of managing polypharmacy effectively.⁶)

Screening for medications as a cause of signs and symptoms

As noted earlier, a prescribing cascade arises when a drug administered to a patient causes an adverse event that is then mistakenly identified as a new condition, resulting in a new medication being prescribed.⁹ The pattern of a cascade then repeats itself, resulting in inappropriate polypharmacy.

Erroneous treatment of an adverse drug event as a medical condition is often the result of a lack of pharmacologic knowledge—which is why it is necessary to evaluate each new symptom with the mindset that a medication might, in fact, be causing the sign or symptom and with the aim of reducing the risk of a prescribing cascade.^8,9 Routinely update a patient’s medication list in the event that a medication no longer has an indication aligned with the patient’s problem list; then, ideally, the initial therapy can be adjusted instead of starting additional medications.⁹

CASE

A review of Mr. W’s home medications reveals 1 therapeutic duplication and 2 drugs that lacked an indication. Application of the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP)¹⁵ and Beers criteria¹⁰ helped the pharmacist identify additional elements of inappropriate polypharmacy, including inappropriate medication use, drug–disease interactions, contraindications, and recommendations for dosage adjustment based on kidney function. Specifically:

• Aripiprazole and quetiapine: Present an increased risk of falls. (General recommendation: Avoid using Frutiger LT Std≥ 3 drugs that act on the central nervous system [CNS], due to an increased risk of falls.)
• Fluoxetine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Gabapentin: Presents an increased risk of CNS adverse effects. Reduce the dosage when the estimated creatinine clearance is < 60 mL/min.
• Hydrocodone–acetaminophen: Presents an increased risk of falls. (Again, avoid or minimize the number of drugs that act on the CNS.)
• Lorazepam: Indication is missing. Avoid use of this drug due to an increased risk of cognitive impairment and decreased metabolism of medication.
• Mirtazapine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Pantoprazole: Avoid scheduled use for > 8 weeks, except in high-risk patients, due to the risk of Clostridium difficile infection and bone loss and fractures.
• Prazosin: Indication is missing. Avoid use of this drug as an antihypertensive due to the high risk of orthostatic hypotension.
• Ranitidine: Duplicates concurrent treatment with pantoprazole. Reduce the dosage when the estimated creatinine clearance is < 50 mL/min.

The value of deprescribing

Direct evidence of the efficacy and safety of deprescribing, and strategies for deprescribing, have been documented in the literature:

Observational study. Cessation of inappropriate antihypertensive agents was associated with fewer cardiovascular events and deaths over a 5-year follow-up period.²⁰

Continue to: Deprescribing protocol

Deprescribing protocol. A method developed by Scott and co-workers²¹ is an additional resource to consider. Appropriate times to consider deprescribing are (1) when new symptoms suggest an adverse drug effect; (2) in the presence of end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all care; (3) upon receipt of high-risk medications or combinations; and (4) upon receipt of preventive medications for which risk outweighs benefit.²¹

Assess every new symptom as a potential adverse effect of a current therapy to reduce the risk of a prescribing cascade.

This suggested method of deprescribing comprises several steps: (1) collecting all medications that the patient is taking and identifying the indication for each; (2) considering the overall risk of drug-induced harm to determine necessary intensity of deprescribing; (3) assessing each drug for its eligibility to be discontinued, such as no indication, part of a prescribing cascade, or lack of benefit; (4) prioritizing drugs for discontinuation; and (5) implementing and monitoring the drug discontinuation regimen.²¹

Drug-by-drug elimination trial. Reducing the dosage of, or stopping, only 1 medication at a time has been shown to be paramount to assessing development of medication-associated problems and then identifying a likely cause.¹⁴

Reduce the dosage of, or stop, only 1 medication at a time to best assess the development of medication-associated problems.

Good Palliative-Geriatric Practice algorithm. This algorithm²² can be used to guide discontinuation of inappropriate medications and improve drug therapy in community-dwelling older adults. The algorithm has been shown to improve the overall well-being of patients studied; however, it has been tested only in patients in long-term care settings and community-dwelling palliative care ­patients, limiting its generalizability to a larger population. The algorithm is also difficult to apply to patients who have multiple comorbidities.

Risks of discontinuing chronic medication might outweigh benefit. Consider those risks before removing or reducing a medication.

Risk vs. benefit of discontinuing chronic medical therapy. A systematic review of the effects of discontinuing chronic medication reveals that the risk of doing so might outweigh benefit¹⁴; this finding is thought to be due to potential relapse in the disease state being treated.¹¹ The risks of discontinuation should be contemplated before removing the medication or reducing the dosage. Medications that can be considered to present a risk when discontinued include, but are not limited to, benzodiazepines, oral corticosteroids, antidepressants, acid suppressants, bisphosphonates, statins, and transdermal opioids.¹

Continue to: CASE

CASE

After applying Beers criteria¹⁰ and STOPP¹⁵, the pharmacist makes several recommendations:

• Use aripiprazole and quetiapine with caution.
• Consider discontinuing fluoxetine, hydrocodone–acetaminophen, lorazepam, pantoprazole, and ranitidine.
• Reduce the dosage of gabapentin.
• Clarify the indication for prazosin. Consider discontinuing if being used as an antihypertensive.

In addition, the pharmacist recommends holding metformin because lactic acidosis can develop (however rarely) when a person taking metformin experiences acute kidney injury.

CORRESPONDENCE
Tracy Mahvan, PharmD, BCGP, University of Wyoming, School of Pharmacy, 1000 East University Avenue, Laramie, WY 82071; tbaher@uwyo.edu

CASE

Ronald W^a is a 74-year old man with an extensive medical history: diabetes, hypertension, heart failure, atrial fibrillation, pancreatitis, hyperlipidemia, gout, depression, generalized anxiety, obstructive sleep apnea, and benign prostatic hypertrophy. He arrives at the emergency department (ED) of the hospital by nonemergent ambulance from home for evaluation of lethargy and confusion over the past week.

In the ED, Mr. W is afebrile, normotensive, and oxygenating on room air. Mucous membranes are dry. On physical examination, he appears pale, fatigued, and modestly confused but is able to state his name and birthday, although not the location or date.

Laboratory testing reveals: blood glucose, 107 mg/dL; serum creatinine, 2.3 mg/dL; sodium, 127 mEq/L; and hemoglobin level and hematocrit, within normal limits. Urinalysis is negative. Renal ultrasonography is unremarkable, without evidence of urinary tract obstruction.

Mr. W is admitted to the general medical unit with hyponatremia. The pharmacy admission specialist begins reconciliation of the long list of the patient’s home medications.

Overprescribing: Often, more is not better

Some experts consider prescribing medication to be the most common form of medical intervention; beyond that, polypharmacy—often defined as the use of more medications than are medically necessary (see the next section on terminology)—is recognized as an increasingly serious problem in many medical specialties.¹ Here are specifics about the extent of, and harm caused by, the problem^2,3:

• The US General Accounting Office reports that inappropriate polypharmacy is associated with significant morbidity and mortality.² Research has established a strong relationship between polypharmacy and harmful clinical consequences,³ to which the older patient population is most susceptible.  
• Polypharmacy is also recognized as an expensive practice; the US Center for Medicare and Medicaid Services estimates that polypharmacy cost US health insurers more than $50 billion annually.²
• Worldwide, with more and more people older than 65 years, polypharmacy is becoming more prevalent, and a growing concern, in older adults; approximately 50% of them take ≥ 1 medications that are medically unnecessary.³

Despite many programs to help with deprescribing, drug–drug interactions and the so-called prescribing cascade (ie, when signs and symptoms of an adverse drug effect are misdiagnosed as a new medical condition) continue to affect patients, leading to comorbidities. It is important, therefore, for physicians to be aware of commonly used tools to prevent polypharmacy and its consequences.

What is “polypharmacy” understood to mean?

Despite the compelling association of polypharmacy with the presence of multiple morbidities in the older patient population, there is no consensus on its definition:

• Starting with the dictionary, “polypharmacy” derives from 2 words in Ancient Greek: poly, “more than one,” and “pharmakon, “drug.”³
• The definition can vary based on the number of drugs a patient has been prescribed, their safety, and the appropriateness of their use.¹
• Another definition is the use of more medications than are medically necessary; such a grouping includes agents that are not indicated, are ineffective, or constitute a therapeutic duplication. Although this definition is more clinically relevant than the others, it is premised on undertaking a clinical review of a medication regimen.³
• A numerical definition is the most commonly reported category, a number that varies from study to study—from ≥ 2 to ≥ 11 medications. When applied to health care settings, accepted definitions are ≥ 5 medications at hospital discharge and ≥ 10 during a hospital stay.⁴ Numerical definitions of polypharmacy do not ascertain the clinical appropriateness of therapy nor the process of rationalizing those medications.¹

^aA composite, hypothetical patient, based on the authors' clinical experience.

Continue to: Appropriateness

Appropriateness

Polypharmacy is classified as appropriate or inappropriate:

• Appropriate polypharmacy is the optimization of medications for patients with complex or multiple conditions, when the use of medicine is in agreement with best evidence.
• Inappropriate polypharmacy can increase the risk of adverse drug effects and drug–drug interactions and can be characterized by medication underuse and duplication.⁴

There are subdefinitions of “appropriateness,” but these are beyond the scope of this article.

What variables contribute to polypharmacy?

Polypharmacy is not only medically unnecessary; it also causes significant morbidity and mortality and is expensive.

Multimorbidity is common in the older population. The presence of multiple chronic conditions increases the complexity of therapeutic management for health professionals and patients; such complexity can have a harmful impact on health outcomes. Combinations of medications to treat chronic diseases automatically push many patients into polypharmacy. Few treatment guidelines provide recommendations on when to stop medications.

Consequences of polypharmacy, some of which are masked as syndromes in the older patient, include delirium and dementia, urinary incontinence, dizziness, falls, adverse drug reactions, increased length of hospital stay, readmission soon after discharge, and death.^3-5 Relatively high rates of drug consumption and other variables (eg, decreased renal and hepatic function, decreased total body water and lean body mass, cognitive impairment, age-related decline in vision and hearing, frequency of chronic diseases and medical comorbidities, communication barriers, prescribing cascades, and health care delivery involving multiple prescribers) can contribute to an increased prevalence of medication-associated morbidity and mortality as the result of polypharmacy.

In a descriptive study⁶ that examined these variables, researchers explored whether general practitioners experience barriers to medication review in multimorbid patients with polypharmacy. They concluded that the primary barriers were (1) lack of communication and teamwork with specialists and (2) the challenge of handling polypharmacy in a culture that encourages adding medications and inhibits conversations about medication withdrawal.⁶

Continue to: Reducing consequences of polypharmacy

 

 

Reducing consequences of polypharmacy

Collaborative medication review

Interventions to help physicians reduce polypharmacy include reviewing medications with older patients at every office visit and during transitions of care into and out of the hospital or other care facility. A 2016 Cochrane review of 5 randomized trials of inpatient medication reviews led by pharmacists, physicians, and other health care professionals showed a 36% reduction in ED visits 30 days to 1 year after discharge.⁷

Consequences of polypharmacy can be masked as syndromes in older patients—eg, delirium, urinary incontinence, dizziness.

Patients can collaborate in this effort by bringing all medications to each appointment or upon hospital admission—not just a list but the actual supply, to ensure that a correct medication list is compiled and a thorough review conducted.⁸ Explicitly ask open-ended questions of the patient about over-the-counter medications, herbal products, and other home remedies that have not been prescribed; many patients may have trouble with recall or are uncertain what fits the definition of a nonprescription medication.^8,9

Compare the medication list with the patient’s current problem list; consider removing medications that do not have a pertinent indication. (Physicians can help in this regard when prescribing by making note in the medical record of the indication for each medication they prescribe.)

Evaluate the patient’s signs and symptoms as a possible drug-related adverse effect, thus making an effort to minimize the chance of a prescribing cascade.⁹

Use Beers criteria,¹⁰ which list potentially inappropriate medications to be avoided in older adults. The criteria serve as a filter when considering starting a new medication and aiding in the review process.⁸

Continue to: The NO TEARS tool...

The NO TEARS tool¹¹ can be useful for simplifying the medication review process. Components of this tool are:

• Need and indication: Does the patient still require each of his medications? Was long-term treatment anticipated?
• Open questions: Ask the patient for his views about his medications; for example, “Do you think the drugs you take work?”
• Tests and monitoring: Are any of the patient’s conditions undertreated, based on laboratory and clinical findings?
• Evidence and guidelines: Has the base of evidence been updated for each of the patient’s medications since they were started?
• Adverse events: Is the patient experiencing adverse effects of medication? Have possible adverse drug interactions been noted?
• Risk reduction or prevention: Does the patient face risks of treatment (eg, loss of appetite, urinary incontinence) that can be reduced by optimizing the medication plan?
• Simplification and switches: Can treatment be simplified while maintaining effectiveness?

There are strategies to promote patient advocacy, as well. Encourage patients to use a holistic approach by asking you, their other physicians, and their pharmacist about how their condition is being treated:

• What other treatment options exist, including nonpharmacotherapeutic options?
• What are the possible benefits and harms of medical therapy?
• Under what circumstances would discontinuing a medication be appropriate?¹²

CASE

Medication reconciliation identifies > 20 medications that had been prescribed for the patient to take at home (TABLE 1). A clinical pharmacist then performs a home medication review as part of routine patient care upon transition of care into the hospital.

Identifying polypharmacy

Implementing polypharmacy identification tools is a necessary first step in the process of mitigating the risk of multiple concurrent medications (TABLE 2^2,10,12-18). In addition to tools that are used to identify polypharmacy, there are steps that physicians and pharmacists can take to decrease the risk of polypharmacy.

Get patients to collaborate on deprescribing by having them bring all medications to appointments and hospital admissions—the actual supply, not just a list.

For example, in a longitudinal, time-series cohort study measuring polypharmacy events, a pharmacist intervention was used as the means to decrease polypharmacy.¹⁹ Pharmacists intervened twice (each intervention separated by 1 year) to identify and manage 5 categories of high-risk drugs in patients whose care was provided by a managed care plan.¹⁹ During that time, pharmacists provided drug therapy reviews, education to physicians and patients about drug safety, and information for physicians on ways to correct problems with polypharmacy.¹⁹

Continue to: Over the course of the 2 interventions...

Over the course of the 2 interventions, the overall rate of polypharmacy events decreased 67% after the first intervention and 39% after the second. The practice of having pharmacists spearhead this task was shown to reduce the cost and number of prescriptions in patients at risk for polypharmacy. (In fact, some general practitioners report that they deem multidisciplinary decision-making with pharmacists a necessary component of managing polypharmacy effectively.⁶)

Screening for medications as a cause of signs and symptoms

As noted earlier, a prescribing cascade arises when a drug administered to a patient causes an adverse event that is then mistakenly identified as a new condition, resulting in a new medication being prescribed.⁹ The pattern of a cascade then repeats itself, resulting in inappropriate polypharmacy.

Erroneous treatment of an adverse drug event as a medical condition is often the result of a lack of pharmacologic knowledge—which is why it is necessary to evaluate each new symptom with the mindset that a medication might, in fact, be causing the sign or symptom and with the aim of reducing the risk of a prescribing cascade.^8,9 Routinely update a patient’s medication list in the event that a medication no longer has an indication aligned with the patient’s problem list; then, ideally, the initial therapy can be adjusted instead of starting additional medications.⁹

CASE

A review of Mr. W’s home medications reveals 1 therapeutic duplication and 2 drugs that lacked an indication. Application of the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP)¹⁵ and Beers criteria¹⁰ helped the pharmacist identify additional elements of inappropriate polypharmacy, including inappropriate medication use, drug–disease interactions, contraindications, and recommendations for dosage adjustment based on kidney function. Specifically:

• Aripiprazole and quetiapine: Present an increased risk of falls. (General recommendation: Avoid using Frutiger LT Std≥ 3 drugs that act on the central nervous system [CNS], due to an increased risk of falls.)
• Fluoxetine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Gabapentin: Presents an increased risk of CNS adverse effects. Reduce the dosage when the estimated creatinine clearance is < 60 mL/min.
• Hydrocodone–acetaminophen: Presents an increased risk of falls. (Again, avoid or minimize the number of drugs that act on the CNS.)
• Lorazepam: Indication is missing. Avoid use of this drug due to an increased risk of cognitive impairment and decreased metabolism of medication.
• Mirtazapine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Pantoprazole: Avoid scheduled use for > 8 weeks, except in high-risk patients, due to the risk of Clostridium difficile infection and bone loss and fractures.
• Prazosin: Indication is missing. Avoid use of this drug as an antihypertensive due to the high risk of orthostatic hypotension.
• Ranitidine: Duplicates concurrent treatment with pantoprazole. Reduce the dosage when the estimated creatinine clearance is < 50 mL/min.

The value of deprescribing

Direct evidence of the efficacy and safety of deprescribing, and strategies for deprescribing, have been documented in the literature:

Observational study. Cessation of inappropriate antihypertensive agents was associated with fewer cardiovascular events and deaths over a 5-year follow-up period.²⁰

Continue to: Deprescribing protocol

Deprescribing protocol. A method developed by Scott and co-workers²¹ is an additional resource to consider. Appropriate times to consider deprescribing are (1) when new symptoms suggest an adverse drug effect; (2) in the presence of end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all care; (3) upon receipt of high-risk medications or combinations; and (4) upon receipt of preventive medications for which risk outweighs benefit.²¹

Assess every new symptom as a potential adverse effect of a current therapy to reduce the risk of a prescribing cascade.

This suggested method of deprescribing comprises several steps: (1) collecting all medications that the patient is taking and identifying the indication for each; (2) considering the overall risk of drug-induced harm to determine necessary intensity of deprescribing; (3) assessing each drug for its eligibility to be discontinued, such as no indication, part of a prescribing cascade, or lack of benefit; (4) prioritizing drugs for discontinuation; and (5) implementing and monitoring the drug discontinuation regimen.²¹

Drug-by-drug elimination trial. Reducing the dosage of, or stopping, only 1 medication at a time has been shown to be paramount to assessing development of medication-associated problems and then identifying a likely cause.¹⁴

Reduce the dosage of, or stop, only 1 medication at a time to best assess the development of medication-associated problems.

Good Palliative-Geriatric Practice algorithm. This algorithm²² can be used to guide discontinuation of inappropriate medications and improve drug therapy in community-dwelling older adults. The algorithm has been shown to improve the overall well-being of patients studied; however, it has been tested only in patients in long-term care settings and community-dwelling palliative care ­patients, limiting its generalizability to a larger population. The algorithm is also difficult to apply to patients who have multiple comorbidities.

Risks of discontinuing chronic medication might outweigh benefit. Consider those risks before removing or reducing a medication.

Risk vs. benefit of discontinuing chronic medical therapy. A systematic review of the effects of discontinuing chronic medication reveals that the risk of doing so might outweigh benefit¹⁴; this finding is thought to be due to potential relapse in the disease state being treated.¹¹ The risks of discontinuation should be contemplated before removing the medication or reducing the dosage. Medications that can be considered to present a risk when discontinued include, but are not limited to, benzodiazepines, oral corticosteroids, antidepressants, acid suppressants, bisphosphonates, statins, and transdermal opioids.¹

Continue to: CASE

CASE

After applying Beers criteria¹⁰ and STOPP¹⁵, the pharmacist makes several recommendations:

• Use aripiprazole and quetiapine with caution.
• Consider discontinuing fluoxetine, hydrocodone–acetaminophen, lorazepam, pantoprazole, and ranitidine.
• Reduce the dosage of gabapentin.
• Clarify the indication for prazosin. Consider discontinuing if being used as an antihypertensive.

In addition, the pharmacist recommends holding metformin because lactic acidosis can develop (however rarely) when a person taking metformin experiences acute kidney injury.

CORRESPONDENCE
Tracy Mahvan, PharmD, BCGP, University of Wyoming, School of Pharmacy, 1000 East University Avenue, Laramie, WY 82071; tbaher@uwyo.edu

CASE

Ronald W^a is a 74-year old man with an extensive medical history: diabetes, hypertension, heart failure, atrial fibrillation, pancreatitis, hyperlipidemia, gout, depression, generalized anxiety, obstructive sleep apnea, and benign prostatic hypertrophy. He arrives at the emergency department (ED) of the hospital by nonemergent ambulance from home for evaluation of lethargy and confusion over the past week.

In the ED, Mr. W is afebrile, normotensive, and oxygenating on room air. Mucous membranes are dry. On physical examination, he appears pale, fatigued, and modestly confused but is able to state his name and birthday, although not the location or date.

Laboratory testing reveals: blood glucose, 107 mg/dL; serum creatinine, 2.3 mg/dL; sodium, 127 mEq/L; and hemoglobin level and hematocrit, within normal limits. Urinalysis is negative. Renal ultrasonography is unremarkable, without evidence of urinary tract obstruction.

Mr. W is admitted to the general medical unit with hyponatremia. The pharmacy admission specialist begins reconciliation of the long list of the patient’s home medications.

Overprescribing: Often, more is not better

Some experts consider prescribing medication to be the most common form of medical intervention; beyond that, polypharmacy—often defined as the use of more medications than are medically necessary (see the next section on terminology)—is recognized as an increasingly serious problem in many medical specialties.¹ Here are specifics about the extent of, and harm caused by, the problem^2,3:

• The US General Accounting Office reports that inappropriate polypharmacy is associated with significant morbidity and mortality.² Research has established a strong relationship between polypharmacy and harmful clinical consequences,³ to which the older patient population is most susceptible.  
• Polypharmacy is also recognized as an expensive practice; the US Center for Medicare and Medicaid Services estimates that polypharmacy cost US health insurers more than $50 billion annually.²
• Worldwide, with more and more people older than 65 years, polypharmacy is becoming more prevalent, and a growing concern, in older adults; approximately 50% of them take ≥ 1 medications that are medically unnecessary.³

Despite many programs to help with deprescribing, drug–drug interactions and the so-called prescribing cascade (ie, when signs and symptoms of an adverse drug effect are misdiagnosed as a new medical condition) continue to affect patients, leading to comorbidities. It is important, therefore, for physicians to be aware of commonly used tools to prevent polypharmacy and its consequences.

What is “polypharmacy” understood to mean?

Despite the compelling association of polypharmacy with the presence of multiple morbidities in the older patient population, there is no consensus on its definition:

• Starting with the dictionary, “polypharmacy” derives from 2 words in Ancient Greek: poly, “more than one,” and “pharmakon, “drug.”³
• The definition can vary based on the number of drugs a patient has been prescribed, their safety, and the appropriateness of their use.¹
• Another definition is the use of more medications than are medically necessary; such a grouping includes agents that are not indicated, are ineffective, or constitute a therapeutic duplication. Although this definition is more clinically relevant than the others, it is premised on undertaking a clinical review of a medication regimen.³
• A numerical definition is the most commonly reported category, a number that varies from study to study—from ≥ 2 to ≥ 11 medications. When applied to health care settings, accepted definitions are ≥ 5 medications at hospital discharge and ≥ 10 during a hospital stay.⁴ Numerical definitions of polypharmacy do not ascertain the clinical appropriateness of therapy nor the process of rationalizing those medications.¹

^aA composite, hypothetical patient, based on the authors' clinical experience.

Continue to: Appropriateness

Appropriateness

Polypharmacy is classified as appropriate or inappropriate:

• Appropriate polypharmacy is the optimization of medications for patients with complex or multiple conditions, when the use of medicine is in agreement with best evidence.
• Inappropriate polypharmacy can increase the risk of adverse drug effects and drug–drug interactions and can be characterized by medication underuse and duplication.⁴

There are subdefinitions of “appropriateness,” but these are beyond the scope of this article.

What variables contribute to polypharmacy?

Polypharmacy is not only medically unnecessary; it also causes significant morbidity and mortality and is expensive.

Multimorbidity is common in the older population. The presence of multiple chronic conditions increases the complexity of therapeutic management for health professionals and patients; such complexity can have a harmful impact on health outcomes. Combinations of medications to treat chronic diseases automatically push many patients into polypharmacy. Few treatment guidelines provide recommendations on when to stop medications.

Consequences of polypharmacy, some of which are masked as syndromes in the older patient, include delirium and dementia, urinary incontinence, dizziness, falls, adverse drug reactions, increased length of hospital stay, readmission soon after discharge, and death.^3-5 Relatively high rates of drug consumption and other variables (eg, decreased renal and hepatic function, decreased total body water and lean body mass, cognitive impairment, age-related decline in vision and hearing, frequency of chronic diseases and medical comorbidities, communication barriers, prescribing cascades, and health care delivery involving multiple prescribers) can contribute to an increased prevalence of medication-associated morbidity and mortality as the result of polypharmacy.

In a descriptive study⁶ that examined these variables, researchers explored whether general practitioners experience barriers to medication review in multimorbid patients with polypharmacy. They concluded that the primary barriers were (1) lack of communication and teamwork with specialists and (2) the challenge of handling polypharmacy in a culture that encourages adding medications and inhibits conversations about medication withdrawal.⁶

Continue to: Reducing consequences of polypharmacy

 

 

Reducing consequences of polypharmacy

Collaborative medication review

Interventions to help physicians reduce polypharmacy include reviewing medications with older patients at every office visit and during transitions of care into and out of the hospital or other care facility. A 2016 Cochrane review of 5 randomized trials of inpatient medication reviews led by pharmacists, physicians, and other health care professionals showed a 36% reduction in ED visits 30 days to 1 year after discharge.⁷

Consequences of polypharmacy can be masked as syndromes in older patients—eg, delirium, urinary incontinence, dizziness.

Patients can collaborate in this effort by bringing all medications to each appointment or upon hospital admission—not just a list but the actual supply, to ensure that a correct medication list is compiled and a thorough review conducted.⁸ Explicitly ask open-ended questions of the patient about over-the-counter medications, herbal products, and other home remedies that have not been prescribed; many patients may have trouble with recall or are uncertain what fits the definition of a nonprescription medication.^8,9

Compare the medication list with the patient’s current problem list; consider removing medications that do not have a pertinent indication. (Physicians can help in this regard when prescribing by making note in the medical record of the indication for each medication they prescribe.)

Evaluate the patient’s signs and symptoms as a possible drug-related adverse effect, thus making an effort to minimize the chance of a prescribing cascade.⁹

Use Beers criteria,¹⁰ which list potentially inappropriate medications to be avoided in older adults. The criteria serve as a filter when considering starting a new medication and aiding in the review process.⁸

Continue to: The NO TEARS tool...

The NO TEARS tool¹¹ can be useful for simplifying the medication review process. Components of this tool are:

• Need and indication: Does the patient still require each of his medications? Was long-term treatment anticipated?
• Open questions: Ask the patient for his views about his medications; for example, “Do you think the drugs you take work?”
• Tests and monitoring: Are any of the patient’s conditions undertreated, based on laboratory and clinical findings?
• Evidence and guidelines: Has the base of evidence been updated for each of the patient’s medications since they were started?
• Adverse events: Is the patient experiencing adverse effects of medication? Have possible adverse drug interactions been noted?
• Risk reduction or prevention: Does the patient face risks of treatment (eg, loss of appetite, urinary incontinence) that can be reduced by optimizing the medication plan?
• Simplification and switches: Can treatment be simplified while maintaining effectiveness?

There are strategies to promote patient advocacy, as well. Encourage patients to use a holistic approach by asking you, their other physicians, and their pharmacist about how their condition is being treated:

• What other treatment options exist, including nonpharmacotherapeutic options?
• What are the possible benefits and harms of medical therapy?
• Under what circumstances would discontinuing a medication be appropriate?¹²

CASE

Medication reconciliation identifies > 20 medications that had been prescribed for the patient to take at home (TABLE 1). A clinical pharmacist then performs a home medication review as part of routine patient care upon transition of care into the hospital.

Identifying polypharmacy

Implementing polypharmacy identification tools is a necessary first step in the process of mitigating the risk of multiple concurrent medications (TABLE 2^2,10,12-18). In addition to tools that are used to identify polypharmacy, there are steps that physicians and pharmacists can take to decrease the risk of polypharmacy.

Get patients to collaborate on deprescribing by having them bring all medications to appointments and hospital admissions—the actual supply, not just a list.

For example, in a longitudinal, time-series cohort study measuring polypharmacy events, a pharmacist intervention was used as the means to decrease polypharmacy.¹⁹ Pharmacists intervened twice (each intervention separated by 1 year) to identify and manage 5 categories of high-risk drugs in patients whose care was provided by a managed care plan.¹⁹ During that time, pharmacists provided drug therapy reviews, education to physicians and patients about drug safety, and information for physicians on ways to correct problems with polypharmacy.¹⁹

Continue to: Over the course of the 2 interventions...

Over the course of the 2 interventions, the overall rate of polypharmacy events decreased 67% after the first intervention and 39% after the second. The practice of having pharmacists spearhead this task was shown to reduce the cost and number of prescriptions in patients at risk for polypharmacy. (In fact, some general practitioners report that they deem multidisciplinary decision-making with pharmacists a necessary component of managing polypharmacy effectively.⁶)

Screening for medications as a cause of signs and symptoms

As noted earlier, a prescribing cascade arises when a drug administered to a patient causes an adverse event that is then mistakenly identified as a new condition, resulting in a new medication being prescribed.⁹ The pattern of a cascade then repeats itself, resulting in inappropriate polypharmacy.

Erroneous treatment of an adverse drug event as a medical condition is often the result of a lack of pharmacologic knowledge—which is why it is necessary to evaluate each new symptom with the mindset that a medication might, in fact, be causing the sign or symptom and with the aim of reducing the risk of a prescribing cascade.^8,9 Routinely update a patient’s medication list in the event that a medication no longer has an indication aligned with the patient’s problem list; then, ideally, the initial therapy can be adjusted instead of starting additional medications.⁹

CASE

A review of Mr. W’s home medications reveals 1 therapeutic duplication and 2 drugs that lacked an indication. Application of the Screening Tool of Older Persons’ potentially inappropriate Prescriptions (STOPP)¹⁵ and Beers criteria¹⁰ helped the pharmacist identify additional elements of inappropriate polypharmacy, including inappropriate medication use, drug–disease interactions, contraindications, and recommendations for dosage adjustment based on kidney function. Specifically:

• Aripiprazole and quetiapine: Present an increased risk of falls. (General recommendation: Avoid using Frutiger LT Std≥ 3 drugs that act on the central nervous system [CNS], due to an increased risk of falls.)
• Fluoxetine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Gabapentin: Presents an increased risk of CNS adverse effects. Reduce the dosage when the estimated creatinine clearance is < 60 mL/min.
• Hydrocodone–acetaminophen: Presents an increased risk of falls. (Again, avoid or minimize the number of drugs that act on the CNS.)
• Lorazepam: Indication is missing. Avoid use of this drug due to an increased risk of cognitive impairment and decreased metabolism of medication.
• Mirtazapine: Can cause the syndrome of inappropriate secretion of antidiuretic hormone. Use with caution.
• Pantoprazole: Avoid scheduled use for > 8 weeks, except in high-risk patients, due to the risk of Clostridium difficile infection and bone loss and fractures.
• Prazosin: Indication is missing. Avoid use of this drug as an antihypertensive due to the high risk of orthostatic hypotension.
• Ranitidine: Duplicates concurrent treatment with pantoprazole. Reduce the dosage when the estimated creatinine clearance is < 50 mL/min.

The value of deprescribing

Direct evidence of the efficacy and safety of deprescribing, and strategies for deprescribing, have been documented in the literature:

Observational study. Cessation of inappropriate antihypertensive agents was associated with fewer cardiovascular events and deaths over a 5-year follow-up period.²⁰

Continue to: Deprescribing protocol

Deprescribing protocol. A method developed by Scott and co-workers²¹ is an additional resource to consider. Appropriate times to consider deprescribing are (1) when new symptoms suggest an adverse drug effect; (2) in the presence of end-stage disease, terminal illness, dementia, extreme frailty, or full dependence on others for all care; (3) upon receipt of high-risk medications or combinations; and (4) upon receipt of preventive medications for which risk outweighs benefit.²¹

Assess every new symptom as a potential adverse effect of a current therapy to reduce the risk of a prescribing cascade.

This suggested method of deprescribing comprises several steps: (1) collecting all medications that the patient is taking and identifying the indication for each; (2) considering the overall risk of drug-induced harm to determine necessary intensity of deprescribing; (3) assessing each drug for its eligibility to be discontinued, such as no indication, part of a prescribing cascade, or lack of benefit; (4) prioritizing drugs for discontinuation; and (5) implementing and monitoring the drug discontinuation regimen.²¹

Drug-by-drug elimination trial. Reducing the dosage of, or stopping, only 1 medication at a time has been shown to be paramount to assessing development of medication-associated problems and then identifying a likely cause.¹⁴

Reduce the dosage of, or stop, only 1 medication at a time to best assess the development of medication-associated problems.

Good Palliative-Geriatric Practice algorithm. This algorithm²² can be used to guide discontinuation of inappropriate medications and improve drug therapy in community-dwelling older adults. The algorithm has been shown to improve the overall well-being of patients studied; however, it has been tested only in patients in long-term care settings and community-dwelling palliative care ­patients, limiting its generalizability to a larger population. The algorithm is also difficult to apply to patients who have multiple comorbidities.

Risks of discontinuing chronic medication might outweigh benefit. Consider those risks before removing or reducing a medication.

Risk vs. benefit of discontinuing chronic medical therapy. A systematic review of the effects of discontinuing chronic medication reveals that the risk of doing so might outweigh benefit¹⁴; this finding is thought to be due to potential relapse in the disease state being treated.¹¹ The risks of discontinuation should be contemplated before removing the medication or reducing the dosage. Medications that can be considered to present a risk when discontinued include, but are not limited to, benzodiazepines, oral corticosteroids, antidepressants, acid suppressants, bisphosphonates, statins, and transdermal opioids.¹

Continue to: CASE

CASE

After applying Beers criteria¹⁰ and STOPP¹⁵, the pharmacist makes several recommendations:

• Use aripiprazole and quetiapine with caution.
• Consider discontinuing fluoxetine, hydrocodone–acetaminophen, lorazepam, pantoprazole, and ranitidine.
• Reduce the dosage of gabapentin.
• Clarify the indication for prazosin. Consider discontinuing if being used as an antihypertensive.

In addition, the pharmacist recommends holding metformin because lactic acidosis can develop (however rarely) when a person taking metformin experiences acute kidney injury.

CORRESPONDENCE
Tracy Mahvan, PharmD, BCGP, University of Wyoming, School of Pharmacy, 1000 East University Avenue, Laramie, WY 82071; tbaher@uwyo.edu

ANSWER

The correct interpretation is atrial fibrillation with aberrantly conducted complexes. The lead I rhythm strip at the bottom of the ECG shows the irregularly irregular rate. There are narrow complexes (see beats 3-7 and 16-18), indicating normal conduction through the atrioventricular node and His-Purkinje system. The remainder of the complexes are wide and aberrantly conducted and are in the same vector as the normally conducted (narrow) complexes.

An important take-away from this case: The computer reading includes a PR interval as well as a QRS duration of 88 ms. There is no PR interval in atrial fibrillation—highlighting the importance of reading the ECG and not relying on the computer’s interpretation. The QRS duration is measured in the normally conducted beats only; it does not include the aberrantly conducted beats.

ANSWER

The correct interpretation is atrial fibrillation with aberrantly conducted complexes. The lead I rhythm strip at the bottom of the ECG shows the irregularly irregular rate. There are narrow complexes (see beats 3-7 and 16-18), indicating normal conduction through the atrioventricular node and His-Purkinje system. The remainder of the complexes are wide and aberrantly conducted and are in the same vector as the normally conducted (narrow) complexes.

An important take-away from this case: The computer reading includes a PR interval as well as a QRS duration of 88 ms. There is no PR interval in atrial fibrillation—highlighting the importance of reading the ECG and not relying on the computer’s interpretation. The QRS duration is measured in the normally conducted beats only; it does not include the aberrantly conducted beats.

ANSWER

The correct interpretation is atrial fibrillation with aberrantly conducted complexes. The lead I rhythm strip at the bottom of the ECG shows the irregularly irregular rate. There are narrow complexes (see beats 3-7 and 16-18), indicating normal conduction through the atrioventricular node and His-Purkinje system. The remainder of the complexes are wide and aberrantly conducted and are in the same vector as the normally conducted (narrow) complexes.

An important take-away from this case: The computer reading includes a PR interval as well as a QRS duration of 88 ms. There is no PR interval in atrial fibrillation—highlighting the importance of reading the ECG and not relying on the computer’s interpretation. The QRS duration is measured in the normally conducted beats only; it does not include the aberrantly conducted beats.

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.

ORLANDO – The burden of osteoporosis and fragility fractures in the United States remains high, particularly in older women and minorities, according to a speaker at the annual meeting of the American Society for Bone and Mineral Research.

For non-Hispanic Asian, non-Hispanic white, and Hispanic patients of various ethnic groups, as well as in women and older patients, osteoporosis and fragility fractures continue to be a problem, said Nicole C. Wright, PhD, MPH, of the department of epidemiology at the University of Alabama at Birmingham.

“It remains costly; it remains associated with more health care utilization,” Dr. Wright said. “We may be seeing some declines in some fragility fractures, but [we] are seeing increases in hip fractures.”

As part of the fourth edition of the U.S. Bone and Joint Initiative publication, “The Burden of Musculoskeletal Diseases in the United States,” Dr. Wright and colleagues examined the changes in osteoporosis burden between the third and fourth editions of the publication. They used data from the National Inpatient Sample (NIS) in 2013 and 2014 as well as the National Emergency Department Sample (NEDS) of national ED visits regardless of hospital admission status. In both databases, researchers analyzed data from adults aged 50 years or older where the primary discharge ICD-9 or ICD-10 code was a diagnosis of fracture.

Using National Health and Nutrition Examination Survey data, the researchers estimated an 11.0% osteoporosis prevalence for adults aged 50 years or older overall, a 16.5% prevalence in women, and a 5.1% prevalence in men as assessed by femoral neck and lumbar spine bone mineral density. Osteoporosis was most prevalent in Asian women (40.0%) and Asian men (7.5%), while there was a difference in prevalence in patients of Hispanic race depending on their origin; for example, Puerto Rican men had a higher prevalence of osteoporosis at 8.6%, compared with Hispanic men (2.3%) and non-Hispanic white men of other races (3.9%).

Of 19.5 million hospitalizations in the NIS database between 2013 and 2014, there were approximately 540,000 fragility fractures (2.8%), of which about 300,000 were hip fractures and about 100,000 discharges were for spine fractures, Dr. Wright said. In the NEDS database, the estimate of fragility fracture prevalence was 0.9% of 46.7 million ED visits between 2013 and 2014. Fracture prevalence was increased in women and in older age, with patients aged 80 years or older and those of non-Hispanic white race having the highest prevalence of hip fracture. However, she noted that NEDS data also showed higher prevalences of wrist and humerus fractures, which are not normally fractures that a patient visits the hospital as an inpatient for. “We need both data sets to ascertain fractures in the United States,” she said.

When examining fracture site trends over time, Dr. Wright and colleagues found hip fracture prevalence increased by 3.5% between 2010 and 2014, while there was a decrease of 11.9% in the prevalence of spine fractures over the same time period.

According to data from the Medical Expenditures Panel Survey, the direct cost of osteoporosis in aggregate was $73.6 billion between 2012 and 2014, which was 118% higher than between 1998 and 2000 when the costs were $28.1 billion. The costs were spread across ambulatory care, inpatient, and prescription costs equally, the researchers said.

Although the study was limited by examining fracture prevalence rather than incidence, the potential for missing some fractures based on methodology, and limited patient characteristics and follow-up information, the goal of the presentation was to highlight the new osteoporosis prevalence data and the continued burden of the disease.

“We hope that these new prevalence estimates continue to increase the awareness of osteoporosis and prevention,” she said.

Dr. Wright reported receiving grants from Amgen and serving as an expert witness for the law firm Norton Rose Fulbright and Pfizer.

SOURCE: Wright NC et al. ASBMR 2019, Abstract 1079.