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The aducanumab revolution
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
Choosing the right R-CHOP dosage for elderly patients with DLBCL
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
FROM BLOOD ADVANCES
FDA approves controversial Alzheimer’s drug aducanumab (Aduhelm)
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
Differences in Palliative Care Delivery Among Adults With Cancer and With Terminal Noncancer Illness in Their Last Year of Life
Study Overview
Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.
Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.
Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).
Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.
Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).
Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.
Commentary
Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.1 Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.2 This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes3; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.
A particular challenge in determining when to initiate palliative care lies in predicting outcomes,4 particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.5 These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.
Applications for Clinical Practice
Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.
1. Kavalieratos D, Corbelli J, Zhang D, et al. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA. 2016;316(20):2104-2114.
2. Quinn KL, Stukel T, Stall NM, et al. Association between palliative care and healthcare outcomes among adults with terminal non-cancer illness: population based matched cohort study. BMJ. 2020;370:m2257.
3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010;363:733-742.
4. White N, Reid F, Harris A, et al. A Systematic Review of Predictions of Survival in Palliative Care: How Accurate Are Clinicians and Who Are the Experts? PLoS One. 2016;11(8):e0161407.
5. Manz CR, Parikh RB, Small DS, et al. Effect of Integrating Machine Learning Mortality Estimates With Behavioral Nudges to Clinicians on Serious Illness Conversations Among Patients With Cancer: A Stepped-Wedge Cluster Randomized Clinical Trial. JAMA Oncol. 2020;6(12):e204759.
Study Overview
Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.
Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.
Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).
Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.
Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).
Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.
Commentary
Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.1 Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.2 This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes3; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.
A particular challenge in determining when to initiate palliative care lies in predicting outcomes,4 particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.5 These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.
Applications for Clinical Practice
Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.
Study Overview
Objective. To examine the patterns in palliative care delivery in the last year of life among adults with cancer compared with adults with a noncancer terminal diagnosis.
Design. Population-based cohort study in Ontario, Canada, using linked administrative and clinical databases. The study included all adults ages 18 and over who died of cancer or noncancer terminal illnesses and received physician-delivered palliative care that was initiated in the last year of life between January 2010 and December 2017. These palliative care services are identified through the use of claims fee codes by physicians that account for delivery of palliative care, such as symptom management and counseling, that are intended to be palliative rather than curative. Exclusion criteria include patients who had 2 or more palliative care service claims the year prior to the last year of life, which may indicate existing palliative care services rather than initiation of new palliative care services in the last year of life. Other patients who were excluded from the study had palliative care services initiated within 7 days of death, as it is less likely that services and support would be arranged prior to death given the short time frame. The types of noncancer illnesses included heart failure, chronic obstructive pulmonary disease, end-stage renal disease, cirrhosis, stroke, and dementia. For the comparison of palliative care services, types of illnesses were divided into cancer, chronic organ failure (heart failure, chronic pulmonary disease, end-stage renal disease, cirrhosis, or stroke), and dementia, as they may represent different trajectories of illnesses and needs.
Setting and participants. The study included 145 709 adults who died during the study period, among 351 941 adults who died from illnesses described above. Another 105 587 were excluded because there were no palliative care services before death, 48 525 were excluded because of existing palliative care services prior to the last year of life, and 44 164 were excluded because palliative care was initiated within 7 days of death. Among the study population included, 21 054 died of chronic organ failure, 14 033 died of dementia, and 110 622 died of cancer. The median age of the study population was 78 years, with an interquartile range of 67 to 86 years, and 50.7% were female. Approximately 12.8% of the study population reside in rural areas; median frailty score (hospital frailty risk score) among those who died of chronic organ failure was 10, and the score among those who died of dementia was 13. The frailty score among those who died of cancer was 3, indicating less frailty. Those who died of organ failure and dementia also had a high mean number of prescription medications (18 and 16, respectively) compared with those with cancer (11).
Main outcome measures. Study outcome measures include the timing of palliative care initiation (primary outcome), categorized into time frames of ≤ 30 days, 31 to 90 days, and > 90 days before death; location of initiation of palliative care services, categorized into clinic, home, hospital, subacute care, and case management; models of care, categorized as generalist, consultative, or specialist palliative care; total number of palliative care visits before death; and location of death. The models of palliative care delivery were categorized based on the proportion of palliative care fee codes claimed by physicians. Physicians whose annual billing included more than 10% of palliative care service codes were considered palliative care specialists. Using this designation, models of palliative care were categorized into those delivered by palliative care specialists, generalists (nonpalliative care specialists), or both.
Main results. The study found that the timing of palliative care initiation was earlier among those who died of cancer compared with those with organ failure or dementia (28.9% vs 15.9% and 15.3%, respectively). After adjustment, those who died of organ failure and those who died of dementia were less likely to have palliative care services initiated > 90 days prior to death (odds ratio [OR] 0.48 and 0.42, respectively) and between 31 to 90 days prior to death (OR 0.77 and 0.60, respectively), when compared with those who died of cancer (who served as the reference group). Regarding location of palliative care initiation, adults who died of cancer were less likely to have palliative care services initiated at home (14.5%) compared with those who died of organ failure (32.8%) or dementia (27.9%). Overall, those who died of cancer received more palliative care visits from initiation to death (median of 11 visits) compared with those who died oforgan failure (median 4 visits) and dementia (median 4 visits). Regarding models of palliative care delivery, a higher proportion of palliative care was delivered by palliative care specialists rather than generalists among cancer patients (72.9%) compared with those with organ failure (43.3%) or dementia (40.1%). The proportion of patients with cancer who died at home was 62.6%, which was higher than those with organ failure (53.3%) but lower than those with dementia (75%).
Conclusion. There are differences in the delivery of palliative care among patients with cancer and other noncancer terminal illnesses, including timing of initiation of palliative care services, location of services, number of visits, and delivery by types of practitioners of palliative care. Understanding these disparities and targeting them are potentially important steps to ensuring appropriate access to palliative care across settings and disease types.
Commentary
Palliative care improves the quality of life of patients with serious illnesses and reduces symptom burden, and results in better satisfaction and less burdensome care.1 Although palliative care approaches have been championed for cancer management, there is increasing evidence that palliative care also improves outcomes for patients with noncancer illnesses such as heart failure.2 This study highlights the differences in palliative care delivery for patients who have cancer and noncancer diagnoses, demonstrating that timing, location, and care delivery models differ among patients with different diagnoses. The finding that noncancer terminal illness often has later palliative care initiation is a significant one, as early palliative care has been associated with improved patient outcomes3; thus, efforts to initiate palliative care earlier in the course of illness may benefit these patients.
A particular challenge in determining when to initiate palliative care lies in predicting outcomes,4 particularly for different types of illnesses, which may have different trajectories of advancing disease and functional change. Recent research has tested novel prognostic approaches, such as using machine learning to generate mortality estimates and integrating them into clinical decision support.5 These approaches may have the potential to enhance palliative care delivery and may be adapted to be used in managing patients with noncancer illnesses as well. The study also found that patients with cancer were more likely to receive palliative care from specialists rather than generalists, although this could be due to how palliative care is integrated in hospitals, clinics, and systems of care that serve patients with cancer. Identifying approaches that yield better palliative care models and delivery may help to further enhance care for patients with noncancer illnesses.
Applications for Clinical Practice
Identifying differences in patterns of palliative care delivery among those with cancer and other diagnoses may be an important step towards identifying gaps and avenues to improve palliative care delivery. The underlying reasons for these differences could be targeted so that patients across settings and diagnoses may have equal access to palliative care to improve their symptoms and quality of life. Policy makers and health system leaders may consider learning from how palliative care has been integrated into oncology care, to help transform care delivery for other noncancer terminal illnesses. It may also involve broadening education to providers in different specialties, so that the value and importance of palliative care may be recognized beyond oncological care.
1. Kavalieratos D, Corbelli J, Zhang D, et al. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA. 2016;316(20):2104-2114.
2. Quinn KL, Stukel T, Stall NM, et al. Association between palliative care and healthcare outcomes among adults with terminal non-cancer illness: population based matched cohort study. BMJ. 2020;370:m2257.
3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010;363:733-742.
4. White N, Reid F, Harris A, et al. A Systematic Review of Predictions of Survival in Palliative Care: How Accurate Are Clinicians and Who Are the Experts? PLoS One. 2016;11(8):e0161407.
5. Manz CR, Parikh RB, Small DS, et al. Effect of Integrating Machine Learning Mortality Estimates With Behavioral Nudges to Clinicians on Serious Illness Conversations Among Patients With Cancer: A Stepped-Wedge Cluster Randomized Clinical Trial. JAMA Oncol. 2020;6(12):e204759.
1. Kavalieratos D, Corbelli J, Zhang D, et al. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA. 2016;316(20):2104-2114.
2. Quinn KL, Stukel T, Stall NM, et al. Association between palliative care and healthcare outcomes among adults with terminal non-cancer illness: population based matched cohort study. BMJ. 2020;370:m2257.
3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med. 2010;363:733-742.
4. White N, Reid F, Harris A, et al. A Systematic Review of Predictions of Survival in Palliative Care: How Accurate Are Clinicians and Who Are the Experts? PLoS One. 2016;11(8):e0161407.
5. Manz CR, Parikh RB, Small DS, et al. Effect of Integrating Machine Learning Mortality Estimates With Behavioral Nudges to Clinicians on Serious Illness Conversations Among Patients With Cancer: A Stepped-Wedge Cluster Randomized Clinical Trial. JAMA Oncol. 2020;6(12):e204759.
Fall prevention advice for patients with Parkinson’s
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
A 75-year-old man with Parkinson’s disease has had three falls over the past 4 weeks. He has been compliant with his Parkinson’s treatment. Which of the following options would most help decrease his fall risk?
A. Vitamin D supplementation
B. Vitamin B12 supplementation
C. Calcium supplementation
D. Tai chi
There has been recent evidence that vitamin D supplementation is not helpful in preventing falls in most community-dwelling older adults. Bolland and colleagues performed a meta-analysis of 81 randomized, controlled trials and found that vitamin D supplementation does not prevent fractures or falls.1 They found no difference or benefit in high-dose versus low-dose vitamin D supplementation.
The U.S. Preventive Services Task Force recommends against vitamin D supplementation for the purpose of preventing falls in community-dwelling adults over the age of 65.2 The same USPSTF report recommends exercise intervention, as having the strongest evidence for fall prevention in community-dwelling adults age 65 or older who are at risk for falls.
The benefits of tai chi
Tai chi with it’s emphasis on balance, strength training as well as stress reduction is an excellent option for older adults.
Lui and colleagues performed a meta-analyses of five randomized, controlled trials (355 patients) of tai chi in patients with Parkinson disease.3 Tai chi significantly decreased fall rates (odds ratio, 0.47; 95% confidence interval, 0.30-0.74; P = .001) and significantly improved balance and functional mobility (P < .001) in people with Parkinson disease, compared with no training.
Tai chi can also help prevent falls in a more general population of elderly patients. Lomas-Vega and colleagues performed a meta-analysis of 10 high-quality studies that met inclusion criteria evaluating tai chi for fall prevention.4 Fall risk was reduced over short-term follow-up (incident rate ratio, 0.57; 95% CI, 0.46-0.70) and a small protective effect was seen over long-term follow-up (IRR, 0.87; 95% CI, 0.77-0.98).
Pearl: Consider tai chi in your elderly patients with fall risk to increase their balance and reduce risks of falls.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. Bolland MJ et al. Lancet Diabetes Endocrinol. 2018;6(11):847.
2. U.S. Preventive Services Task Force. JAMA. 2018;319(16):1696.
3. Liu HH et al. Parkinsons Dis. 2019 Feb 21;2019:9626934
4. Lomas-Vega R et al. J Am Geriatr Soc. 2017;65(9):2037.
Novel rehab program fights frailty, boosts capacity in advanced HF
A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.
The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.
A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.
At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.
The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.
Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.
An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”
The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”
This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
Guidance from telemedicine?
The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.
“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.
“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.
However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.
“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”
Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
Four functional domains
Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.
Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.
The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.
“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”
The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).
The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.
They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.
The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.
“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”
They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
Similar results across most subgroups
In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.
Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.
Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”
The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.
However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.
He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.
“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.
The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.
A version of this article first appeared on Medscape.com.
A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.
The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.
A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.
At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.
The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.
Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.
An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”
The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”
This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
Guidance from telemedicine?
The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.
“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.
“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.
However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.
“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”
Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
Four functional domains
Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.
Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.
The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.
“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”
The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).
The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.
They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.
The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.
“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”
They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
Similar results across most subgroups
In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.
Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.
Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”
The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.
However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.
He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.
“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.
The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.
A version of this article first appeared on Medscape.com.
A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.
The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.
A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.
At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.
The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.
Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.
An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”
The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”
This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
Guidance from telemedicine?
The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.
“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.
“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.
However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.
“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”
Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
Four functional domains
Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.
Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.
The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.
“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”
The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).
The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.
They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.
The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.
“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”
They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
Similar results across most subgroups
In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.
Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.
Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”
The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.
However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.
He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.
“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.
The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.
A version of this article first appeared on Medscape.com.
Use of Comprehensive Geriatric Assessment in Oncology Patients to Guide Treatment Decisions and Predict Chemotherapy Toxicity
Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.1 While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.2 Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.3 With a rapidly growing older population, there will be increasing demand for cancer care.
Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.4 Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.
Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.
What Is Geriatric Assessment?
Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.6 CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.7 Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.6 In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.
Components of CGA
Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.8
Comorbidity
The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.9 Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.10 In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.11 Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.12
The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.13 It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.14 The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.15
Polypharmacy
Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”16 The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.17
Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.18 While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.18
Functional Status
Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.19 IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.11
Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.20 Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.12 Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.21 Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.11 Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.
Cognition
Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.11
Psychological and Social Status
A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.22 In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.23 All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.24 A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.
Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.23 Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.
Nutrition
Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.25 The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.11 This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.
Effectiveness of CGA
Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.26 Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).27
In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.28 A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.29 Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.
Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.
Geriatric Assessment Screening Tools
A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.32 The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.12 The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.33
Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.34 However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.
CARG Chemotoxicity Calculator
Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.35 They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.12 This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).31
Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.31 An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.
CRASH Score
The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.30 A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).30
Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.12 Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.30 Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.
Conclusions
In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.36 Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.35 Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.5 In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.39
Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.
Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.
1. Sharless NE. The challenging landscape of cancer and aging: charting a way forward. Published January 24, 2018. Accessed April 16, 2021. https://www.cancer.gov/news-events/cancer-currents-blog/2018/sharpless-aging-cancer-research
2. National Cancer Institute. Age and cancer risk. Updated March 5, 2021. Accessed April 16, 2021. https://www.cancer.gov/about-cancer/causes-prevention/risk/age
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551 4. Sawhney R, Sehl M, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part I. Cancer J. 2005;11(6):449-460. doi:10.1097/00130404-200511000-00004
5. Kenis C, Bron D, Libert Y, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol. 2013;24(5):1306-1312. doi:10.1093/annonc/mds619
6. Loh KP, Soto-Perez-de-Celis E, Hsu T, et al. What every oncologist should know about geriatric assessment for older patients with cancer: Young International Society of Geriatric Oncology position paper. J Oncol Pract. 2018;14(2):85-94. doi:10.1200/JOP.2017.026435
7. Cohen HJ. Evolution of geriatric assessment in oncology. J Oncol Pract. 2018;14(2):95-96. doi:10.1200/JOP.18.00017
8. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595-2603. doi:10.1200/JCO.2013.54.8347
9. American Cancer Society. Cancer facts & figures 2019. Accessed April 16, 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html
10. Williams GR, Mackenzie A, Magnuson A, et al. Comorbidity in older adults with cancer. J Geriatr Oncol. 2016;7(4):249-257. doi:10.1016/j.jgo.2015.12.002
11. Korc-Grodzicki B, Holmes HM, Shahrokni A. Geriatric assessment for oncologists. Cancer Biol Med. 2015;12(4):261-274. doi:10.7497/j.issn.2095-3941.2015.0082
12. Li D, Soto-Perez-de-Celis E, Hurria A. Geriatric assessment and tools for predicting treatment toxicity in older adults with cancer. Cancer J. 2017;23(4):206-210. doi:10.1097/PPO.0000000000000269
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
14. Huang Y, Gou R, Diao Y, et al. Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy. J Zhejiang Univ Sci B. 2014;15(1):58-66. doi:10.1631/jzus.B1300109
15. Osborn KP IV, Nothelle S, Slaven JE, Montz K, Hui S, Torke AM. Cumulative Illness Rating Scale (CIRS) can be used to predict hospital outcomes in older adults. J Geriatric Med Gerontol. 2017;3(2). doi:10.23937/2469-5858/1510030
16. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57-65. doi:10.1517/14740338.2013.827660
17. Shrestha S, Shrestha S, Khanal S. Polypharmacy in elderly cancer patients: challenges and the way clinical pharmacists can contribute in resource-limited settings. Aging Med. 2019;2(1):42-49. doi:10.1002/agm2.12051
18. Sharma M, Loh KP, Nightingale G, Mohile SG, Holmes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol. 2016;7(5):346-353. doi:10.1016/j.jgo.2016.07.010
19. Norburn JE, Bernard SL, Konrad TR, et al. Self-care and assistance from others in coping with functional status limitations among a national sample of older adults. J Gerontol B Psychol Sci Soc Sci. 1995;50(2):S101-S109. doi:10.1093/geronb/50b.2.s101
20. Fragala MS, Alley DE, Shardell MD, et al. Comparison of handgrip and leg extension strength in predicting slow gait speed in older adults. J Am Geriatr Soc. 2016;64(1):144-150. doi:10.1111/jgs.13871
21. Owusu C, Berger NA. Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care. Clin Pract (Lond). 2014;11(6):749-762. doi:10.2217/cpr.14.72
22. Weiss Wiesel TR, Nelson CJ, Tew WP, et al. The relationship between age, anxiety, and depression in older adults with cancer. Psychooncology. 2015;24(6):712-717. doi:10.1002/pon.3638
23. Soto-Perez-de-Celis E, Li D, Yuan Y, Lau YM, Hurria A. Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol. 2018;19(6):e305-e316. doi:10.1016/S1470-2045(18)30348-6
24. Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol. 2014;32(15):1605-1619. doi:10.1200/JCO.2013.52.4611
25. Muscaritoli M, Lucia S, Farcomeni A, et al. Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study. Oncotarget. 2017;8(45):79884-79886. doi:10.18632/oncotarget.20168
26. Ekdahl AW, Axmon A, Sandberg M, Steen Carlsson K. Is care based on comprehensive geriatric assessment with mobile teams better than usual care? A study protocol of a randomised controlled trial (the GerMoT study). BMJ Open. 2018;8(10)e23969. doi:10.1136/bmjopen-2018-023969
27. Mohile SG, Dale W, Somerfield MR, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36(22):2326-2347. doi:10.1200/JCO.2018.78.8687
28. Hernandez Torres C, Hsu T. Comprehensive geriatric assessment in the older adult with cancer: a review. Eur Urol Focus. 2017;3(4-5):330-339. doi:10.1016/j.euf.2017.10.010
29. Janssens K, Specenier P. The prognostic value of the comprehensive geriatric assessment (CGA) in elderly cancer patients (ECP) treated with chemotherapy (CT): a systematic review. Eur J Cancer. 2017;72(1):S164-S165. doi:10.1016/S0959-8049(17)30611-1
30. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High‐Age Patients (CRASH) score. Cancer. 2012;118(13):3377-3386. doi:10.1002/cncr.26646
31. Hurria A, Mohile S, Gajra A, et al. Validation of a prediction tool for chemotherapy toxicity in older adults with cancer. J Clin Oncol. 2016;34(20):2366-2371. doi:10.1200/JCO.2015.65.4327
32. Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. 2015;26(2):288-300. doi:10.1093/annonc/mdu210
33. Schiefen JK, Madsen LT, Dains JE. Instruments that predict oncology treatment risk in the senior population. J Adv Pract Oncol. 2017;8(5):528-533.
34. Ortland I, Mendel Ott M, Kowar M, et al. Comparing the performance of the CARG and the CRASH score for predicting toxicity in older patients with cancer. J Geriatr Oncol. 2020;11(6):997-1005. doi:10.1016/j.jgo.2019.12.016
35. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-3465. doi:10.1200/JCO.2011.34.7625
36. Mohile SG, Velarde C, Hurria A, et al. Geriatric assessment-guided care processes for older adults: a Delphi consensus of geriatric oncology experts. J Natl Compr Canc Netw. 2015;13(9):1120-1130. doi:10.6004/jnccn.2015.0137
37. Schiphorst AHW, Ten Bokkel Huinink D, Breumelhof R, Burgmans JPJ, Pronk A, Hamaker ME. Geriatric consultation can aid in complex treatment decisions for elderly cancer patients. Eur J Cancer Care (Engl). 2016;25(3):365-370. doi:10.1111/ecc.12349
38. Schulkes KJG, Souwer ETD, Hamaker ME, et al. The effect of a geriatric assessment on treatment decisions for patients with lung cancer. Lung. 2017;195(2):225-231. doi:10.1007/s00408-017-9983-7
39. Klepin HD, Ritchie E, Major-Elechi B, et al. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: report of CALGB 361006 (Alliance). J Geriatr Oncol. 2020;11(1):107-113. doi:10.1016/j.jgo.2019.10.002
Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.1 While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.2 Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.3 With a rapidly growing older population, there will be increasing demand for cancer care.
Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.4 Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.
Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.
What Is Geriatric Assessment?
Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.6 CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.7 Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.6 In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.
Components of CGA
Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.8
Comorbidity
The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.9 Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.10 In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.11 Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.12
The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.13 It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.14 The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.15
Polypharmacy
Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”16 The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.17
Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.18 While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.18
Functional Status
Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.19 IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.11
Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.20 Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.12 Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.21 Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.11 Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.
Cognition
Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.11
Psychological and Social Status
A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.22 In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.23 All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.24 A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.
Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.23 Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.
Nutrition
Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.25 The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.11 This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.
Effectiveness of CGA
Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.26 Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).27
In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.28 A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.29 Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.
Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.
Geriatric Assessment Screening Tools
A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.32 The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.12 The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.33
Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.34 However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.
CARG Chemotoxicity Calculator
Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.35 They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.12 This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).31
Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.31 An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.
CRASH Score
The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.30 A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).30
Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.12 Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.30 Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.
Conclusions
In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.36 Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.35 Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.5 In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.39
Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.
Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.
Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.1 While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.2 Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.3 With a rapidly growing older population, there will be increasing demand for cancer care.
Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.4 Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.
Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.
What Is Geriatric Assessment?
Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.6 CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.7 Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.6 In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.
Components of CGA
Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.8
Comorbidity
The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.9 Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.10 In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.11 Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.12
The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.13 It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.14 The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.15
Polypharmacy
Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”16 The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.17
Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.18 While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.18
Functional Status
Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.19 IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.11
Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.20 Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.12 Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.21 Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.11 Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.
Cognition
Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.11
Psychological and Social Status
A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.22 In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.23 All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.24 A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.
Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.23 Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.
Nutrition
Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.25 The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.11 This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.
Effectiveness of CGA
Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.26 Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).27
In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.28 A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.29 Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.
Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.
Geriatric Assessment Screening Tools
A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.32 The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.12 The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.33
Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.34 However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.
CARG Chemotoxicity Calculator
Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.35 They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.12 This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).31
Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.31 An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.
CRASH Score
The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.30 A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).30
Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.12 Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.30 Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.
Conclusions
In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.36 Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.35 Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.5 In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.39
Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.
Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.
1. Sharless NE. The challenging landscape of cancer and aging: charting a way forward. Published January 24, 2018. Accessed April 16, 2021. https://www.cancer.gov/news-events/cancer-currents-blog/2018/sharpless-aging-cancer-research
2. National Cancer Institute. Age and cancer risk. Updated March 5, 2021. Accessed April 16, 2021. https://www.cancer.gov/about-cancer/causes-prevention/risk/age
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551 4. Sawhney R, Sehl M, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part I. Cancer J. 2005;11(6):449-460. doi:10.1097/00130404-200511000-00004
5. Kenis C, Bron D, Libert Y, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol. 2013;24(5):1306-1312. doi:10.1093/annonc/mds619
6. Loh KP, Soto-Perez-de-Celis E, Hsu T, et al. What every oncologist should know about geriatric assessment for older patients with cancer: Young International Society of Geriatric Oncology position paper. J Oncol Pract. 2018;14(2):85-94. doi:10.1200/JOP.2017.026435
7. Cohen HJ. Evolution of geriatric assessment in oncology. J Oncol Pract. 2018;14(2):95-96. doi:10.1200/JOP.18.00017
8. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595-2603. doi:10.1200/JCO.2013.54.8347
9. American Cancer Society. Cancer facts & figures 2019. Accessed April 16, 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html
10. Williams GR, Mackenzie A, Magnuson A, et al. Comorbidity in older adults with cancer. J Geriatr Oncol. 2016;7(4):249-257. doi:10.1016/j.jgo.2015.12.002
11. Korc-Grodzicki B, Holmes HM, Shahrokni A. Geriatric assessment for oncologists. Cancer Biol Med. 2015;12(4):261-274. doi:10.7497/j.issn.2095-3941.2015.0082
12. Li D, Soto-Perez-de-Celis E, Hurria A. Geriatric assessment and tools for predicting treatment toxicity in older adults with cancer. Cancer J. 2017;23(4):206-210. doi:10.1097/PPO.0000000000000269
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
14. Huang Y, Gou R, Diao Y, et al. Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy. J Zhejiang Univ Sci B. 2014;15(1):58-66. doi:10.1631/jzus.B1300109
15. Osborn KP IV, Nothelle S, Slaven JE, Montz K, Hui S, Torke AM. Cumulative Illness Rating Scale (CIRS) can be used to predict hospital outcomes in older adults. J Geriatric Med Gerontol. 2017;3(2). doi:10.23937/2469-5858/1510030
16. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57-65. doi:10.1517/14740338.2013.827660
17. Shrestha S, Shrestha S, Khanal S. Polypharmacy in elderly cancer patients: challenges and the way clinical pharmacists can contribute in resource-limited settings. Aging Med. 2019;2(1):42-49. doi:10.1002/agm2.12051
18. Sharma M, Loh KP, Nightingale G, Mohile SG, Holmes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol. 2016;7(5):346-353. doi:10.1016/j.jgo.2016.07.010
19. Norburn JE, Bernard SL, Konrad TR, et al. Self-care and assistance from others in coping with functional status limitations among a national sample of older adults. J Gerontol B Psychol Sci Soc Sci. 1995;50(2):S101-S109. doi:10.1093/geronb/50b.2.s101
20. Fragala MS, Alley DE, Shardell MD, et al. Comparison of handgrip and leg extension strength in predicting slow gait speed in older adults. J Am Geriatr Soc. 2016;64(1):144-150. doi:10.1111/jgs.13871
21. Owusu C, Berger NA. Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care. Clin Pract (Lond). 2014;11(6):749-762. doi:10.2217/cpr.14.72
22. Weiss Wiesel TR, Nelson CJ, Tew WP, et al. The relationship between age, anxiety, and depression in older adults with cancer. Psychooncology. 2015;24(6):712-717. doi:10.1002/pon.3638
23. Soto-Perez-de-Celis E, Li D, Yuan Y, Lau YM, Hurria A. Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol. 2018;19(6):e305-e316. doi:10.1016/S1470-2045(18)30348-6
24. Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol. 2014;32(15):1605-1619. doi:10.1200/JCO.2013.52.4611
25. Muscaritoli M, Lucia S, Farcomeni A, et al. Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study. Oncotarget. 2017;8(45):79884-79886. doi:10.18632/oncotarget.20168
26. Ekdahl AW, Axmon A, Sandberg M, Steen Carlsson K. Is care based on comprehensive geriatric assessment with mobile teams better than usual care? A study protocol of a randomised controlled trial (the GerMoT study). BMJ Open. 2018;8(10)e23969. doi:10.1136/bmjopen-2018-023969
27. Mohile SG, Dale W, Somerfield MR, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36(22):2326-2347. doi:10.1200/JCO.2018.78.8687
28. Hernandez Torres C, Hsu T. Comprehensive geriatric assessment in the older adult with cancer: a review. Eur Urol Focus. 2017;3(4-5):330-339. doi:10.1016/j.euf.2017.10.010
29. Janssens K, Specenier P. The prognostic value of the comprehensive geriatric assessment (CGA) in elderly cancer patients (ECP) treated with chemotherapy (CT): a systematic review. Eur J Cancer. 2017;72(1):S164-S165. doi:10.1016/S0959-8049(17)30611-1
30. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High‐Age Patients (CRASH) score. Cancer. 2012;118(13):3377-3386. doi:10.1002/cncr.26646
31. Hurria A, Mohile S, Gajra A, et al. Validation of a prediction tool for chemotherapy toxicity in older adults with cancer. J Clin Oncol. 2016;34(20):2366-2371. doi:10.1200/JCO.2015.65.4327
32. Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. 2015;26(2):288-300. doi:10.1093/annonc/mdu210
33. Schiefen JK, Madsen LT, Dains JE. Instruments that predict oncology treatment risk in the senior population. J Adv Pract Oncol. 2017;8(5):528-533.
34. Ortland I, Mendel Ott M, Kowar M, et al. Comparing the performance of the CARG and the CRASH score for predicting toxicity in older patients with cancer. J Geriatr Oncol. 2020;11(6):997-1005. doi:10.1016/j.jgo.2019.12.016
35. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-3465. doi:10.1200/JCO.2011.34.7625
36. Mohile SG, Velarde C, Hurria A, et al. Geriatric assessment-guided care processes for older adults: a Delphi consensus of geriatric oncology experts. J Natl Compr Canc Netw. 2015;13(9):1120-1130. doi:10.6004/jnccn.2015.0137
37. Schiphorst AHW, Ten Bokkel Huinink D, Breumelhof R, Burgmans JPJ, Pronk A, Hamaker ME. Geriatric consultation can aid in complex treatment decisions for elderly cancer patients. Eur J Cancer Care (Engl). 2016;25(3):365-370. doi:10.1111/ecc.12349
38. Schulkes KJG, Souwer ETD, Hamaker ME, et al. The effect of a geriatric assessment on treatment decisions for patients with lung cancer. Lung. 2017;195(2):225-231. doi:10.1007/s00408-017-9983-7
39. Klepin HD, Ritchie E, Major-Elechi B, et al. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: report of CALGB 361006 (Alliance). J Geriatr Oncol. 2020;11(1):107-113. doi:10.1016/j.jgo.2019.10.002
1. Sharless NE. The challenging landscape of cancer and aging: charting a way forward. Published January 24, 2018. Accessed April 16, 2021. https://www.cancer.gov/news-events/cancer-currents-blog/2018/sharpless-aging-cancer-research
2. National Cancer Institute. Age and cancer risk. Updated March 5, 2021. Accessed April 16, 2021. https://www.cancer.gov/about-cancer/causes-prevention/risk/age
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551 4. Sawhney R, Sehl M, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part I. Cancer J. 2005;11(6):449-460. doi:10.1097/00130404-200511000-00004
5. Kenis C, Bron D, Libert Y, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol. 2013;24(5):1306-1312. doi:10.1093/annonc/mds619
6. Loh KP, Soto-Perez-de-Celis E, Hsu T, et al. What every oncologist should know about geriatric assessment for older patients with cancer: Young International Society of Geriatric Oncology position paper. J Oncol Pract. 2018;14(2):85-94. doi:10.1200/JOP.2017.026435
7. Cohen HJ. Evolution of geriatric assessment in oncology. J Oncol Pract. 2018;14(2):95-96. doi:10.1200/JOP.18.00017
8. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595-2603. doi:10.1200/JCO.2013.54.8347
9. American Cancer Society. Cancer facts & figures 2019. Accessed April 16, 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html
10. Williams GR, Mackenzie A, Magnuson A, et al. Comorbidity in older adults with cancer. J Geriatr Oncol. 2016;7(4):249-257. doi:10.1016/j.jgo.2015.12.002
11. Korc-Grodzicki B, Holmes HM, Shahrokni A. Geriatric assessment for oncologists. Cancer Biol Med. 2015;12(4):261-274. doi:10.7497/j.issn.2095-3941.2015.0082
12. Li D, Soto-Perez-de-Celis E, Hurria A. Geriatric assessment and tools for predicting treatment toxicity in older adults with cancer. Cancer J. 2017;23(4):206-210. doi:10.1097/PPO.0000000000000269
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
14. Huang Y, Gou R, Diao Y, et al. Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy. J Zhejiang Univ Sci B. 2014;15(1):58-66. doi:10.1631/jzus.B1300109
15. Osborn KP IV, Nothelle S, Slaven JE, Montz K, Hui S, Torke AM. Cumulative Illness Rating Scale (CIRS) can be used to predict hospital outcomes in older adults. J Geriatric Med Gerontol. 2017;3(2). doi:10.23937/2469-5858/1510030
16. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57-65. doi:10.1517/14740338.2013.827660
17. Shrestha S, Shrestha S, Khanal S. Polypharmacy in elderly cancer patients: challenges and the way clinical pharmacists can contribute in resource-limited settings. Aging Med. 2019;2(1):42-49. doi:10.1002/agm2.12051
18. Sharma M, Loh KP, Nightingale G, Mohile SG, Holmes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol. 2016;7(5):346-353. doi:10.1016/j.jgo.2016.07.010
19. Norburn JE, Bernard SL, Konrad TR, et al. Self-care and assistance from others in coping with functional status limitations among a national sample of older adults. J Gerontol B Psychol Sci Soc Sci. 1995;50(2):S101-S109. doi:10.1093/geronb/50b.2.s101
20. Fragala MS, Alley DE, Shardell MD, et al. Comparison of handgrip and leg extension strength in predicting slow gait speed in older adults. J Am Geriatr Soc. 2016;64(1):144-150. doi:10.1111/jgs.13871
21. Owusu C, Berger NA. Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care. Clin Pract (Lond). 2014;11(6):749-762. doi:10.2217/cpr.14.72
22. Weiss Wiesel TR, Nelson CJ, Tew WP, et al. The relationship between age, anxiety, and depression in older adults with cancer. Psychooncology. 2015;24(6):712-717. doi:10.1002/pon.3638
23. Soto-Perez-de-Celis E, Li D, Yuan Y, Lau YM, Hurria A. Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol. 2018;19(6):e305-e316. doi:10.1016/S1470-2045(18)30348-6
24. Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol. 2014;32(15):1605-1619. doi:10.1200/JCO.2013.52.4611
25. Muscaritoli M, Lucia S, Farcomeni A, et al. Prevalence of malnutrition in patients at first medical oncology visit: the PreMiO study. Oncotarget. 2017;8(45):79884-79886. doi:10.18632/oncotarget.20168
26. Ekdahl AW, Axmon A, Sandberg M, Steen Carlsson K. Is care based on comprehensive geriatric assessment with mobile teams better than usual care? A study protocol of a randomised controlled trial (the GerMoT study). BMJ Open. 2018;8(10)e23969. doi:10.1136/bmjopen-2018-023969
27. Mohile SG, Dale W, Somerfield MR, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36(22):2326-2347. doi:10.1200/JCO.2018.78.8687
28. Hernandez Torres C, Hsu T. Comprehensive geriatric assessment in the older adult with cancer: a review. Eur Urol Focus. 2017;3(4-5):330-339. doi:10.1016/j.euf.2017.10.010
29. Janssens K, Specenier P. The prognostic value of the comprehensive geriatric assessment (CGA) in elderly cancer patients (ECP) treated with chemotherapy (CT): a systematic review. Eur J Cancer. 2017;72(1):S164-S165. doi:10.1016/S0959-8049(17)30611-1
30. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High‐Age Patients (CRASH) score. Cancer. 2012;118(13):3377-3386. doi:10.1002/cncr.26646
31. Hurria A, Mohile S, Gajra A, et al. Validation of a prediction tool for chemotherapy toxicity in older adults with cancer. J Clin Oncol. 2016;34(20):2366-2371. doi:10.1200/JCO.2015.65.4327
32. Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. 2015;26(2):288-300. doi:10.1093/annonc/mdu210
33. Schiefen JK, Madsen LT, Dains JE. Instruments that predict oncology treatment risk in the senior population. J Adv Pract Oncol. 2017;8(5):528-533.
34. Ortland I, Mendel Ott M, Kowar M, et al. Comparing the performance of the CARG and the CRASH score for predicting toxicity in older patients with cancer. J Geriatr Oncol. 2020;11(6):997-1005. doi:10.1016/j.jgo.2019.12.016
35. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-3465. doi:10.1200/JCO.2011.34.7625
36. Mohile SG, Velarde C, Hurria A, et al. Geriatric assessment-guided care processes for older adults: a Delphi consensus of geriatric oncology experts. J Natl Compr Canc Netw. 2015;13(9):1120-1130. doi:10.6004/jnccn.2015.0137
37. Schiphorst AHW, Ten Bokkel Huinink D, Breumelhof R, Burgmans JPJ, Pronk A, Hamaker ME. Geriatric consultation can aid in complex treatment decisions for elderly cancer patients. Eur J Cancer Care (Engl). 2016;25(3):365-370. doi:10.1111/ecc.12349
38. Schulkes KJG, Souwer ETD, Hamaker ME, et al. The effect of a geriatric assessment on treatment decisions for patients with lung cancer. Lung. 2017;195(2):225-231. doi:10.1007/s00408-017-9983-7
39. Klepin HD, Ritchie E, Major-Elechi B, et al. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: report of CALGB 361006 (Alliance). J Geriatr Oncol. 2020;11(1):107-113. doi:10.1016/j.jgo.2019.10.002
When to refer patients with new memory loss
Initial questions should zero in on what the patient is forgetting, said Megan Richie, MD, a neurohospitalist at the University of California, San Francisco, who spoke to a virtual audience at the American College of Physicians (ACP) annual Internal Medicine meeting.
Is the patient forgetting to buy things in a store, having trouble recalling events, forgetting important dates? How often do these incidents occur?
These questions “will help get at how pervasive and how likely the memory loss is affecting their lives, versus a subjective complaint that doesn’t have much impact on the day-to-day function,” she said.
It’s also important to ask whether other neurocognitive symptoms accompany the memory loss, Dr. Richie noted.
Does the patient search for words, struggle with attention, or have problems with executive function? Does the patient have psychiatric symptoms, such as hallucinations or delusions, or other neurologic complaints, including weakness, numbness, vision change, or movement disorders?
“When you know how many neurocognitive symptoms they have, think about how [those symptoms] are affecting their safety and functional status. How are they on their activities of daily living?” Dr. Richie suggests.
Also ask whether the patient is taking medications and whether they drive a vehicle. If they do drive, do they get lost?
“These are all going to help you determine the acuity of the workup,” she said.
After a thorough history, cognitive screening is the next consideration.
Cognitive screening can be performed in minutes
One of the tests Dr. Richie recommends is the Mini-Cog. It takes 3 minutes to administer and has been formally recommended by the Alzheimer’s Association because it can be completed in the time frame of a Medicare wellness visit, she said.
It entails a three-word recall and clock-drawing test.
Dr. Richie said it’s important to eliminate some key causes first: “Certainly if the patient has signs and symptoms of depression, pseudodementia is a very real and treatable disease you do not want to miss and should consider in these patients,” she pointed out.
Systemic medical conditions can also lead to memory loss.
If there’s an acute component to the complaint, a new infection or medication withdrawal or a side effect could be driving it, so that’s key in questioning.
Dr. Richie explained that the American Academy of Neurology recommends a very limited workup.
“It’s really just to check their thyroid, their vitamin B12 levels, and then a one-time picture of their brain, which can be either MRI or a CT, to look for structural problems or vascular dementia or hydrocephalus, etc.”
“You do not routinely need spinal fluid testing or an EEG,” she emphasized.
Signs that a neurologist should be involved include a rapid decline, signs of potential seizures, or that the patient doesn’t seem safe in their condition.
Neuropsychological testing is helpful, but it takes nearly 3 hours and may not be a good choice for restless or aggressive patients, Dr. Richie said.
Such testing is often not available, and if it is, insurance coverage is often a barrier because many plans don’t cover it.
Patients often ask about drugs and supplements they see advertised to help with memory loss. Medications are not helpful for mild cognitive impairment, although there is evidence that some are beneficial for patients with dementia, Dr. Richie said.
Celine Goetz, MD, assistant professor of internal medicine at Rush University Medical Center, Chicago, Illinois, told this news organization that it’s easy to relate to the fear that patients and families feel when cognitive impairment begins to emerge.
“[Dr.] Richie’s talk was right on point for internists like myself who see many patients with memory complaints, cognitive impairment, and dementia. I think we’re all terrified of losing our memory and the social and functional impairment that comes with that,” she said.
Although cognitive impairment and dementia aren’t curable or reversible, Dr. Goetz noted, internists can help patients optimize management of conditions such as diabetes and heart disease, which can affect cognitive function.
Dr. Richie pointed out that some interventions lack evidence for the treatment of mild cognitive impairment, but Dr. Goetz emphasized that resources are plentiful and can be effective in combination.
“Engaging social workers, pharmacists, nutritionists, physical and occupational therapists, and, on the inpatient side, delirium protocols, chaplains, and music therapists make a huge difference in patient care,” she said.
Dr. Richie and Dr. Goetz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Initial questions should zero in on what the patient is forgetting, said Megan Richie, MD, a neurohospitalist at the University of California, San Francisco, who spoke to a virtual audience at the American College of Physicians (ACP) annual Internal Medicine meeting.
Is the patient forgetting to buy things in a store, having trouble recalling events, forgetting important dates? How often do these incidents occur?
These questions “will help get at how pervasive and how likely the memory loss is affecting their lives, versus a subjective complaint that doesn’t have much impact on the day-to-day function,” she said.
It’s also important to ask whether other neurocognitive symptoms accompany the memory loss, Dr. Richie noted.
Does the patient search for words, struggle with attention, or have problems with executive function? Does the patient have psychiatric symptoms, such as hallucinations or delusions, or other neurologic complaints, including weakness, numbness, vision change, or movement disorders?
“When you know how many neurocognitive symptoms they have, think about how [those symptoms] are affecting their safety and functional status. How are they on their activities of daily living?” Dr. Richie suggests.
Also ask whether the patient is taking medications and whether they drive a vehicle. If they do drive, do they get lost?
“These are all going to help you determine the acuity of the workup,” she said.
After a thorough history, cognitive screening is the next consideration.
Cognitive screening can be performed in minutes
One of the tests Dr. Richie recommends is the Mini-Cog. It takes 3 minutes to administer and has been formally recommended by the Alzheimer’s Association because it can be completed in the time frame of a Medicare wellness visit, she said.
It entails a three-word recall and clock-drawing test.
Dr. Richie said it’s important to eliminate some key causes first: “Certainly if the patient has signs and symptoms of depression, pseudodementia is a very real and treatable disease you do not want to miss and should consider in these patients,” she pointed out.
Systemic medical conditions can also lead to memory loss.
If there’s an acute component to the complaint, a new infection or medication withdrawal or a side effect could be driving it, so that’s key in questioning.
Dr. Richie explained that the American Academy of Neurology recommends a very limited workup.
“It’s really just to check their thyroid, their vitamin B12 levels, and then a one-time picture of their brain, which can be either MRI or a CT, to look for structural problems or vascular dementia or hydrocephalus, etc.”
“You do not routinely need spinal fluid testing or an EEG,” she emphasized.
Signs that a neurologist should be involved include a rapid decline, signs of potential seizures, or that the patient doesn’t seem safe in their condition.
Neuropsychological testing is helpful, but it takes nearly 3 hours and may not be a good choice for restless or aggressive patients, Dr. Richie said.
Such testing is often not available, and if it is, insurance coverage is often a barrier because many plans don’t cover it.
Patients often ask about drugs and supplements they see advertised to help with memory loss. Medications are not helpful for mild cognitive impairment, although there is evidence that some are beneficial for patients with dementia, Dr. Richie said.
Celine Goetz, MD, assistant professor of internal medicine at Rush University Medical Center, Chicago, Illinois, told this news organization that it’s easy to relate to the fear that patients and families feel when cognitive impairment begins to emerge.
“[Dr.] Richie’s talk was right on point for internists like myself who see many patients with memory complaints, cognitive impairment, and dementia. I think we’re all terrified of losing our memory and the social and functional impairment that comes with that,” she said.
Although cognitive impairment and dementia aren’t curable or reversible, Dr. Goetz noted, internists can help patients optimize management of conditions such as diabetes and heart disease, which can affect cognitive function.
Dr. Richie pointed out that some interventions lack evidence for the treatment of mild cognitive impairment, but Dr. Goetz emphasized that resources are plentiful and can be effective in combination.
“Engaging social workers, pharmacists, nutritionists, physical and occupational therapists, and, on the inpatient side, delirium protocols, chaplains, and music therapists make a huge difference in patient care,” she said.
Dr. Richie and Dr. Goetz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Initial questions should zero in on what the patient is forgetting, said Megan Richie, MD, a neurohospitalist at the University of California, San Francisco, who spoke to a virtual audience at the American College of Physicians (ACP) annual Internal Medicine meeting.
Is the patient forgetting to buy things in a store, having trouble recalling events, forgetting important dates? How often do these incidents occur?
These questions “will help get at how pervasive and how likely the memory loss is affecting their lives, versus a subjective complaint that doesn’t have much impact on the day-to-day function,” she said.
It’s also important to ask whether other neurocognitive symptoms accompany the memory loss, Dr. Richie noted.
Does the patient search for words, struggle with attention, or have problems with executive function? Does the patient have psychiatric symptoms, such as hallucinations or delusions, or other neurologic complaints, including weakness, numbness, vision change, or movement disorders?
“When you know how many neurocognitive symptoms they have, think about how [those symptoms] are affecting their safety and functional status. How are they on their activities of daily living?” Dr. Richie suggests.
Also ask whether the patient is taking medications and whether they drive a vehicle. If they do drive, do they get lost?
“These are all going to help you determine the acuity of the workup,” she said.
After a thorough history, cognitive screening is the next consideration.
Cognitive screening can be performed in minutes
One of the tests Dr. Richie recommends is the Mini-Cog. It takes 3 minutes to administer and has been formally recommended by the Alzheimer’s Association because it can be completed in the time frame of a Medicare wellness visit, she said.
It entails a three-word recall and clock-drawing test.
Dr. Richie said it’s important to eliminate some key causes first: “Certainly if the patient has signs and symptoms of depression, pseudodementia is a very real and treatable disease you do not want to miss and should consider in these patients,” she pointed out.
Systemic medical conditions can also lead to memory loss.
If there’s an acute component to the complaint, a new infection or medication withdrawal or a side effect could be driving it, so that’s key in questioning.
Dr. Richie explained that the American Academy of Neurology recommends a very limited workup.
“It’s really just to check their thyroid, their vitamin B12 levels, and then a one-time picture of their brain, which can be either MRI or a CT, to look for structural problems or vascular dementia or hydrocephalus, etc.”
“You do not routinely need spinal fluid testing or an EEG,” she emphasized.
Signs that a neurologist should be involved include a rapid decline, signs of potential seizures, or that the patient doesn’t seem safe in their condition.
Neuropsychological testing is helpful, but it takes nearly 3 hours and may not be a good choice for restless or aggressive patients, Dr. Richie said.
Such testing is often not available, and if it is, insurance coverage is often a barrier because many plans don’t cover it.
Patients often ask about drugs and supplements they see advertised to help with memory loss. Medications are not helpful for mild cognitive impairment, although there is evidence that some are beneficial for patients with dementia, Dr. Richie said.
Celine Goetz, MD, assistant professor of internal medicine at Rush University Medical Center, Chicago, Illinois, told this news organization that it’s easy to relate to the fear that patients and families feel when cognitive impairment begins to emerge.
“[Dr.] Richie’s talk was right on point for internists like myself who see many patients with memory complaints, cognitive impairment, and dementia. I think we’re all terrified of losing our memory and the social and functional impairment that comes with that,” she said.
Although cognitive impairment and dementia aren’t curable or reversible, Dr. Goetz noted, internists can help patients optimize management of conditions such as diabetes and heart disease, which can affect cognitive function.
Dr. Richie pointed out that some interventions lack evidence for the treatment of mild cognitive impairment, but Dr. Goetz emphasized that resources are plentiful and can be effective in combination.
“Engaging social workers, pharmacists, nutritionists, physical and occupational therapists, and, on the inpatient side, delirium protocols, chaplains, and music therapists make a huge difference in patient care,” she said.
Dr. Richie and Dr. Goetz report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM INTERNAL MEDICINE 2021
Nutritional support may be lifesaving in heart failure
Personalized nutritional support for adults hospitalized with chronic heart failure and deemed to be at high nutritional risk reduced the risk of death or adverse cardiovascular events, compared with standard hospital food, new research indicates.
The Swiss EFFORT trial focused on patients with chronic heart failure and high risk of malnutrition defined by low body mass index, weight loss, and low food intake upon hospital admission.
“This high-risk group of chronic heart failure patients showed a significant improvement in mortality over 30 and 180 days, as well as other clinical outcomes, when individualized nutritional support interventions were offered to patients,” Philipp Schuetz, MD, MPH, Kantonsspital Aarau, Switzerland, said in an interview.
“While monitoring the nutritional status should be done also in outpatient settings by [general practitioners], malnutrition screening upon hospital admission may help to identify high-risk patients with high risk for nutritional status deterioration during the hospital stay who will benefit from nutritional assessment and treatment,” said Dr. Schuetz.
The study was published online May 3 in the Journal of the American College of Cardiology.
It’s not all about salt
The findings are based on a prespecified secondary analysis of outcomes in 645 patients (median age, 78.8 years, 52% men) hospitalized with chronic heart failure who participated in the open-label EFFORT study.
One-third of patients were hospitalized for acute decompensated heart failure and two-thirds had chronic heart failure and other acute medical illnesses requiring hospitalization.
All patients were at risk of malnutrition based on a Nutritional Risk Screening (NRS) score of 3 points or higher. They were randomly allocated 1:1 to individualized nutritional support to reach energy, protein, and micronutrient goals or usual hospital food (control group).
By 30 days, 27 of 321 patients (8.4%) receiving nutritional support had died compared with 48 of 324 patients (14.8%) in the control group (adjusted odds ratio [OR]: 0.44; 95% confidence interval, 0.26-0.75; P = .002)
Patients with high nutritional risk (NRS >4 points) showed the most benefit from nutritional support.
Compared with patients with moderate nutritional risk scores (NRS score 3-4), those with high nutritional risk (NRS >4) had a highly significant 65% increased mortality risk over 180 days.
The individual component of the NRS with the strongest association with mortality was low food intake in the week before hospitalization.
Patients who received nutritional support in the hospital also had a lower risk for major cardiovascular events at 30 days (17.4% vs. 26.9%; OR, 0.50; 95% CI, 0.34-0.75; P = .001).
“Historically, cardiologists and internists caring for patients with heart failure have mainly focused on salt-restrictive diets to reduce blood volume and thus optimize heart function. Yet, reduction of salt intake has not been shown to effectively improve clinical outcome but may, on the contrary, increase the risk of malnutrition as low-salt diets are often not tasty,” Dr. Schuetz said.
“Our data suggest that we should move our focus away from salt-restrictive diets to high-protein diets to cover individual nutritional goals in this high-risk group of patients, which includes screening, assessment, and nutritional support by dietitians,” Dr. Schuetz said.
In a linked editorial, Sheldon Gottlieb, MD, Johns Hopkins University, Baltimore, said there has been “relatively little attention” paid to the role of diet in heart failure other than recommending reduced salt intake.
In fact, in the 2021 American College of Cardiology expert consensus recommendations for optimizing heart failure treatment, roughly five words are devoted to diet and exercise and there is no mention of nutrition assessment by a dietitian, he points out.
“This study adds another tile to the still-fragmentary mosaic picture of the patient with heart failure at nutritional risk who might benefit from nutritional support,” Dr. Dr. Gottlieb wrote.
“ ‘Good medical care’ dictates that all hospitalized patients deserve to have a standardized nutritional assessment; the challenge remains: how to determine which patient with heart failure at nutritional risk will benefit by medical nutrition therapy,” Dr. Gottlieb said.
The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau provided funding for the trial. Dr. Schuetz’s institution has previously received unrestricted grant money unrelated to this project from Nestle Health Science and Abbott Nutrition. Dr. Gottlieb owns a federal trademark for the “Greens, Beans, and Leans” diet, and has a pending federal trademark for “FLOATS”: flax + oats cereal.
A version of this article first appeared on Medscape.com.
Personalized nutritional support for adults hospitalized with chronic heart failure and deemed to be at high nutritional risk reduced the risk of death or adverse cardiovascular events, compared with standard hospital food, new research indicates.
The Swiss EFFORT trial focused on patients with chronic heart failure and high risk of malnutrition defined by low body mass index, weight loss, and low food intake upon hospital admission.
“This high-risk group of chronic heart failure patients showed a significant improvement in mortality over 30 and 180 days, as well as other clinical outcomes, when individualized nutritional support interventions were offered to patients,” Philipp Schuetz, MD, MPH, Kantonsspital Aarau, Switzerland, said in an interview.
“While monitoring the nutritional status should be done also in outpatient settings by [general practitioners], malnutrition screening upon hospital admission may help to identify high-risk patients with high risk for nutritional status deterioration during the hospital stay who will benefit from nutritional assessment and treatment,” said Dr. Schuetz.
The study was published online May 3 in the Journal of the American College of Cardiology.
It’s not all about salt
The findings are based on a prespecified secondary analysis of outcomes in 645 patients (median age, 78.8 years, 52% men) hospitalized with chronic heart failure who participated in the open-label EFFORT study.
One-third of patients were hospitalized for acute decompensated heart failure and two-thirds had chronic heart failure and other acute medical illnesses requiring hospitalization.
All patients were at risk of malnutrition based on a Nutritional Risk Screening (NRS) score of 3 points or higher. They were randomly allocated 1:1 to individualized nutritional support to reach energy, protein, and micronutrient goals or usual hospital food (control group).
By 30 days, 27 of 321 patients (8.4%) receiving nutritional support had died compared with 48 of 324 patients (14.8%) in the control group (adjusted odds ratio [OR]: 0.44; 95% confidence interval, 0.26-0.75; P = .002)
Patients with high nutritional risk (NRS >4 points) showed the most benefit from nutritional support.
Compared with patients with moderate nutritional risk scores (NRS score 3-4), those with high nutritional risk (NRS >4) had a highly significant 65% increased mortality risk over 180 days.
The individual component of the NRS with the strongest association with mortality was low food intake in the week before hospitalization.
Patients who received nutritional support in the hospital also had a lower risk for major cardiovascular events at 30 days (17.4% vs. 26.9%; OR, 0.50; 95% CI, 0.34-0.75; P = .001).
“Historically, cardiologists and internists caring for patients with heart failure have mainly focused on salt-restrictive diets to reduce blood volume and thus optimize heart function. Yet, reduction of salt intake has not been shown to effectively improve clinical outcome but may, on the contrary, increase the risk of malnutrition as low-salt diets are often not tasty,” Dr. Schuetz said.
“Our data suggest that we should move our focus away from salt-restrictive diets to high-protein diets to cover individual nutritional goals in this high-risk group of patients, which includes screening, assessment, and nutritional support by dietitians,” Dr. Schuetz said.
In a linked editorial, Sheldon Gottlieb, MD, Johns Hopkins University, Baltimore, said there has been “relatively little attention” paid to the role of diet in heart failure other than recommending reduced salt intake.
In fact, in the 2021 American College of Cardiology expert consensus recommendations for optimizing heart failure treatment, roughly five words are devoted to diet and exercise and there is no mention of nutrition assessment by a dietitian, he points out.
“This study adds another tile to the still-fragmentary mosaic picture of the patient with heart failure at nutritional risk who might benefit from nutritional support,” Dr. Dr. Gottlieb wrote.
“ ‘Good medical care’ dictates that all hospitalized patients deserve to have a standardized nutritional assessment; the challenge remains: how to determine which patient with heart failure at nutritional risk will benefit by medical nutrition therapy,” Dr. Gottlieb said.
The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau provided funding for the trial. Dr. Schuetz’s institution has previously received unrestricted grant money unrelated to this project from Nestle Health Science and Abbott Nutrition. Dr. Gottlieb owns a federal trademark for the “Greens, Beans, and Leans” diet, and has a pending federal trademark for “FLOATS”: flax + oats cereal.
A version of this article first appeared on Medscape.com.
Personalized nutritional support for adults hospitalized with chronic heart failure and deemed to be at high nutritional risk reduced the risk of death or adverse cardiovascular events, compared with standard hospital food, new research indicates.
The Swiss EFFORT trial focused on patients with chronic heart failure and high risk of malnutrition defined by low body mass index, weight loss, and low food intake upon hospital admission.
“This high-risk group of chronic heart failure patients showed a significant improvement in mortality over 30 and 180 days, as well as other clinical outcomes, when individualized nutritional support interventions were offered to patients,” Philipp Schuetz, MD, MPH, Kantonsspital Aarau, Switzerland, said in an interview.
“While monitoring the nutritional status should be done also in outpatient settings by [general practitioners], malnutrition screening upon hospital admission may help to identify high-risk patients with high risk for nutritional status deterioration during the hospital stay who will benefit from nutritional assessment and treatment,” said Dr. Schuetz.
The study was published online May 3 in the Journal of the American College of Cardiology.
It’s not all about salt
The findings are based on a prespecified secondary analysis of outcomes in 645 patients (median age, 78.8 years, 52% men) hospitalized with chronic heart failure who participated in the open-label EFFORT study.
One-third of patients were hospitalized for acute decompensated heart failure and two-thirds had chronic heart failure and other acute medical illnesses requiring hospitalization.
All patients were at risk of malnutrition based on a Nutritional Risk Screening (NRS) score of 3 points or higher. They were randomly allocated 1:1 to individualized nutritional support to reach energy, protein, and micronutrient goals or usual hospital food (control group).
By 30 days, 27 of 321 patients (8.4%) receiving nutritional support had died compared with 48 of 324 patients (14.8%) in the control group (adjusted odds ratio [OR]: 0.44; 95% confidence interval, 0.26-0.75; P = .002)
Patients with high nutritional risk (NRS >4 points) showed the most benefit from nutritional support.
Compared with patients with moderate nutritional risk scores (NRS score 3-4), those with high nutritional risk (NRS >4) had a highly significant 65% increased mortality risk over 180 days.
The individual component of the NRS with the strongest association with mortality was low food intake in the week before hospitalization.
Patients who received nutritional support in the hospital also had a lower risk for major cardiovascular events at 30 days (17.4% vs. 26.9%; OR, 0.50; 95% CI, 0.34-0.75; P = .001).
“Historically, cardiologists and internists caring for patients with heart failure have mainly focused on salt-restrictive diets to reduce blood volume and thus optimize heart function. Yet, reduction of salt intake has not been shown to effectively improve clinical outcome but may, on the contrary, increase the risk of malnutrition as low-salt diets are often not tasty,” Dr. Schuetz said.
“Our data suggest that we should move our focus away from salt-restrictive diets to high-protein diets to cover individual nutritional goals in this high-risk group of patients, which includes screening, assessment, and nutritional support by dietitians,” Dr. Schuetz said.
In a linked editorial, Sheldon Gottlieb, MD, Johns Hopkins University, Baltimore, said there has been “relatively little attention” paid to the role of diet in heart failure other than recommending reduced salt intake.
In fact, in the 2021 American College of Cardiology expert consensus recommendations for optimizing heart failure treatment, roughly five words are devoted to diet and exercise and there is no mention of nutrition assessment by a dietitian, he points out.
“This study adds another tile to the still-fragmentary mosaic picture of the patient with heart failure at nutritional risk who might benefit from nutritional support,” Dr. Dr. Gottlieb wrote.
“ ‘Good medical care’ dictates that all hospitalized patients deserve to have a standardized nutritional assessment; the challenge remains: how to determine which patient with heart failure at nutritional risk will benefit by medical nutrition therapy,” Dr. Gottlieb said.
The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau provided funding for the trial. Dr. Schuetz’s institution has previously received unrestricted grant money unrelated to this project from Nestle Health Science and Abbott Nutrition. Dr. Gottlieb owns a federal trademark for the “Greens, Beans, and Leans” diet, and has a pending federal trademark for “FLOATS”: flax + oats cereal.
A version of this article first appeared on Medscape.com.
Only a third of adults with diabetes receive ADA-recommended care
In 2017-2018, only one in three U.S. adults with diabetes received five basic elements of care recommended by the American Diabetes Association, new research indicates.
The proportions of patients who visited a physician for diabetes care and received hemoglobin A1c testing, foot and eye exams, and cholesterol testing increased from 2005 to 2018. However, this increase was primarily among those aged 65 years and older, and therefore eligible for Medicare.
“Our study suggests that providing affordable health care coverage can help ensure people with diabetes get recommended care. We also found that patients who were not receiving recommended care were more likely to be younger, newly diagnosed with diabetes, and not on diabetes medication. Clinicians can pay more attention to these patient populations to improve recommended care delivery and prevent diabetes-related complications,” lead author Jung-Im Shin, MD, said in an interview.
The data predate the COVID-19 pandemic, which has also had major effects on delivery of diabetes care, added Dr. Shin of Johns Hopkins University, Baltimore.
“Routine visits to the doctor and important screenings for retinopathy or foot examination have been postponed. People with diabetes have had to reschedule or cancel nonurgent visits, some have lost ... insurance following unemployment, and many have avoided health care facilities out of fear. We are only just beginning to understand the consequences of the pandemic on the health of people with diabetes,” Dr. Shin noted.
Overall improvements seen only in those aged 65 and older
The data, from 4,069 adults aged 20 years and older from the 2005-2018 National Health and Nutrition and Examination Survey (NHANES), were published online April 16, 2021, in Diabetes Care.
Dr. Shin and colleagues defined receipt of diabetes care as meeting all of the following five criteria in the past 12 months, based on the ADA Standards of Care and NHANES data availability: seeing a primary doctor for diabetes care, receiving A1c testing, receiving a foot examination, receiving an eye examination, and receiving cholesterol testing.
Over the entire 13-year period, 29.2% of respondents reported having received all five components.
That proportion increased significantly over time, from 25.0% in 2005-2006 to 34.1% in 2017-2018 (P = .004). However, among the individual components, only receiving A1c testing increased significantly over time, from 64.4% to 85.3%, in all age groups (P < .001).
Moreover, when stratified by age, receipt of all five components only increased significantly among participants aged 65 and older, from 29.3% in 2005-2006 to 44.2% in 2017-2018 (P = .001).
The proportion remained unchanged among those aged 40-64 (25.2% to 25.8%; P = .457) and showed a nonsignificant increase in those aged 20-39 (9.9% to 26.0%; P = .401).
In adjusted analyses, older age, higher income and education, health insurance, longer duration of diabetes, use of diabetes medications, and hypercholesterolemia were significantly associated with receipt of ADA guideline–recommended diabetes care.
Factors not found to be associated with care receipt included sex, race/ethnicity, body mass index, smoking status, A1c, hypertension, cardiovascular disease, chronic kidney disease, and depressive symptoms.
Participants who received ADA guideline–recommended care were significantly more likely to achieve A1c below 7.5% (adjusted odds ratio, 1.52), blood pressure less than 140/90 mm Hg (aOR, 1.47), and LDL cholesterol below 100 mg/dL (aOR, 1.47), and to receive cholesterol-lowering medication (aOR, 1.79).
Dr. Shin said that it will be “important to study the impact of COVID-19 on diabetes care when new data are available.”
The project was supported by a research grant from Merck to Johns Hopkins University. Shin has reported receiving a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Two coauthors are Merck employees.
A version of this article first appeared on Medscape.com.
In 2017-2018, only one in three U.S. adults with diabetes received five basic elements of care recommended by the American Diabetes Association, new research indicates.
The proportions of patients who visited a physician for diabetes care and received hemoglobin A1c testing, foot and eye exams, and cholesterol testing increased from 2005 to 2018. However, this increase was primarily among those aged 65 years and older, and therefore eligible for Medicare.
“Our study suggests that providing affordable health care coverage can help ensure people with diabetes get recommended care. We also found that patients who were not receiving recommended care were more likely to be younger, newly diagnosed with diabetes, and not on diabetes medication. Clinicians can pay more attention to these patient populations to improve recommended care delivery and prevent diabetes-related complications,” lead author Jung-Im Shin, MD, said in an interview.
The data predate the COVID-19 pandemic, which has also had major effects on delivery of diabetes care, added Dr. Shin of Johns Hopkins University, Baltimore.
“Routine visits to the doctor and important screenings for retinopathy or foot examination have been postponed. People with diabetes have had to reschedule or cancel nonurgent visits, some have lost ... insurance following unemployment, and many have avoided health care facilities out of fear. We are only just beginning to understand the consequences of the pandemic on the health of people with diabetes,” Dr. Shin noted.
Overall improvements seen only in those aged 65 and older
The data, from 4,069 adults aged 20 years and older from the 2005-2018 National Health and Nutrition and Examination Survey (NHANES), were published online April 16, 2021, in Diabetes Care.
Dr. Shin and colleagues defined receipt of diabetes care as meeting all of the following five criteria in the past 12 months, based on the ADA Standards of Care and NHANES data availability: seeing a primary doctor for diabetes care, receiving A1c testing, receiving a foot examination, receiving an eye examination, and receiving cholesterol testing.
Over the entire 13-year period, 29.2% of respondents reported having received all five components.
That proportion increased significantly over time, from 25.0% in 2005-2006 to 34.1% in 2017-2018 (P = .004). However, among the individual components, only receiving A1c testing increased significantly over time, from 64.4% to 85.3%, in all age groups (P < .001).
Moreover, when stratified by age, receipt of all five components only increased significantly among participants aged 65 and older, from 29.3% in 2005-2006 to 44.2% in 2017-2018 (P = .001).
The proportion remained unchanged among those aged 40-64 (25.2% to 25.8%; P = .457) and showed a nonsignificant increase in those aged 20-39 (9.9% to 26.0%; P = .401).
In adjusted analyses, older age, higher income and education, health insurance, longer duration of diabetes, use of diabetes medications, and hypercholesterolemia were significantly associated with receipt of ADA guideline–recommended diabetes care.
Factors not found to be associated with care receipt included sex, race/ethnicity, body mass index, smoking status, A1c, hypertension, cardiovascular disease, chronic kidney disease, and depressive symptoms.
Participants who received ADA guideline–recommended care were significantly more likely to achieve A1c below 7.5% (adjusted odds ratio, 1.52), blood pressure less than 140/90 mm Hg (aOR, 1.47), and LDL cholesterol below 100 mg/dL (aOR, 1.47), and to receive cholesterol-lowering medication (aOR, 1.79).
Dr. Shin said that it will be “important to study the impact of COVID-19 on diabetes care when new data are available.”
The project was supported by a research grant from Merck to Johns Hopkins University. Shin has reported receiving a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Two coauthors are Merck employees.
A version of this article first appeared on Medscape.com.
In 2017-2018, only one in three U.S. adults with diabetes received five basic elements of care recommended by the American Diabetes Association, new research indicates.
The proportions of patients who visited a physician for diabetes care and received hemoglobin A1c testing, foot and eye exams, and cholesterol testing increased from 2005 to 2018. However, this increase was primarily among those aged 65 years and older, and therefore eligible for Medicare.
“Our study suggests that providing affordable health care coverage can help ensure people with diabetes get recommended care. We also found that patients who were not receiving recommended care were more likely to be younger, newly diagnosed with diabetes, and not on diabetes medication. Clinicians can pay more attention to these patient populations to improve recommended care delivery and prevent diabetes-related complications,” lead author Jung-Im Shin, MD, said in an interview.
The data predate the COVID-19 pandemic, which has also had major effects on delivery of diabetes care, added Dr. Shin of Johns Hopkins University, Baltimore.
“Routine visits to the doctor and important screenings for retinopathy or foot examination have been postponed. People with diabetes have had to reschedule or cancel nonurgent visits, some have lost ... insurance following unemployment, and many have avoided health care facilities out of fear. We are only just beginning to understand the consequences of the pandemic on the health of people with diabetes,” Dr. Shin noted.
Overall improvements seen only in those aged 65 and older
The data, from 4,069 adults aged 20 years and older from the 2005-2018 National Health and Nutrition and Examination Survey (NHANES), were published online April 16, 2021, in Diabetes Care.
Dr. Shin and colleagues defined receipt of diabetes care as meeting all of the following five criteria in the past 12 months, based on the ADA Standards of Care and NHANES data availability: seeing a primary doctor for diabetes care, receiving A1c testing, receiving a foot examination, receiving an eye examination, and receiving cholesterol testing.
Over the entire 13-year period, 29.2% of respondents reported having received all five components.
That proportion increased significantly over time, from 25.0% in 2005-2006 to 34.1% in 2017-2018 (P = .004). However, among the individual components, only receiving A1c testing increased significantly over time, from 64.4% to 85.3%, in all age groups (P < .001).
Moreover, when stratified by age, receipt of all five components only increased significantly among participants aged 65 and older, from 29.3% in 2005-2006 to 44.2% in 2017-2018 (P = .001).
The proportion remained unchanged among those aged 40-64 (25.2% to 25.8%; P = .457) and showed a nonsignificant increase in those aged 20-39 (9.9% to 26.0%; P = .401).
In adjusted analyses, older age, higher income and education, health insurance, longer duration of diabetes, use of diabetes medications, and hypercholesterolemia were significantly associated with receipt of ADA guideline–recommended diabetes care.
Factors not found to be associated with care receipt included sex, race/ethnicity, body mass index, smoking status, A1c, hypertension, cardiovascular disease, chronic kidney disease, and depressive symptoms.
Participants who received ADA guideline–recommended care were significantly more likely to achieve A1c below 7.5% (adjusted odds ratio, 1.52), blood pressure less than 140/90 mm Hg (aOR, 1.47), and LDL cholesterol below 100 mg/dL (aOR, 1.47), and to receive cholesterol-lowering medication (aOR, 1.79).
Dr. Shin said that it will be “important to study the impact of COVID-19 on diabetes care when new data are available.”
The project was supported by a research grant from Merck to Johns Hopkins University. Shin has reported receiving a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Two coauthors are Merck employees.
A version of this article first appeared on Medscape.com.