Geriatrics

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

msullivan@mededge.com

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

msullivan@mededge.com

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

LOS ANGELES – Benzodiazepines and hypnotics, including the so-called “Z drugs,” don’t significantly increase the pathological features typical of Alzheimer’s disease but long-term users may experience some neuronal loss in the nucleus basalis, Chris Fox, MD, reported at the Alzheimer’s Association International Conference.

Michele G. Sullivan/MDedge News

The nucleus basalis is rich in cholinergic neurons and associated with arousing stimuli, including positive and aversive appetite, sustained attention, and the interplay of reality and visual perception.

“Neuronal loss in the nucleus basalis offers mechanisms for the impact of benzodiazepine and anticholinergic drug use on the aging brain and highlights important areas for future research,” said Dr. Fox, professor of clinical psychiatry at the University of East Anglia, Norwich, England.

“The risk [for taking a Z drug] in the United Kingdom is high, with about 7.5 million older adults using potentially inappropriately prescribed anticholinergic and/or Z-drug medications. Despite well-documented cognitive impairment associated with these medicines, hypnotics are still used for long durations and exceed the recommended limits,” Dr. Fox said. “There’s no association with better cognition, quality of life, or improved behavior when they are given to people with dementia. In fact, we’ve seen a 60% increased risk of hip fractures – an increase from a 3% to a 15% yearly risk.”

Dr. Fox and colleagues studied the brains of 337 subjects who were included in the U.K. Medical Research Council’s Cognitive Function and Ageing Studies (CFAS). The study was intended to explore the incidence of dementia in the United Kingdom, examine incidence variation among regions, and explore factors increasing dementia risk and rate of progression.

The first study, which began in 1989 and lasted until 2015, followed subjects older than 65 years for up to 12 years. Each subject was regularly interviewed and underwent cognitive testing about every 1.5 years. Benzodiazepine use was considered an especially important aspect, because the medications are frequently used in the elderly and seem linked to injuries and cognitive status at last follow-up.

In CFAS, 21% of subjects reported at least one incidence of anticholinergic use, and 12% reported recurrent use. Another 17% reported any hypnotic use, and 11% reported recurrent use. The main indications were as an antidepressant (13%), for urological issues (4%), as antiparkinsonism drugs (1%), as antipsychotics (3%), and as antihistamines (3%). Overall, 18% reported concurrent use of benzodiazepines and hypnotics. At time of death, 46% had a diagnosis of dementia.

“Those reporting benzodiazepine use were more likely to be women and to have depression or sleep problems,” Dr. Fox noted, although he didn’t give specific hazard ratios. After adjustment for numerous factors, including age, sex, stroke, hypertension, depression, anxiety, asthma, Parkinson’s disease, duration of sleep problems, education, and smoking, he found no statistically increased risk of amyloid brain plaques or tau tangles, the pathologic hallmarks of Alzheimer’s disease.

Anticholinergic use was associated with a significant 60% reduction in cortical atrophy (odds ratio, 0.40) and recurrent use with a 61% reduction in amyloid angiopathy (OR, 0.39).

However, both medication classes were associated with greater neuronal loss in the nucleus basalis. Recurrent use of anticholinergic drugs increased neuronal loss by 300% (OR, 4.12), while any use nearly tripled it (OR, 2.87). Recurrent use of benzodiazepines was associated with increased neuronal loss in the region (OR, 3.76) as well. However, these associations did not reach statistical significance. But there was a statistically significant association with any use of benzodiazepines and neuronal loss in the nucleus basalis (OR, 6.84).

“We did find greater neuronal loss in the nucleus basalis associated with benzodiazepine and anticholinergic drugs use,” Dr. Fox said. “The nucleus basalis is rich in neurons that stimulate the cholinergic system of the neocortex. Neuronal loss in this region is thought to occur in the early stages of Alzheimer’s. Other studies have suggested that volume loss in the basal forebrain cholinergic site leads to widespread cortical atrophy in patients with mild cognitive impairment. We did not observe the widespread cortical atrophy, however.

“Given that the strongest associations were observed for benzodiazepines and neuronal loss in the nucleus basalis, it may be that the drugs were prescribed to treat the symptoms of ‘cholinergic deficiency syndrome,’ Our findings suggest that the symptoms of dementia lead to an increase of benzodiazepines as opposed to the medications actually causing Alzheimer’s disease,” he said.

Dr. Fox reported no financial disclosures.

msullivan@mededge.com

SOURCE: Fox C et al. AAIC 2019, Abstract 34017.

The patient grabbed my attention as I glanced through our clinic schedule. It was his age: He was 99 years old and scheduled for eye surgery. The plastic surgery resident’s note read: “Patient understands that this would involve surgery under general anesthesia and is agreeable to moving forward...Extremely high risk of anesthesia emphasized.”

I reviewed the patient’s history. At baseline, he had severe pulmonary hypertension, severe aortic stenosis (AS), diastolic heart failure, chronic atrial fibrillation, chronic kidney disease (estimated glomerular filtration rate of 26 mL/min [normal is > 60 mL/min]), anemia (hematocrit 26%), and a standing do not resuscitate (DNR) order. His maximal daily exercise was walking slowly across a room, primarily limited by joint pain. Recent geropsychiatry notes indicated mild cognitive impairment. The anesthesia record from an urgent hip fracture repair 7 months before under general anesthesia was unremarkable.

I phoned the attending plastic surgeon. Our conversation was as follows:

“Hi, I’m about to see a 99-year-old patient with a DNR who is scheduled for resection of an eyelid tumor. His medical history makes me nervous. Are you sure this is a good idea?”“Hmmm, 99-year-old…okay, that’s right,” he responded. “He has an invasive squamous that could become a big problem. The actual procedure is under 10 minutes. Waiting for the pathology report will be the longest part of the procedure.”

“Can it be done under local?” I asked.

“Yes,” he replied.

“Okay, I’ll talk to him and call you back.”

I found the patient in the waiting room, flanked by his 2 daughters and invited them into the clinic room. After introductions, I began asking whether they had any questions about the anesthesia. By midsentence a daughter was prompting him to discuss what happened “last time.” He described a history of posttraumatic stress disorder (PTSD) stemming from his hip surgery, which he blamed squarely on the anesthesia. His emotion was evident in the gathering pauses. “I hate that I am so emotional since they kept me awake during my surgery.”

Through the fog of multiple accounts, it became clear that he was traumatized by the loss of control during the administration of and emergence from the anesthesia.

“They told me it was only oxygen,” he said. “They lied. There was a taste to it…I was awake and skinned alive…They said I was a monster when I woke up thrashing.” He went on, explaining that in the recovery room “there were 2 people bothering me, man-handling me, asking me questions.”

One of his daughters showed me pictures of bruises on his face from ripping off the mask and pulling out the breathing tube. They were visibly upset by the memory of his postoperative combativeness and paranoia. The note written by the orthopedic surgery resident on the day after surgery stated succinctly, “Doing well, had some delirium from anesthesia overnight.” Subsequent geropsychiatry home visits attested to intrusive thoughts, flashbacks, and nightmares from his time as a combat soldier in World War II, 65 years in the past.

“It took me months…months to recover,” he said.

He was in the mood to reminisce, however, perhaps a willful distraction. He had the floor for at least 30 minutes, during which I spoke about 5 sentences. With every sad story he told there was a happy, humorous one, such as meeting his future wife while on leave in New Zealand during the war, recalled down to exact dates. And another story:
 

There we were in New Caledonia. All our supplies went out to replace what sank on [USS] Coolidge, including a lot of food. Well, there were deer on the island. So we took out a truck and a rifle and wouldn’t you know we came upon a roadblock in the form of a big steer. We figured it looked enough like a deer. My buddy shot it dead with one shot. We dressed it and loaded it into the jeep. Hardly before we even got back to the mess hall, the officers’ cook came sniffing around. He and our captain agreed it was easily the biggest deer they’d ever seen and appropriated it to the officers’ mess. Next day the CO [commanding officer] of the whole outfit came by and announced it was the best tasting ‘venison’ he’d ever had. I heard the farmer got paid a pretty penny for that steer. I didn’t get a damn bite.

He delivered this last bit with relish.

When the conversation returned to anesthesia, I read them the record of his hip fracture repair. I explained that on the face of it, the report seemed uneventful. One daughter asked astute questions about his awareness. I explained that although awareness during general anesthesia is possible, it seemed from the record, he’d had plenty of anesthesia during the case and that there is always less at the beginning and end, the periods that apparently had caused him distress. I also explained that most studies report the incidence of true awareness as at most 1 out of thousands of events and that he had none of the established risk factors for it, such as female gender, young age, chronic substance abuse, cardiac and obstetric surgery, and history of awareness.¹

The other daughter wondered why he was so agitated afterward. I recited data on the frequency of postoperative delirium in elderly patients but explained that the range is wide, depending on the study and population, from about 1% in elderly patients undergoing ambulatory surgery to 65% for open aortic surgery.^2,3 I added that their father had 2 of the strongest risk factors for delirium, advanced age and cognitive impairment.³ Only after airing each question about the hip surgery in detail were they ready to discuss the eye surgery.

He started that conversation with the right question: “Do I really need it?”

I quoted my surgical colleague’s concern. I told him that, should he opt to undergo the surgery, I was confident that this time around his experience would be different from the last.

“If you’re okay with it, all you need is some numbing medicine from the surgeon; you won’t need any anesthesia from me.”

I walked step-by-step through what they could expect on the day of surgery. Maintaining control was of obvious importance to him. He felt comfortable going forward. His daughters intuited that less would be more for a quick recovery.

We then addressed the DNR directive. I acknowledged his absolute right to self-determination and explained that the need for resuscitation is, at times, a consequence of the surgery and anesthesia. I reassured them that our plan made resuscitation and intubation highly unlikely. They also asked to use any interventions necessary to restart his heart if it should stop beating. I documented their decision in my notes and communicated it to the surgical team. We had talked for 90 minutes.

I met the patient and his daughters on the day of surgery in the preoperative holding area. I inserted an IV, applied electrocardiography leads, and affixed a pulse oximeter and a noninvasive blood pressure cuff. In the operating room (OR) we took time to place his 99-year-old joints into, as he said, the “least worst” position. He tolerated the injection of the local by the surgeon perfectly well. We were in the OR for 3 hours, during which he taught me a fair amount about boating and outboard engines among other things. Pathology reported clean margins. He was discharged home soon after and had an uneventful recovery.

Patient-First Approach

A core competency of the Accreditation Council for Graduate Medical Education for an anesthesia residency is the Interpersonal and Communication Skills program. A comprehensive discussion of communication is far beyond the scope here. But not surprisingly, deficient communication between physicians and patients can cause emotional distress, significant dissatisfaction among family members, and negative patient judgment of how well we communicate.^4-6 These observations are particularly true in our increasingly elderly surgical population, in which both surgeons and anesthesiologists often feel unequal to the task of discussing concepts such as code status.^7,8

In our practice and in residency training, the preoperative clinic often is the location where patient/provider communication occurs. Here we consider the latest American College of Cardiology/American Heart Association guidelines, examine airways, review electrocardiograms, and formulate plans agreeable to and understood by our anxious patients and their families. The potent anxiolytic effect of a preoperative visit by an anesthesiologist is well established.⁹ Anxiety about surgery is a risk factor for impaired decision making before surgery.¹⁰ And surgery is traumatic—as many as 7.6% of postoperative patients experience symptoms consistent with PTSD attributable to the surgery, placing it on a par with being mugged (8.0%).^11,12

The patient in this case presented several communication challenges even absent his revelation of prior traumatic experience with anesthesia. He was elderly, anxious, and had multiple comorbidities. He had mild cognitive impairment and required a code status discussion. There also were the clinical challenges—navigating a 99-year-old with severe aortic stenosis and a right ventricular systolic pressure > 90 mm Hg through a general anesthetic gave me a sinking feeling.

He was fortunate that the procedure could be done with local anesthesia, mitigating his risk of cognitive dysfunction, including delirium. He also was fortunate in that his anesthesiologist and surgeon had created a collaborative, patient-first approach and that his US Department of Veterans Affairs (VA) clinic had the time, space, and staffing to accommodate an unexpected 90-minute visit. A big investment in communication, mainly my keeping quiet, made the intraoperative management simple. Such is life in an integrated health care system without financial incentives for high-volume care—and another reminder that VA physicians are blessed to guide patients through some of the most vulnerable and distressing moments of their lives.

Postscript

During the preparation of this manuscript, the patient passed away at the age of 100. His obituary was consistent with what I had learned about him and his family during our 2 encounters: a long successful career in local industry; extensive involvement in his community; an avid sportsman; and nearly 30 grandchildren, great-grandchildren, and great-great grandchildren. But there was one more detail that never came up during my extensive discussion with him and his daughters: He was awarded the Purple Heart for his service in World War II.

The patient grabbed my attention as I glanced through our clinic schedule. It was his age: He was 99 years old and scheduled for eye surgery. The plastic surgery resident’s note read: “Patient understands that this would involve surgery under general anesthesia and is agreeable to moving forward...Extremely high risk of anesthesia emphasized.”

I reviewed the patient’s history. At baseline, he had severe pulmonary hypertension, severe aortic stenosis (AS), diastolic heart failure, chronic atrial fibrillation, chronic kidney disease (estimated glomerular filtration rate of 26 mL/min [normal is > 60 mL/min]), anemia (hematocrit 26%), and a standing do not resuscitate (DNR) order. His maximal daily exercise was walking slowly across a room, primarily limited by joint pain. Recent geropsychiatry notes indicated mild cognitive impairment. The anesthesia record from an urgent hip fracture repair 7 months before under general anesthesia was unremarkable.

I phoned the attending plastic surgeon. Our conversation was as follows:

“Hi, I’m about to see a 99-year-old patient with a DNR who is scheduled for resection of an eyelid tumor. His medical history makes me nervous. Are you sure this is a good idea?”“Hmmm, 99-year-old…okay, that’s right,” he responded. “He has an invasive squamous that could become a big problem. The actual procedure is under 10 minutes. Waiting for the pathology report will be the longest part of the procedure.”

“Can it be done under local?” I asked.

“Yes,” he replied.

“Okay, I’ll talk to him and call you back.”

I found the patient in the waiting room, flanked by his 2 daughters and invited them into the clinic room. After introductions, I began asking whether they had any questions about the anesthesia. By midsentence a daughter was prompting him to discuss what happened “last time.” He described a history of posttraumatic stress disorder (PTSD) stemming from his hip surgery, which he blamed squarely on the anesthesia. His emotion was evident in the gathering pauses. “I hate that I am so emotional since they kept me awake during my surgery.”

Through the fog of multiple accounts, it became clear that he was traumatized by the loss of control during the administration of and emergence from the anesthesia.

“They told me it was only oxygen,” he said. “They lied. There was a taste to it…I was awake and skinned alive…They said I was a monster when I woke up thrashing.” He went on, explaining that in the recovery room “there were 2 people bothering me, man-handling me, asking me questions.”

One of his daughters showed me pictures of bruises on his face from ripping off the mask and pulling out the breathing tube. They were visibly upset by the memory of his postoperative combativeness and paranoia. The note written by the orthopedic surgery resident on the day after surgery stated succinctly, “Doing well, had some delirium from anesthesia overnight.” Subsequent geropsychiatry home visits attested to intrusive thoughts, flashbacks, and nightmares from his time as a combat soldier in World War II, 65 years in the past.

“It took me months…months to recover,” he said.

He was in the mood to reminisce, however, perhaps a willful distraction. He had the floor for at least 30 minutes, during which I spoke about 5 sentences. With every sad story he told there was a happy, humorous one, such as meeting his future wife while on leave in New Zealand during the war, recalled down to exact dates. And another story:
 

There we were in New Caledonia. All our supplies went out to replace what sank on [USS] Coolidge, including a lot of food. Well, there were deer on the island. So we took out a truck and a rifle and wouldn’t you know we came upon a roadblock in the form of a big steer. We figured it looked enough like a deer. My buddy shot it dead with one shot. We dressed it and loaded it into the jeep. Hardly before we even got back to the mess hall, the officers’ cook came sniffing around. He and our captain agreed it was easily the biggest deer they’d ever seen and appropriated it to the officers’ mess. Next day the CO [commanding officer] of the whole outfit came by and announced it was the best tasting ‘venison’ he’d ever had. I heard the farmer got paid a pretty penny for that steer. I didn’t get a damn bite.

He delivered this last bit with relish.

When the conversation returned to anesthesia, I read them the record of his hip fracture repair. I explained that on the face of it, the report seemed uneventful. One daughter asked astute questions about his awareness. I explained that although awareness during general anesthesia is possible, it seemed from the record, he’d had plenty of anesthesia during the case and that there is always less at the beginning and end, the periods that apparently had caused him distress. I also explained that most studies report the incidence of true awareness as at most 1 out of thousands of events and that he had none of the established risk factors for it, such as female gender, young age, chronic substance abuse, cardiac and obstetric surgery, and history of awareness.¹

The other daughter wondered why he was so agitated afterward. I recited data on the frequency of postoperative delirium in elderly patients but explained that the range is wide, depending on the study and population, from about 1% in elderly patients undergoing ambulatory surgery to 65% for open aortic surgery.^2,3 I added that their father had 2 of the strongest risk factors for delirium, advanced age and cognitive impairment.³ Only after airing each question about the hip surgery in detail were they ready to discuss the eye surgery.

He started that conversation with the right question: “Do I really need it?”

I quoted my surgical colleague’s concern. I told him that, should he opt to undergo the surgery, I was confident that this time around his experience would be different from the last.

“If you’re okay with it, all you need is some numbing medicine from the surgeon; you won’t need any anesthesia from me.”

I walked step-by-step through what they could expect on the day of surgery. Maintaining control was of obvious importance to him. He felt comfortable going forward. His daughters intuited that less would be more for a quick recovery.

We then addressed the DNR directive. I acknowledged his absolute right to self-determination and explained that the need for resuscitation is, at times, a consequence of the surgery and anesthesia. I reassured them that our plan made resuscitation and intubation highly unlikely. They also asked to use any interventions necessary to restart his heart if it should stop beating. I documented their decision in my notes and communicated it to the surgical team. We had talked for 90 minutes.

I met the patient and his daughters on the day of surgery in the preoperative holding area. I inserted an IV, applied electrocardiography leads, and affixed a pulse oximeter and a noninvasive blood pressure cuff. In the operating room (OR) we took time to place his 99-year-old joints into, as he said, the “least worst” position. He tolerated the injection of the local by the surgeon perfectly well. We were in the OR for 3 hours, during which he taught me a fair amount about boating and outboard engines among other things. Pathology reported clean margins. He was discharged home soon after and had an uneventful recovery.

Patient-First Approach

A core competency of the Accreditation Council for Graduate Medical Education for an anesthesia residency is the Interpersonal and Communication Skills program. A comprehensive discussion of communication is far beyond the scope here. But not surprisingly, deficient communication between physicians and patients can cause emotional distress, significant dissatisfaction among family members, and negative patient judgment of how well we communicate.^4-6 These observations are particularly true in our increasingly elderly surgical population, in which both surgeons and anesthesiologists often feel unequal to the task of discussing concepts such as code status.^7,8

In our practice and in residency training, the preoperative clinic often is the location where patient/provider communication occurs. Here we consider the latest American College of Cardiology/American Heart Association guidelines, examine airways, review electrocardiograms, and formulate plans agreeable to and understood by our anxious patients and their families. The potent anxiolytic effect of a preoperative visit by an anesthesiologist is well established.⁹ Anxiety about surgery is a risk factor for impaired decision making before surgery.¹⁰ And surgery is traumatic—as many as 7.6% of postoperative patients experience symptoms consistent with PTSD attributable to the surgery, placing it on a par with being mugged (8.0%).^11,12

The patient in this case presented several communication challenges even absent his revelation of prior traumatic experience with anesthesia. He was elderly, anxious, and had multiple comorbidities. He had mild cognitive impairment and required a code status discussion. There also were the clinical challenges—navigating a 99-year-old with severe aortic stenosis and a right ventricular systolic pressure > 90 mm Hg through a general anesthetic gave me a sinking feeling.

He was fortunate that the procedure could be done with local anesthesia, mitigating his risk of cognitive dysfunction, including delirium. He also was fortunate in that his anesthesiologist and surgeon had created a collaborative, patient-first approach and that his US Department of Veterans Affairs (VA) clinic had the time, space, and staffing to accommodate an unexpected 90-minute visit. A big investment in communication, mainly my keeping quiet, made the intraoperative management simple. Such is life in an integrated health care system without financial incentives for high-volume care—and another reminder that VA physicians are blessed to guide patients through some of the most vulnerable and distressing moments of their lives.

Postscript

During the preparation of this manuscript, the patient passed away at the age of 100. His obituary was consistent with what I had learned about him and his family during our 2 encounters: a long successful career in local industry; extensive involvement in his community; an avid sportsman; and nearly 30 grandchildren, great-grandchildren, and great-great grandchildren. But there was one more detail that never came up during my extensive discussion with him and his daughters: He was awarded the Purple Heart for his service in World War II.

The patient grabbed my attention as I glanced through our clinic schedule. It was his age: He was 99 years old and scheduled for eye surgery. The plastic surgery resident’s note read: “Patient understands that this would involve surgery under general anesthesia and is agreeable to moving forward...Extremely high risk of anesthesia emphasized.”

I reviewed the patient’s history. At baseline, he had severe pulmonary hypertension, severe aortic stenosis (AS), diastolic heart failure, chronic atrial fibrillation, chronic kidney disease (estimated glomerular filtration rate of 26 mL/min [normal is > 60 mL/min]), anemia (hematocrit 26%), and a standing do not resuscitate (DNR) order. His maximal daily exercise was walking slowly across a room, primarily limited by joint pain. Recent geropsychiatry notes indicated mild cognitive impairment. The anesthesia record from an urgent hip fracture repair 7 months before under general anesthesia was unremarkable.

I phoned the attending plastic surgeon. Our conversation was as follows:

“Hi, I’m about to see a 99-year-old patient with a DNR who is scheduled for resection of an eyelid tumor. His medical history makes me nervous. Are you sure this is a good idea?”“Hmmm, 99-year-old…okay, that’s right,” he responded. “He has an invasive squamous that could become a big problem. The actual procedure is under 10 minutes. Waiting for the pathology report will be the longest part of the procedure.”

“Can it be done under local?” I asked.

“Yes,” he replied.

“Okay, I’ll talk to him and call you back.”

I found the patient in the waiting room, flanked by his 2 daughters and invited them into the clinic room. After introductions, I began asking whether they had any questions about the anesthesia. By midsentence a daughter was prompting him to discuss what happened “last time.” He described a history of posttraumatic stress disorder (PTSD) stemming from his hip surgery, which he blamed squarely on the anesthesia. His emotion was evident in the gathering pauses. “I hate that I am so emotional since they kept me awake during my surgery.”

Through the fog of multiple accounts, it became clear that he was traumatized by the loss of control during the administration of and emergence from the anesthesia.

“They told me it was only oxygen,” he said. “They lied. There was a taste to it…I was awake and skinned alive…They said I was a monster when I woke up thrashing.” He went on, explaining that in the recovery room “there were 2 people bothering me, man-handling me, asking me questions.”

One of his daughters showed me pictures of bruises on his face from ripping off the mask and pulling out the breathing tube. They were visibly upset by the memory of his postoperative combativeness and paranoia. The note written by the orthopedic surgery resident on the day after surgery stated succinctly, “Doing well, had some delirium from anesthesia overnight.” Subsequent geropsychiatry home visits attested to intrusive thoughts, flashbacks, and nightmares from his time as a combat soldier in World War II, 65 years in the past.

“It took me months…months to recover,” he said.

He was in the mood to reminisce, however, perhaps a willful distraction. He had the floor for at least 30 minutes, during which I spoke about 5 sentences. With every sad story he told there was a happy, humorous one, such as meeting his future wife while on leave in New Zealand during the war, recalled down to exact dates. And another story:
 

There we were in New Caledonia. All our supplies went out to replace what sank on [USS] Coolidge, including a lot of food. Well, there were deer on the island. So we took out a truck and a rifle and wouldn’t you know we came upon a roadblock in the form of a big steer. We figured it looked enough like a deer. My buddy shot it dead with one shot. We dressed it and loaded it into the jeep. Hardly before we even got back to the mess hall, the officers’ cook came sniffing around. He and our captain agreed it was easily the biggest deer they’d ever seen and appropriated it to the officers’ mess. Next day the CO [commanding officer] of the whole outfit came by and announced it was the best tasting ‘venison’ he’d ever had. I heard the farmer got paid a pretty penny for that steer. I didn’t get a damn bite.

He delivered this last bit with relish.

When the conversation returned to anesthesia, I read them the record of his hip fracture repair. I explained that on the face of it, the report seemed uneventful. One daughter asked astute questions about his awareness. I explained that although awareness during general anesthesia is possible, it seemed from the record, he’d had plenty of anesthesia during the case and that there is always less at the beginning and end, the periods that apparently had caused him distress. I also explained that most studies report the incidence of true awareness as at most 1 out of thousands of events and that he had none of the established risk factors for it, such as female gender, young age, chronic substance abuse, cardiac and obstetric surgery, and history of awareness.¹

The other daughter wondered why he was so agitated afterward. I recited data on the frequency of postoperative delirium in elderly patients but explained that the range is wide, depending on the study and population, from about 1% in elderly patients undergoing ambulatory surgery to 65% for open aortic surgery.^2,3 I added that their father had 2 of the strongest risk factors for delirium, advanced age and cognitive impairment.³ Only after airing each question about the hip surgery in detail were they ready to discuss the eye surgery.

He started that conversation with the right question: “Do I really need it?”

I quoted my surgical colleague’s concern. I told him that, should he opt to undergo the surgery, I was confident that this time around his experience would be different from the last.

“If you’re okay with it, all you need is some numbing medicine from the surgeon; you won’t need any anesthesia from me.”

I walked step-by-step through what they could expect on the day of surgery. Maintaining control was of obvious importance to him. He felt comfortable going forward. His daughters intuited that less would be more for a quick recovery.

We then addressed the DNR directive. I acknowledged his absolute right to self-determination and explained that the need for resuscitation is, at times, a consequence of the surgery and anesthesia. I reassured them that our plan made resuscitation and intubation highly unlikely. They also asked to use any interventions necessary to restart his heart if it should stop beating. I documented their decision in my notes and communicated it to the surgical team. We had talked for 90 minutes.

I met the patient and his daughters on the day of surgery in the preoperative holding area. I inserted an IV, applied electrocardiography leads, and affixed a pulse oximeter and a noninvasive blood pressure cuff. In the operating room (OR) we took time to place his 99-year-old joints into, as he said, the “least worst” position. He tolerated the injection of the local by the surgeon perfectly well. We were in the OR for 3 hours, during which he taught me a fair amount about boating and outboard engines among other things. Pathology reported clean margins. He was discharged home soon after and had an uneventful recovery.

Patient-First Approach

A core competency of the Accreditation Council for Graduate Medical Education for an anesthesia residency is the Interpersonal and Communication Skills program. A comprehensive discussion of communication is far beyond the scope here. But not surprisingly, deficient communication between physicians and patients can cause emotional distress, significant dissatisfaction among family members, and negative patient judgment of how well we communicate.^4-6 These observations are particularly true in our increasingly elderly surgical population, in which both surgeons and anesthesiologists often feel unequal to the task of discussing concepts such as code status.^7,8

In our practice and in residency training, the preoperative clinic often is the location where patient/provider communication occurs. Here we consider the latest American College of Cardiology/American Heart Association guidelines, examine airways, review electrocardiograms, and formulate plans agreeable to and understood by our anxious patients and their families. The potent anxiolytic effect of a preoperative visit by an anesthesiologist is well established.⁹ Anxiety about surgery is a risk factor for impaired decision making before surgery.¹⁰ And surgery is traumatic—as many as 7.6% of postoperative patients experience symptoms consistent with PTSD attributable to the surgery, placing it on a par with being mugged (8.0%).^11,12

The patient in this case presented several communication challenges even absent his revelation of prior traumatic experience with anesthesia. He was elderly, anxious, and had multiple comorbidities. He had mild cognitive impairment and required a code status discussion. There also were the clinical challenges—navigating a 99-year-old with severe aortic stenosis and a right ventricular systolic pressure > 90 mm Hg through a general anesthetic gave me a sinking feeling.

He was fortunate that the procedure could be done with local anesthesia, mitigating his risk of cognitive dysfunction, including delirium. He also was fortunate in that his anesthesiologist and surgeon had created a collaborative, patient-first approach and that his US Department of Veterans Affairs (VA) clinic had the time, space, and staffing to accommodate an unexpected 90-minute visit. A big investment in communication, mainly my keeping quiet, made the intraoperative management simple. Such is life in an integrated health care system without financial incentives for high-volume care—and another reminder that VA physicians are blessed to guide patients through some of the most vulnerable and distressing moments of their lives.

Postscript

During the preparation of this manuscript, the patient passed away at the age of 100. His obituary was consistent with what I had learned about him and his family during our 2 encounters: a long successful career in local industry; extensive involvement in his community; an avid sportsman; and nearly 30 grandchildren, great-grandchildren, and great-great grandchildren. But there was one more detail that never came up during my extensive discussion with him and his daughters: He was awarded the Purple Heart for his service in World War II.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

Discontinuing statins was associated with an increased risk of hospital admission for a cardiovascular event, according to a study of elderly French patients with no history of heart disease.

RogerAshford/Thinkstock

“The results of this study suggest potential cardiovascular risk reduction associated with continuing statin therapy after the age of 75 years in persons already taking these drugs for primary prevention,” wrote Philippe Giral, MD, of Hôpital La Pitié Salpêtrière (France) and coauthors. The study was published in the European Heart Journal.

To determine if statins are a cardiovascular benefit or detriment to older people, the researchers reviewed data from 120,173 patients in French health care databases who turned 75 during 2012-2014. Patients with a diagnosis of cardiovascular disease in the previous 2 years were excluded, and all eligible patients were required to have a statin medication possession ratio of at least 80% in each of the previous 2 years.

Over a follow-up period that averaged 2.4 years, 17,204 patients (14.3%) discontinued statins and 5,396 (4.5%) were admitted for a cardiovascular event. The adjusted hazard ratios for admissions after statin discontinuation were 1.33 (95% confidence interval, 1.18-1.50) for a cardiovascular event, 1.46 (95% CI, 1.21-1.75) for a coronary event, 1.26 (95% CI, 1.05-1.51) for a cerebrovascular event, and 1.02 (95% CI, 0.74-1.40) for other vascular events, respectively.

The coauthors acknowledged their study’s limitations, including being unable to account for certain cardiovascular risk factors such as baseline LDL cholesterol level, tobacco use, obesity, and frailty markers. In addition, no information was available as to why patients discontinued statins. However, the presence of other major cardiovascular risk factors was investigated and accounted for, as was discontinuation of other cardiovascular drug therapies.

The study was not funded, and the authors declared no conflicts of interest.

SOURCE: Giral P at al. Eur Heart J. 2019 July 31. doi: 10.1093/eurheartj/ehz458.

Discontinuing statins was associated with an increased risk of hospital admission for a cardiovascular event, according to a study of elderly French patients with no history of heart disease.

RogerAshford/Thinkstock

“The results of this study suggest potential cardiovascular risk reduction associated with continuing statin therapy after the age of 75 years in persons already taking these drugs for primary prevention,” wrote Philippe Giral, MD, of Hôpital La Pitié Salpêtrière (France) and coauthors. The study was published in the European Heart Journal.

To determine if statins are a cardiovascular benefit or detriment to older people, the researchers reviewed data from 120,173 patients in French health care databases who turned 75 during 2012-2014. Patients with a diagnosis of cardiovascular disease in the previous 2 years were excluded, and all eligible patients were required to have a statin medication possession ratio of at least 80% in each of the previous 2 years.

Over a follow-up period that averaged 2.4 years, 17,204 patients (14.3%) discontinued statins and 5,396 (4.5%) were admitted for a cardiovascular event. The adjusted hazard ratios for admissions after statin discontinuation were 1.33 (95% confidence interval, 1.18-1.50) for a cardiovascular event, 1.46 (95% CI, 1.21-1.75) for a coronary event, 1.26 (95% CI, 1.05-1.51) for a cerebrovascular event, and 1.02 (95% CI, 0.74-1.40) for other vascular events, respectively.

The coauthors acknowledged their study’s limitations, including being unable to account for certain cardiovascular risk factors such as baseline LDL cholesterol level, tobacco use, obesity, and frailty markers. In addition, no information was available as to why patients discontinued statins. However, the presence of other major cardiovascular risk factors was investigated and accounted for, as was discontinuation of other cardiovascular drug therapies.

The study was not funded, and the authors declared no conflicts of interest.

SOURCE: Giral P at al. Eur Heart J. 2019 July 31. doi: 10.1093/eurheartj/ehz458.

Discontinuing statins was associated with an increased risk of hospital admission for a cardiovascular event, according to a study of elderly French patients with no history of heart disease.

RogerAshford/Thinkstock

“The results of this study suggest potential cardiovascular risk reduction associated with continuing statin therapy after the age of 75 years in persons already taking these drugs for primary prevention,” wrote Philippe Giral, MD, of Hôpital La Pitié Salpêtrière (France) and coauthors. The study was published in the European Heart Journal.

To determine if statins are a cardiovascular benefit or detriment to older people, the researchers reviewed data from 120,173 patients in French health care databases who turned 75 during 2012-2014. Patients with a diagnosis of cardiovascular disease in the previous 2 years were excluded, and all eligible patients were required to have a statin medication possession ratio of at least 80% in each of the previous 2 years.

Over a follow-up period that averaged 2.4 years, 17,204 patients (14.3%) discontinued statins and 5,396 (4.5%) were admitted for a cardiovascular event. The adjusted hazard ratios for admissions after statin discontinuation were 1.33 (95% confidence interval, 1.18-1.50) for a cardiovascular event, 1.46 (95% CI, 1.21-1.75) for a coronary event, 1.26 (95% CI, 1.05-1.51) for a cerebrovascular event, and 1.02 (95% CI, 0.74-1.40) for other vascular events, respectively.

The coauthors acknowledged their study’s limitations, including being unable to account for certain cardiovascular risk factors such as baseline LDL cholesterol level, tobacco use, obesity, and frailty markers. In addition, no information was available as to why patients discontinued statins. However, the presence of other major cardiovascular risk factors was investigated and accounted for, as was discontinuation of other cardiovascular drug therapies.

The study was not funded, and the authors declared no conflicts of interest.

SOURCE: Giral P at al. Eur Heart J. 2019 July 31. doi: 10.1093/eurheartj/ehz458.

Study Overview

Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.

Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.

Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.

Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I² statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.

Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.

Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.

Commentary

Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.^1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.

Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.³ However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.

The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.^4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.

The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.

The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.

Applications for Clinical Practice

Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.

—Fred Ko, MD, MS

Study Overview

Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.

Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.

Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.

Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I² statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.

Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.

Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.

Commentary

Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.^1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.

Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.³ However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.

The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.^4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.

The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.

The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.

Applications for Clinical Practice

Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.

—Fred Ko, MD, MS

Study Overview

Objective. To evaluate the association between long-term exercise interventions (duration ≥ 1 year) and risks of falls, injurious falls, multiple falls, fractures, hospitalization, and mortality in older adults.

Design. A systematic review of randomized controlled trials (RCTs) with preplanned meta-analysis was conducted to investigate the association between long-term exercise interventions and falls and fall-related adverse outcomes in adults older than 60 years. A literature search using electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, SportDiscus, PsychInfo, and Ageline, was performed between February 20 and March 5, 2018. Studies selected were RCTs with exercise duration of 1 year or longer, where effects of exercise intervention were compared with a comparator group of participants aged 60 years or older. Articles were independently screened, abstracted, and assessed for risk of bias by 2 raters, who resolved divergences in data extraction and synthesis via in-person meetings.

Setting and participants. A total of 46 studies (22,709 participants; median of 203 participants per study) were included in the review and 40 studies (21,868 participants) were included in the meta-analysis. The participants’ mean age was 73.1 ± 7.1 years, and 66.3% (15,054 participants) were women. Studies were mostly conducted in Europe (n = 15), North America (n = 13), and Oceania (n = 10). Multicomponent training involving multiple exercises (eg, aerobic, strength and balance; 29 RCTs) was the most common intervention modality, followed by aerobic (8 RCTs) and strength (5 RCTs) training. Exercise interventions had a mean frequency of 3 times/week, with each session lasting approximately 50 minutes, and were administered at a moderate intensity. The average compliance rate with exercise training was 65%. Comparator groups were often active controls that ranged from attention controls to more intensive interventions.

Main outcome measures. The 6 binary outcomes investigated were fallers who fell at least once, multiple times, or at least twice; fractures; hospitalization; and mortality. Estimates of outcomes were combined using risk ratios (RRs) using DerSimonian and Laird’s random-effects model (Mantel-Haenszel method). Heterogeneity was evaluated using I² statistics, and trials with low rates of compliance (< 30%) with exercise intervention or high attrition (> 40%) were excluded in primary analyses.

Main results. Exercise training significantly reduced the risk of falls by 12% (n = 20 RCTs; 4420 participants; RR, 0.88; 95% confidence interval [CI], 0.79-0.98) and injurious falls by 26% (9 RCTs; 4481 participants; RR, 0.74; 95% CI, 0.62-0.88), and reduced the risk of fractures by 16% (19 RCTs; 8410 participants; RR, 0.84; 95% CI, 0.71-1.00; P = 0.05). Exercise training did not decrease the risk of multiple falls (13 RCTs; 3060 participants; RR, 0.86; 95% CI, 0.68-1.08), hospitalization (12 RCTs; 5639 participants; RR 0.94; 95% CI, 0.80-1.12), or mortality (29 RCTs; 11,441 participants; RR 0.96; 95% CI, 0.85-1.09). Sensitivity analyses yielded similar results, with the exception of the fixed-effect meta-analysis for the risk of fracture that showed a significant effect of long-term exercise training (RR, 0.84; 95% CI, 0.70-1.00; P = 0.047). Meta-regression analysis on mortality and falls suggested that exercise frequency between 2 and 3 times per week was optimal and beneficial.

Conclusion. Long-term exercise training of 1 year or longer in duration is associated with a reduction in falls, injurious falls, and fractures in older adults. Moreover, moderate intensity, multicomponent exercise training performed 2 to 3 times weekly is likely safe and effective in this vulnerable population.

Commentary

Falls are exceedingly common (1 in 3 older Americans fall each year) and are the leading cause of fatal and nonfatal injuries in persons over the age of 65 years.^1,2 While fall prevention is a public health priority and a topic of interest in many research studies, there are important gaps in knowledge regarding optimal strategies to prevent falls and fall-related injuries in this high-risk population. The study reported by de Souto Barreto and colleagues provides new insights to address several of these gaps and may have a significant impact on the clinical practice of fall prevention in geriatric medicine.

Studies show that a single exercise intervention of short- to medium-term duration can prevent falls in community-dwelling older adults.³ However, the effects of long-term exercise training (ie, intervention lasting longer than a year) on fall prevention in this population is less well characterized. This study is the first meta-analysis that aimed to evaluate the potential beneficial impact of long-term exercise training on falls and adverse fall-related outcomes in adults ≥ 60 years of age who are prone to falls. The study’s findings indicate that long-term exercise training reduces the risk of falling by 12%, injurious falls by 26%, and factures by 16%. These results are important in that they add compelling evidence that exercise training of any duration can reduce falls and some fall-related adverse outcomes. Furthermore, the positive effects of long-term exercise training appear to mitigate some of the fatal and nonfatal injuries attributable to falls—the leading cause of such injuries in older adults.

The modality (type) and dose (frequency) of exercise training are important components of “exercise prescription” for older adults. However, there is a lack of research evidence to help clearly define these exercise parameters to better guide development of consensus exercise recommendations for older patients. This gap in knowledge limits the clinicians’ ability to recommend evidence-based treatment regimens to older adults who are at higher risk for falls. Moreover, although exercise programs are rarely associated with serious adverse events, recent findings from the Lifestyle Interventions and Independence for Elders (LIFE) study found a modest and nonstatistically significant association between long-term, moderate-intensity physical activity programs and an increase in hospitalizations and mortality in older adults.^4,5 Taken together, these gaps in knowledge highlight the urgent need to better understand the optimal methods for administering exercise programs in older adults as well as the need for critical appraisals of the benefits and harms associated with long-term exercise training in this vulnerable population.

The results reported by de Souto Barreto and colleagues helped to address these questions. In this study, the authors found that long-term multicomponent training, particularly moderate intensity with balance exercises performed 2 to 3 times a week, appears to be a safe and effective intervention for reducing falls and injurious falls in older adults. Importantly, this type of long-term exercise regimen does not increase hospitalization and mortality, and thus supports the notion that exercise therapy is safe in older adults. Therefore, information gained from this meta-analysis should help to guide clinicians to devise a patient-centered exercise prescription for fall prevention.

The current study was well designed and has a number of strengths. The design of the systematic review and meta-analysis allowed aggregation of data from multiple trials, resulting in a more robust point estimate to evaluate the effects of long-term exercise training on falls and fall-related outcomes that otherwise cannot be achieved with individual trials. In addition, the emphasis on long-term exercise training in older adults in the setting of falls and adverse fall-related outcomes addresses a key area of research that currently lacks a sufficient evidence base. There are also several limitations in this study, primarily due to the nature of its meta-analysis design. For instance, the study populations included in the analysis are highly heterogeneous and range from those with dementia to healthy participants. In addition, long-term exercise training, defined as a duration ≥ 1 year, was arbitrarily established as the minimum period of intervention. Thus, potential important studies that include interventions of significant duration, but less than 1 year, may not have been captured in this analysis.

Applications for Clinical Practice

Falls in older adults are common and may lead to devastating health consequences. The implementation of a long-term, multicomponent, moderate-intensity exercise regimen performed 2 to 3 times weekly can reduce falls and injurious falls in older adults.

—Fred Ko, MD, MS

Diabetes management in adults aged 65 years and older involves special considerations, because the effects of aging on metabolic regulation can exacerbate the disease and accelerate the development of common complications, according to a new guideline on diabetes care for older adults issued by the Endocrine Society.

“The prevalence of diabetes in the United States is projected to increase dramatically during the next 3 decades as the population ages, the numbers of higher-risk minority groups increase, and people with diabetes live longer because of decreasing rates of cardiovascular deaths,” wrote Derek LeRoith, MD, of Icahn School of Medicine at Mount Sinai, New York, and his writing committee colleagues. They said their goal was to provide health care providers with guidance for the management of type 1 or type 2 diabetes in older patients, with a focus on simplifying medication regimens and management strategies to avoid “unnecessary and/or harmful adverse effects.”

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, is based mainly on evidence from controlled trials in two systematic reviews that specifically focused on adults aged 65 years and older. The guideline addresses six areas of consideration for this patient population:

• Role of the endocrinologist and diabetes care specialist.
• Screening for diabetes and prediabetes, and diabetes prevention.
• Assessment of older patients with diabetes.
• Treatment of hyperglycemia.
• Treating complications of diabetes.
• Special settings and populations.

Partnerships and screening

The guideline recommends that primary care providers partner with an endocrinologist or diabetes specialist in the care of patients aged 65 and older with newly diagnosed diabetes, and that the specialist take primary responsibility for diabetes care of patients with type 1 diabetes or those who need more complex intervention to achieve treatment goals.

Screening for diabetes in adults aged 65 years and older using fasting plasma glucose and/or hemoglobin A_1c should occur every 2 years, but that schedule should be adjusted based on shared decision making with the patient, the committee said. Providers are advised to assess the patient’s overall health and personal values before settling on treatment goals and strategies. The writing group also recommends periodic cognitive screening and that medication regimens be simplified as much as possible.
 

Tackling hyperglycemia

For treatment of hyperglycemia, the guideline recommends outpatient strategies to minimize hypoglycemia and periodic or continuous glucose monitoring. The strategies include lifestyle modifications as a first-line intervention for ambulatory patients, as well as nutritional assessment. A high-protein diet is recommended for older patients with frailty, but no restrictions on diet are advised for patients who cannot meet glycemic targets with lifestyle modification and who are at risk for malnutrition.

Metformin is the first-choice recommendation for patients with diabetes aged 65 and older who need medical management in addition to lifestyle modification, but it is not recommended for individuals with impaired kidney function or gastrointestinal intolerance, according to the guideline. Oral and injectable drugs and/or insulin are recommended if metformin and lifestyle changes are insufficient to meet glycemic targets, the writers noted.
 

Managing complications

Hypertension is among the diabetes-related complications that need to be managed in older adults, and the guideline recommends a target blood pressure of 140/90 mm Hg, but other targets – based on patient-provider shared decision making – may be considered for patients in high-risk groups.

The guideline calls for management of hyperlipidemia with statin therapy and “use of an annual lipid profile to achieve the recommended levels for reducing absolute cardiovascular disease events and all-cause mortality.” The committee does not specify low-density lipoprotein cholesterol targets because of insufficient evidence, but recommends alternative treatments, including ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors, if statin therapy is not enough to help the patients meet goals. The writers also advocate fish oil and/or fenofibrate for patients with fasting triglycerides of more than 500 mg/dL.

To manage congestive heart failure in older patients with diabetes, the guideline recommends following standard clinical practice guidelines for the condition, and cautious use of oral hypoglycemic agents, including glinides, rosiglitazone, pioglitazone, and dipeptidyl peptidase–4 inhibitors. The writers noted that low-dose aspirin is recommended for patients with diabetes with a history of atherosclerotic cardiovascular disease.

The committee also recommends an annual comprehensive eye exam for patients with diabetes aged 65 years and older to identify retinal disease and suggests that actions, such as physical therapy and reduced use of sedatives, be taken to minimize the risk of falls in patients with neuropathy or problems with balance and gait.

Older patients with diabetes also should be screened annually for chronic kidney disease, and the dosage of diabetes medications should be adjusted to minimize side effects in patients with kidney problems.
 

Tailoring care to setting

Finally, the guideline addresses special settings and populations, including managing diabetes in hospitals or nursing homes, or in patients who are transitioning to homes or long-term care facilities. Recommendations in this category include simplifying medications for older adults with terminal illness or severe comorbidities, as well as setting glycemic targets as part of a hospital discharge plan.

“The most important aspect of successful transition is effective, detailed, and thorough bidirectional communication between the discharging and receiving teams of health care providers,” the writers emphasized.

The guideline is cosponsored by the European Society of Endocrinology, the Gerontological Society of America, and the Obesity Society. The chair of the committee had no relevant financial conflicts to disclose, and at least 50% of the committee members were free of relevant conflicts of interest.

SOURCE: LeRoith D et al. J Clin Endocrinol Metab. 2019;104:1520-74.

Diabetes management in adults aged 65 years and older involves special considerations, because the effects of aging on metabolic regulation can exacerbate the disease and accelerate the development of common complications, according to a new guideline on diabetes care for older adults issued by the Endocrine Society.

“The prevalence of diabetes in the United States is projected to increase dramatically during the next 3 decades as the population ages, the numbers of higher-risk minority groups increase, and people with diabetes live longer because of decreasing rates of cardiovascular deaths,” wrote Derek LeRoith, MD, of Icahn School of Medicine at Mount Sinai, New York, and his writing committee colleagues. They said their goal was to provide health care providers with guidance for the management of type 1 or type 2 diabetes in older patients, with a focus on simplifying medication regimens and management strategies to avoid “unnecessary and/or harmful adverse effects.”

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, is based mainly on evidence from controlled trials in two systematic reviews that specifically focused on adults aged 65 years and older. The guideline addresses six areas of consideration for this patient population:

• Role of the endocrinologist and diabetes care specialist.
• Screening for diabetes and prediabetes, and diabetes prevention.
• Assessment of older patients with diabetes.
• Treatment of hyperglycemia.
• Treating complications of diabetes.
• Special settings and populations.

Partnerships and screening

The guideline recommends that primary care providers partner with an endocrinologist or diabetes specialist in the care of patients aged 65 and older with newly diagnosed diabetes, and that the specialist take primary responsibility for diabetes care of patients with type 1 diabetes or those who need more complex intervention to achieve treatment goals.

Screening for diabetes in adults aged 65 years and older using fasting plasma glucose and/or hemoglobin A_1c should occur every 2 years, but that schedule should be adjusted based on shared decision making with the patient, the committee said. Providers are advised to assess the patient’s overall health and personal values before settling on treatment goals and strategies. The writing group also recommends periodic cognitive screening and that medication regimens be simplified as much as possible.
 

Tackling hyperglycemia

For treatment of hyperglycemia, the guideline recommends outpatient strategies to minimize hypoglycemia and periodic or continuous glucose monitoring. The strategies include lifestyle modifications as a first-line intervention for ambulatory patients, as well as nutritional assessment. A high-protein diet is recommended for older patients with frailty, but no restrictions on diet are advised for patients who cannot meet glycemic targets with lifestyle modification and who are at risk for malnutrition.

Metformin is the first-choice recommendation for patients with diabetes aged 65 and older who need medical management in addition to lifestyle modification, but it is not recommended for individuals with impaired kidney function or gastrointestinal intolerance, according to the guideline. Oral and injectable drugs and/or insulin are recommended if metformin and lifestyle changes are insufficient to meet glycemic targets, the writers noted.
 

Managing complications

Hypertension is among the diabetes-related complications that need to be managed in older adults, and the guideline recommends a target blood pressure of 140/90 mm Hg, but other targets – based on patient-provider shared decision making – may be considered for patients in high-risk groups.

The guideline calls for management of hyperlipidemia with statin therapy and “use of an annual lipid profile to achieve the recommended levels for reducing absolute cardiovascular disease events and all-cause mortality.” The committee does not specify low-density lipoprotein cholesterol targets because of insufficient evidence, but recommends alternative treatments, including ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors, if statin therapy is not enough to help the patients meet goals. The writers also advocate fish oil and/or fenofibrate for patients with fasting triglycerides of more than 500 mg/dL.

To manage congestive heart failure in older patients with diabetes, the guideline recommends following standard clinical practice guidelines for the condition, and cautious use of oral hypoglycemic agents, including glinides, rosiglitazone, pioglitazone, and dipeptidyl peptidase–4 inhibitors. The writers noted that low-dose aspirin is recommended for patients with diabetes with a history of atherosclerotic cardiovascular disease.

The committee also recommends an annual comprehensive eye exam for patients with diabetes aged 65 years and older to identify retinal disease and suggests that actions, such as physical therapy and reduced use of sedatives, be taken to minimize the risk of falls in patients with neuropathy or problems with balance and gait.

Older patients with diabetes also should be screened annually for chronic kidney disease, and the dosage of diabetes medications should be adjusted to minimize side effects in patients with kidney problems.
 

Tailoring care to setting

Finally, the guideline addresses special settings and populations, including managing diabetes in hospitals or nursing homes, or in patients who are transitioning to homes or long-term care facilities. Recommendations in this category include simplifying medications for older adults with terminal illness or severe comorbidities, as well as setting glycemic targets as part of a hospital discharge plan.

“The most important aspect of successful transition is effective, detailed, and thorough bidirectional communication between the discharging and receiving teams of health care providers,” the writers emphasized.

The guideline is cosponsored by the European Society of Endocrinology, the Gerontological Society of America, and the Obesity Society. The chair of the committee had no relevant financial conflicts to disclose, and at least 50% of the committee members were free of relevant conflicts of interest.

SOURCE: LeRoith D et al. J Clin Endocrinol Metab. 2019;104:1520-74.

Diabetes management in adults aged 65 years and older involves special considerations, because the effects of aging on metabolic regulation can exacerbate the disease and accelerate the development of common complications, according to a new guideline on diabetes care for older adults issued by the Endocrine Society.

“The prevalence of diabetes in the United States is projected to increase dramatically during the next 3 decades as the population ages, the numbers of higher-risk minority groups increase, and people with diabetes live longer because of decreasing rates of cardiovascular deaths,” wrote Derek LeRoith, MD, of Icahn School of Medicine at Mount Sinai, New York, and his writing committee colleagues. They said their goal was to provide health care providers with guidance for the management of type 1 or type 2 diabetes in older patients, with a focus on simplifying medication regimens and management strategies to avoid “unnecessary and/or harmful adverse effects.”

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, is based mainly on evidence from controlled trials in two systematic reviews that specifically focused on adults aged 65 years and older. The guideline addresses six areas of consideration for this patient population:

• Role of the endocrinologist and diabetes care specialist.
• Screening for diabetes and prediabetes, and diabetes prevention.
• Assessment of older patients with diabetes.
• Treatment of hyperglycemia.
• Treating complications of diabetes.
• Special settings and populations.

Partnerships and screening

The guideline recommends that primary care providers partner with an endocrinologist or diabetes specialist in the care of patients aged 65 and older with newly diagnosed diabetes, and that the specialist take primary responsibility for diabetes care of patients with type 1 diabetes or those who need more complex intervention to achieve treatment goals.

Screening for diabetes in adults aged 65 years and older using fasting plasma glucose and/or hemoglobin A_1c should occur every 2 years, but that schedule should be adjusted based on shared decision making with the patient, the committee said. Providers are advised to assess the patient’s overall health and personal values before settling on treatment goals and strategies. The writing group also recommends periodic cognitive screening and that medication regimens be simplified as much as possible.
 

Tackling hyperglycemia

For treatment of hyperglycemia, the guideline recommends outpatient strategies to minimize hypoglycemia and periodic or continuous glucose monitoring. The strategies include lifestyle modifications as a first-line intervention for ambulatory patients, as well as nutritional assessment. A high-protein diet is recommended for older patients with frailty, but no restrictions on diet are advised for patients who cannot meet glycemic targets with lifestyle modification and who are at risk for malnutrition.

Metformin is the first-choice recommendation for patients with diabetes aged 65 and older who need medical management in addition to lifestyle modification, but it is not recommended for individuals with impaired kidney function or gastrointestinal intolerance, according to the guideline. Oral and injectable drugs and/or insulin are recommended if metformin and lifestyle changes are insufficient to meet glycemic targets, the writers noted.
 

Managing complications

Hypertension is among the diabetes-related complications that need to be managed in older adults, and the guideline recommends a target blood pressure of 140/90 mm Hg, but other targets – based on patient-provider shared decision making – may be considered for patients in high-risk groups.

The guideline calls for management of hyperlipidemia with statin therapy and “use of an annual lipid profile to achieve the recommended levels for reducing absolute cardiovascular disease events and all-cause mortality.” The committee does not specify low-density lipoprotein cholesterol targets because of insufficient evidence, but recommends alternative treatments, including ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors, if statin therapy is not enough to help the patients meet goals. The writers also advocate fish oil and/or fenofibrate for patients with fasting triglycerides of more than 500 mg/dL.

To manage congestive heart failure in older patients with diabetes, the guideline recommends following standard clinical practice guidelines for the condition, and cautious use of oral hypoglycemic agents, including glinides, rosiglitazone, pioglitazone, and dipeptidyl peptidase–4 inhibitors. The writers noted that low-dose aspirin is recommended for patients with diabetes with a history of atherosclerotic cardiovascular disease.

The committee also recommends an annual comprehensive eye exam for patients with diabetes aged 65 years and older to identify retinal disease and suggests that actions, such as physical therapy and reduced use of sedatives, be taken to minimize the risk of falls in patients with neuropathy or problems with balance and gait.

Older patients with diabetes also should be screened annually for chronic kidney disease, and the dosage of diabetes medications should be adjusted to minimize side effects in patients with kidney problems.
 

Tailoring care to setting

Finally, the guideline addresses special settings and populations, including managing diabetes in hospitals or nursing homes, or in patients who are transitioning to homes or long-term care facilities. Recommendations in this category include simplifying medications for older adults with terminal illness or severe comorbidities, as well as setting glycemic targets as part of a hospital discharge plan.

“The most important aspect of successful transition is effective, detailed, and thorough bidirectional communication between the discharging and receiving teams of health care providers,” the writers emphasized.

The guideline is cosponsored by the European Society of Endocrinology, the Gerontological Society of America, and the Obesity Society. The chair of the committee had no relevant financial conflicts to disclose, and at least 50% of the committee members were free of relevant conflicts of interest.

SOURCE: LeRoith D et al. J Clin Endocrinol Metab. 2019;104:1520-74.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

Mental health comorbidities increase the rates of opioid use and mortality among breast cancer survivors on endocrine therapy, based on a retrospective study of more than 10,000 patients in a Medicare-linked database.

Screen for mental health conditions in the early stages of cancer care and lean toward opioid alternatives for pain management, advised lead author Raj Desai, MS, of the University of Florida, Gainesville, and colleagues.

“The complex relationship among breast cancer, mental health problems, and the use of opioids is not well understood, despite the high prevalence of mental health comorbidities like depression and anxiety in breast cancer survivors, and the high rate of opioid use in those on AET [adjuvant endocrine therapy],” the investigators wrote in the Journal of Oncology Practice.

“Therefore, this study aimed to determine whether breast cancer survivors with varying levels of mental health comorbidities, such as depression and anxiety, are more likely to use opioids for AET-related pain,” they added.

The study involved 10,452 breast cancer survivors who first filled an AET prescription from 2006 to 2012 and had follow-up records available for at least 2 years. All patients had a diagnosis of incident, primary, hormone receptor–positive, stage I-III breast cancer. Data were drawn from the Surveillance, Epidemiology, and End Results–Medicare linked database. Records were evaluated for diagnoses of mental health conditions such as depression and anxiety, opioid use, and survival.

Analysis showed that the most common mental health conditions were depression and anxiety, diagnosed in 554 and 246 women, respectively. Patients with mental health comorbidities were compared with patients who did not have such problems, using both unmatched and matched cohorts. While unmatched comparison for opioid use was not statistically significant, matched comparison showed that survivors with mental health comorbidities were 33% more likely to use opioids than those without mental health comorbidities (95% confidence interval, 1.06-1.68). Similarly, greater adjusted probabilities of opioid use were reported in the mental health comorbidity cohort (72.5% vs. 66.9%; P = .01).

Concerning survival, unmatched comparison revealed a 44% higher risk of death among women with depression and a 32% increase associated with anxiety. Matched comparison showed an even higher increased risk of mortality among women with any mental health comorbidity (49%; P less than .05).

The investigators concluded that opioid use among breast cancer survivors with mental health comorbidities “remains a significant problem.”

“A need exists for collaborative care in the management of mental health comorbidities in women with breast cancer, which could improve symptoms, adherence to treatment, and recovery from these mental conditions,” the investigators wrote. “Mental health treatments also are recommended to be offered in primary care, which not only would be convenient for patients, but also would reduce the stigma associated with treatments for mental health comorbidities and improve the patient-provider relationship.”

The investigators reported financial relationships with Merck.

SOURCE: Desai R et al. J Oncol Pract. 2019 Jul 19. doi: 10.1200/JOP.18.00781.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

msullivan@mdedge.com

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

msullivan@mdedge.com

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.

LOS ANGELES – Estrogen therapy may have scored another goal in its comeback game, as a 7-year prospective study shows that a transdermal formulation preserves some measures of cognitive function and brain architecture in postmenopausal women.

JackF/thinkstockphotos.com

In addition to performing better on subjective tests of memory, women using the estrogen patch experienced less cortical atrophy and were less likely to show amyloid on brain imaging. The observations were moderately associated with the improved sleep these women reported, Burcu Zeydan, MD, said at the Alzheimer’s Association International Conference.

“By 7 years, among the cognitive domains studied ... [less brain and cognitive change] correlated with lower global sleep score, meaning better sleep quality in the estradiol group,” said Dr. Zeydan, assistant professor of radiology at the Mayo Clinic in Rochester, Minn. “We previously found that preservation of dorsolateral prefrontal cortex over 7 years was associated with lower cortical beta-amyloid deposition on PET only in the estradiol group, pointing out the potential role of estrogen receptors in modulating this relationship.”

Dysregulated sleep is more common among women than men, particularly as menopause approaches and estrogen levels fluctuate, then decline, Dr. Zeydan said.

Dr. Zeydan reported the sleep substudy of KEEPS (the Kronos Early Estrogen Prevention Study), a randomized, double-blind, placebo-controlled, multisite trial that compared oral conjugated equine estrogen with transdermal estradiol. A control group received oral placebo and a placebo patch.*

Brain architecture was similar between the placebo and transdermal groups, but it was actually worse in some measures in the oral-estrogen group, compared with the placebo group. Women taking oral estrogen had more white matter hyperintensities, greater ventricle enlargement, and more cortical thinning. Those differences resolved after they stopped taking the oral formulation, bringing them into line with the transdermal and placebo groups.

The investigation also found that the transdermal group showed lower cerebral amyloid binding on PET scans relative to both placebo and oral estrogen.

“The relative preservation of dorsolateral prefrontal cortical volume in the [transdermal estradiol] group over 7 years indicates that hormone therapy may have long-term effects on the brain,” the team concluded. They noted that the original KEEPS study didn’t find any cognitive correlation with these changes.

The subanalysis looked at 69 women of the KEEPS cohort who had been followed for the full 7 years (4 years on treatment and 3 years off treatment). They were randomized to oral placebo and a placebo patch,* oral conjugated equine estrogen (0.45 mg/day), or transdermal estradiol (50 mcg/day). Participants in the active treatment groups received oral micronized progesterone 12 days each month. All had complete data on cognitive testing and brain imaging. Sleep quality was measured by the Pittsburgh Sleep Quality Index. Dr. Zeydan compared cognition and brain architecture findings in relation to the sleep score; lower scores mean better sleep.

The women were aged 42-58 years at baseline, and within 36 months from menopause. They had no history of menopausal hormone therapy or cardiovascular disease.

The investigators were particularly interested in how estrogen might have modulated the disturbed sleep patterns that often accompany perimenopause and early menopause, and whether the observed brain and cognitive changes tracked with sleep quality.

“During this time, 40% to 60% of women report problems sleeping, and estrogen decline seems to play an important role in sleep disturbances during this phase,” Dr. Zeydan said. “Although poor sleep quality is common in recently menopausal women, sleep quality improves with hormone therapy, as was previously demonstrated in KEEPS hormone therapy trial in recently menopausal women.”

By year 7, the cohort’s mean age was 61 years. The majority had at least some college education. The percentage who carried an apolipoprotein E epsilon-4 allele varied by group, with 15% positivity in the oral group, 48% in the transdermal group, and 16% in the placebo group.


Cognitive function was estimated with a global cognitive measure and four cognitive domain scores: verbal learning and memory, auditory attention and working memory, visual attention and executive function, and mental flexibility.

Higher attention and executive function scores were moderately correlated with a lower sleep score in the transdermal group (r = –0.54, a significant difference compared with the oral formulation). Lower sleep scores also showed a moderate correlation with preserved cortical volume of the dorsolateral prefrontal region (r = –0.47, also significantly different from the oral group).

Lower brain amyloid also positively correlated with better sleep. The correlation between sleep and global amyloid burden in the transdermal group was also moderate (r = 0.45), while the correlation in the oral group was significantly weaker (r = 0.18).

“We can say that sleep quality and transdermal estradiol during early postmenopausal years somehow interact to influence beta-amyloid deposition, preservation of dorsolateral prefrontal cortex volume, and attention and executive function,” Dr. Zeydan said.

Dr. Zeydan had no financial disclosures.

msullivan@mdedge.com

*Correction, 8/7/2019: An earlier version of this story did not make clear that participants in the control group received oral placebo and a placebo patch.

LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.

At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).

Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.

At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).

“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”

It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.


While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.

Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.

Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.

LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.

At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).

Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.

At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).

“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”

It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.


While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.

Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.

Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.

LOS ANGELES – Scientists testing an unusual hypothesis about the pathogenesis of Alzheimer’s disease say that use of an experimental antimicrobial drug to target a common oral infection was associated with biomarker improvements in people with the disease.

At the Alzheimer’s Association International Conference, Michael Detke, MD, PhD, of Cortexyme in South San Francisco, Calif., presented findings from a small cohort (n = 9) of people with mild to moderate Alzheimer’s disease (AD).

Six patients, mean age 72, were randomized to 4 weeks’ treatment with an agent called COR388, which inhibits toxic proteases produced by Porphyromonas gingivalis, a bacterium that colonizes the mouth and gums and has been found in the brains and cerebrospinal fluid of people with AD more than in non-AD patients. Another three subjects were randomized to placebo.

At 28 days, the CSF levels of an Alzheimer’s-associated apolipoprotein E (ApoE) fragment and serum levels of RANTES, a chemokine associated with chronic inflammation, were reduced from baseline by about one-third in treated subjects, compared with placebo subjects (P less than .05).

“In AD, ApoE is known to be fragmented and the fragments are known to be neurotoxic,” Dr. Detke, the lead study author, said in an interview. “We hypothesized that these P. gingivalis proteases may be acting on ApoE cleavage – so if you bind the proteases you should reduce the fragments. We saw in this study that ApoE fragment was reduced by 30%, or back to about normal levels.”

It is difficult to eradicate P. gingivalis infection using conventional antibiotics. The experimental agent COR388 “does not kill the bacteria but rather neutralizes it by binding to the proteases it produces, making the bacteria benign,” Dr. Detke said.


While hypotheses involving infectious causes of Alzheimer’s remain on the periphery of dementia research, Dr. Detke and his colleagues will soon be able to test theirs in a more meaningful way. At the conference, Dr. Detke presented detailed plans for a phase 2/3, placebo-controlled, clinical trial of COR388 in 570 patients aged 55-80 with mild to moderate AD.

Patients in the study are currently being randomized to 48 weeks of treatment with one of two doses, or placebo, with cognitive and biomarker endpoints planned, including for amyloid-beta, tau, and serum, plasma, and CSF markers of neuroinflammation.

Dr. Detke is an employee of Cortexyme, as are another 8 of the study’s 11 authors.