Geriatrics

Among patients with atrial fibrillation, use of direct oral anticoagulants is linked to lower osteoporotic fracture risk versus warfarin, results of a recent population-based cohort study show.

iStock/Thinkstock

The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.

This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.

“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.

The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.

Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.

“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.

There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.

“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.

The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.

In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.

DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.

Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.

“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”

The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.

The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.

“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.

Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).

Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.

Among patients with atrial fibrillation, use of direct oral anticoagulants is linked to lower osteoporotic fracture risk versus warfarin, results of a recent population-based cohort study show.

iStock/Thinkstock

The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.

This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.

“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.

The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.

Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.

“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.

There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.

“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.

The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.

In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.

DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.

Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.

“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”

The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.

The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.

“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.

Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).

Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.

Among patients with atrial fibrillation, use of direct oral anticoagulants is linked to lower osteoporotic fracture risk versus warfarin, results of a recent population-based cohort study show.

iStock/Thinkstock

The choice of direct oral anticoagulant (DOAC) didn’t appear to have an impact, as each individual agent yielded a substantially lower risk of fracture versus the vitamin K antagonist, with risk reductions ranging from 38% to 48%, according to the study authors.

This is one of the latest reports to suggest DOACs could have an edge over warfarin for preventing fractures, providing new evidence that “may help inform the benefit risk assessment” when it comes to choosing an anticoagulant for a patient with atrial fibrillation (AFib) in the clinic, wrote the authors, led by Wallis C.Y. Lau, PhD, with the University College London.

“There exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” Dr. Lau and coauthors wrote in a report on the study that appears in Annals of Internal Medicine.

The case is especially compelling since fracture risk is “often neglected” when choosing an anticoagulant, the authors wrote. Surgeries to treat fracture are difficult because of the need for perioperative management of anticoagulation as “a balance between the risk for stroke and excessive bleeding must be achieved,” they added.

Based on these data, physicians should strongly consider DOACs as an alternative to vitamin K antagonists to reduce the risk of osteoporosis over the long term in patients with AFib, according to Victor Lawrence Roberts, MD, a Florida endocrinologist.

“Osteoporosis takes years, sometimes decades to develop, and if you then overlay warfarin on top of a readily evolving metabolic bone disease, you probably accelerate that process, said Dr. Roberts, professor of internal medicine at the University of Central Florida, Orlando, and editorial advisory board member of Internal Medicine News.

There’s a considerable amount of concerning preclinical data that warfarin could increase osteoporotic fracture risk. Of note, vitamin K antagonists modulate osteocalcin, a calcium-binding bone matrix protein, Dr. Roberts said.

“Osteocalcin is important for bone metabolism and health, and inhibiting osteocalcin will inhibit the ability to have a healthy bone matrix,” he explained.

The impact of anticoagulants on fracture risk is particularly relevant to patients with AFib, according to Dr. Lau and colleagues, who referenced one 2017 report showing a higher incidence of hip fracture among AFib patients versus those without AFib.

In their more recent study, Dr. Lau and colleagues reviewed electronic health records in a Hong Kong database for 23,515 older adults with a new diagnosis of AFib who received a new prescription of warfarin or DOACs including apixaban, dabigatran, or rivaroxaban.

DOAC use was consistently associated with a lower risk of osteoporotic fractures versus warfarin, regardless of the DOAC considered. The hazard ratios were 0.62 (95% confidence interval, 0.41-0.94) for apixaban, 0.65 (95% CI, 0.49-0.86) for dabigatran, and 0.52 (95% CI, 0.37-0.73) for rivaroxaban versus warfarin, the report showed.

Head-to-head comparisons between DOACS didn’t yield any statistically significant differences, though the analyses were underpowered in this respect, according to the investigators.

“This study can only rule out more than a twofold higher or a 50% lower relative risk for osteoporotic fractures between individual DOACs,” they wrote. “However, any absolute risk differences were small and would likely be of minor clinical significance.”

The reduced risk of fracture for DOACs versus warfarin was consistent in men and women with AFib, suggesting that women may particularly benefit from DOACs, given that they have a higher risk of fracture than men, the investigators added.

The results of this study suggest yet another benefit of DOACs over warfarin in patients with AFib, according to internist Noel Deep, MD, who is the chief medical officer of Aspirus Langlade Hospital in Antigo, Wisconsin.

“The lower risk of osteoporotic fractures with DOACS, in addition to other advantages such as lower risk of intracranial bleeding, once- or twice-daily consistent dosing, no dietary restrictions, and no blood tests to regulate the dose might be another reason that physicians may favor them over warfarin in older individuals requiring anticoagulation,” Dr. Deep said in an interview.

Results of this and several other recent studies may help in recommending DOACs to internal medicine patients who have a diagnosis of AFib requiring anticoagulation, according to Dr. Deep, who is also a physician at Aspirus Antigo Clinic and a member of Internal Medicine News’ editorial advisory board. These include a 2019 U.S.-based study of more than 167,000 patients with AFib (JAMA Intern Med. 2019;180[2]:245‐253) showing that use of DOACs, particularly apixaban, were linked to lower fracture risk versus warfarin use. Similarly, a Danish national registry study also published in 2019 showed that the absolute risk of osteoporotic fractures was low overall and significantly lower in patients who received DOACs (J Am Coll Cardiol. 2019;74[17]:2150-2158).

Funding for the study came from the University of Hong Kong and University College London Strategic Planning Fund. The study authors reported disclosures related to Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, IQVIA, and others.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 18. doi: 10.7326/M19-3671.

A leadless right-ventricular pacemaker continued to show an edge over conventional transvenous pacemakers by triggering a substantially reduced rate of complications during the 6 months following placement in a review of more than 10,000 Medicare patients treated over 2 years.

The “largest leadless pacemaker cohort to date” showed that in propensity score–matched cohorts, the 3,276 patients who received the Micra leadless transcatheter pacemaker during routine management and were followed for 6 months had a 3.3% rate of total complications, compared with a 9.4% rate among 7,256 patients who received a conventional VVI pacemaker with a transvenous lead, a statistically significant 66% relative risk reduction, Jonathan P. Piccini, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

The 66% reduced rate of complications – both acutely and with further follow-up – was similar to the complication reductions seen with Micra, compared with historical controls who received transvenous single-chamber pacemakers in both the pivotal study for the device (Heart Rhythm. 2017 May 1;14[3]:702-9) and in a postapproval registry study (Heart Rhythm. 2018 Dec 1;15[12]:1800-7). However, the newly reported advantage came in a population that was notably older and had significantly more comorbidities than in the prior leadless pacemaker studies, said Dr. Piccini, a cardiac electrophysiologist at Duke University, Durham, N.C.

The new Medicare data “tell us that physicians are reaching for these devices [leadless pacemakers] in patients with more comorbidities and a higher risk for complications to give them a [device with] better safety profile,” he said during a press briefing. “At Duke, and I suspect at other centers, when a patients is eligible for a leadless pacemaker that’s the preferred option.”

However, Dr. Piccini cited three examples of the small proportion of patients who are appropriate for the type of pacing the leadless pacemaker supplies but would be better candidates for a device with a transvenous lead: patients who failed treatment with a initial leadless pacemaker and have no suitable alternative subcutaneous spot to place the replacement device in a stable way, those with severe right ventricular enlargement that interferes with optimal placement, and those who don’t currently meet criteria for biventricular pacing but appear likely to switch to that pacing mode in the near term.

The 66% relative reduction in complications was “impressive; I hope this will be a message,” commented Nassir F. Marrouche, MD, a cardiac electrophysiologist and professor of medicine at Tulane University, New Orleans. Importantly, this reduced complication rate occurred in a real-world population that was sicker than any patient group previously studied with the device, he noted as a designated discussant for the report.

But the report’s second designated discussant, Roderick Tung, MD, highlighted some caveats when interpreting the lower complication rate with the leadless device compared with historical controls. He cited the absence of any episodes of pneumothorax among the patients reviewed by Dr. Piccini who received a leadless pacemaker, compared with a 5% rate among the control patients who had received a device with a transvenous lead, a major driver of the overall difference in complication rates. This difference “may not be relevant to operators who use either an axillary extrathoracic vein route for lead placement or a cephalic vein approach,” said Dr. Tung, director of cardiac electrophysiology at the University of Chicago. “There should not be a 5% rate of pneumothorax when implanting a VVI device.” The results reported by Dr. Piccini have the advantages of coming from many patients and from real-world practice, he acknowledged, but interpretation is limited by the lack of a randomized control group and the outsized impact of pneumothorax complications on the safety comparison.

The other major component of the 6-month complication tally was device-related events, which were twice as common in the historical controls who received a transvenous lead at a rate of 3.4%. The sole 6-month event more common among the patients who received a leadless pacemaker was pericarditis, at a rate of 1.3% in the Micra group and 0.5% in the transvenous lead controls, Dr. Piccini reported. The 6-month rate of device revisions was 1.7% with the leadless device and 2.8% with transvenous lead pacemakers, a difference that was not statistically significant. The two treatment arms had virtually identical 6-month mortality rates.

The rate of acute complications during the first 30 days after implant was also virtually the same in the two study arms. Patient who received the leadless device had significantly more puncture-site events, at a rate of 1.2%, and significantly more cardiac effusions or perforations, at a rate of 0.8%. The historical control patients who received devices with transvenous leads had significantly more device-related complications after 30 days, a 2.5% rate.

The 30-day cohorts examined had larger numbers of patients than at 6 months, 5,746 leadless pacemaker recipients and 9,662 matched historical controls who had received a transvenous lead pacemaker. The clinical and demographic profile of the 30-day cohort who received the leadless pacemaker highlighted the sicker nature of these patients compared with earlier studies of the device. They were an average age of 79 years, compared with average ages of 76 years in the two prior Micra studies, and they also had double the prevalence of coronary disease, triple the prevalence of heart failure, more than twice the rate of chronic obstructive pulmonary disease, and almost twice the prevalence of diabetes.

During the period examined in this report from Micra CED (Longitudinal Coverage With Evidence Development Study on Micra Leadless Pacemakers), in 2017-2018, the leadless pacemaker’s initial approved indications were for a circumscribed portion of the overall patient population that needs pacing. Essentially, they were elderly patients with persistent atrial fibrillation who only need ventricular pacing, roughly 15% of the overall cohort of pacing candidates. In January 2020, the FDA added an indication for high-grade atrioventricular block, an expanded population of candidates that roughly tripled the number of potentially appropriate recipients, said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication, in an interview at the time of the revised labeling.

The study was sponsored by Medtronic, which markets the Micra leadless pacemaker. Dr. Piccini has received honoraria from Medtronic and several other companies. Dr. Marrouche has been a consultant to Medtronic as well as to Biosense Webster, Biotronik, Cardiac Design, and Preventice, and has received research funding from Abbott, Biosense Webster, Boston Scientific, and GE Healthcare. Dr. Tung has been a speaker on behalf of Abbott, Boston Scientific, and Biosense Webster. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer.

[email protected]

SOURCE: Piccini JP et al. Heart Rhythm 2020, Abstract D-LBCT04-01.

A leadless right-ventricular pacemaker continued to show an edge over conventional transvenous pacemakers by triggering a substantially reduced rate of complications during the 6 months following placement in a review of more than 10,000 Medicare patients treated over 2 years.

The “largest leadless pacemaker cohort to date” showed that in propensity score–matched cohorts, the 3,276 patients who received the Micra leadless transcatheter pacemaker during routine management and were followed for 6 months had a 3.3% rate of total complications, compared with a 9.4% rate among 7,256 patients who received a conventional VVI pacemaker with a transvenous lead, a statistically significant 66% relative risk reduction, Jonathan P. Piccini, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

The 66% reduced rate of complications – both acutely and with further follow-up – was similar to the complication reductions seen with Micra, compared with historical controls who received transvenous single-chamber pacemakers in both the pivotal study for the device (Heart Rhythm. 2017 May 1;14[3]:702-9) and in a postapproval registry study (Heart Rhythm. 2018 Dec 1;15[12]:1800-7). However, the newly reported advantage came in a population that was notably older and had significantly more comorbidities than in the prior leadless pacemaker studies, said Dr. Piccini, a cardiac electrophysiologist at Duke University, Durham, N.C.

The new Medicare data “tell us that physicians are reaching for these devices [leadless pacemakers] in patients with more comorbidities and a higher risk for complications to give them a [device with] better safety profile,” he said during a press briefing. “At Duke, and I suspect at other centers, when a patients is eligible for a leadless pacemaker that’s the preferred option.”

However, Dr. Piccini cited three examples of the small proportion of patients who are appropriate for the type of pacing the leadless pacemaker supplies but would be better candidates for a device with a transvenous lead: patients who failed treatment with a initial leadless pacemaker and have no suitable alternative subcutaneous spot to place the replacement device in a stable way, those with severe right ventricular enlargement that interferes with optimal placement, and those who don’t currently meet criteria for biventricular pacing but appear likely to switch to that pacing mode in the near term.

The 66% relative reduction in complications was “impressive; I hope this will be a message,” commented Nassir F. Marrouche, MD, a cardiac electrophysiologist and professor of medicine at Tulane University, New Orleans. Importantly, this reduced complication rate occurred in a real-world population that was sicker than any patient group previously studied with the device, he noted as a designated discussant for the report.

But the report’s second designated discussant, Roderick Tung, MD, highlighted some caveats when interpreting the lower complication rate with the leadless device compared with historical controls. He cited the absence of any episodes of pneumothorax among the patients reviewed by Dr. Piccini who received a leadless pacemaker, compared with a 5% rate among the control patients who had received a device with a transvenous lead, a major driver of the overall difference in complication rates. This difference “may not be relevant to operators who use either an axillary extrathoracic vein route for lead placement or a cephalic vein approach,” said Dr. Tung, director of cardiac electrophysiology at the University of Chicago. “There should not be a 5% rate of pneumothorax when implanting a VVI device.” The results reported by Dr. Piccini have the advantages of coming from many patients and from real-world practice, he acknowledged, but interpretation is limited by the lack of a randomized control group and the outsized impact of pneumothorax complications on the safety comparison.

The other major component of the 6-month complication tally was device-related events, which were twice as common in the historical controls who received a transvenous lead at a rate of 3.4%. The sole 6-month event more common among the patients who received a leadless pacemaker was pericarditis, at a rate of 1.3% in the Micra group and 0.5% in the transvenous lead controls, Dr. Piccini reported. The 6-month rate of device revisions was 1.7% with the leadless device and 2.8% with transvenous lead pacemakers, a difference that was not statistically significant. The two treatment arms had virtually identical 6-month mortality rates.

The rate of acute complications during the first 30 days after implant was also virtually the same in the two study arms. Patient who received the leadless device had significantly more puncture-site events, at a rate of 1.2%, and significantly more cardiac effusions or perforations, at a rate of 0.8%. The historical control patients who received devices with transvenous leads had significantly more device-related complications after 30 days, a 2.5% rate.

The 30-day cohorts examined had larger numbers of patients than at 6 months, 5,746 leadless pacemaker recipients and 9,662 matched historical controls who had received a transvenous lead pacemaker. The clinical and demographic profile of the 30-day cohort who received the leadless pacemaker highlighted the sicker nature of these patients compared with earlier studies of the device. They were an average age of 79 years, compared with average ages of 76 years in the two prior Micra studies, and they also had double the prevalence of coronary disease, triple the prevalence of heart failure, more than twice the rate of chronic obstructive pulmonary disease, and almost twice the prevalence of diabetes.

During the period examined in this report from Micra CED (Longitudinal Coverage With Evidence Development Study on Micra Leadless Pacemakers), in 2017-2018, the leadless pacemaker’s initial approved indications were for a circumscribed portion of the overall patient population that needs pacing. Essentially, they were elderly patients with persistent atrial fibrillation who only need ventricular pacing, roughly 15% of the overall cohort of pacing candidates. In January 2020, the FDA added an indication for high-grade atrioventricular block, an expanded population of candidates that roughly tripled the number of potentially appropriate recipients, said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication, in an interview at the time of the revised labeling.

The study was sponsored by Medtronic, which markets the Micra leadless pacemaker. Dr. Piccini has received honoraria from Medtronic and several other companies. Dr. Marrouche has been a consultant to Medtronic as well as to Biosense Webster, Biotronik, Cardiac Design, and Preventice, and has received research funding from Abbott, Biosense Webster, Boston Scientific, and GE Healthcare. Dr. Tung has been a speaker on behalf of Abbott, Boston Scientific, and Biosense Webster. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer.

[email protected]

SOURCE: Piccini JP et al. Heart Rhythm 2020, Abstract D-LBCT04-01.

A leadless right-ventricular pacemaker continued to show an edge over conventional transvenous pacemakers by triggering a substantially reduced rate of complications during the 6 months following placement in a review of more than 10,000 Medicare patients treated over 2 years.

The “largest leadless pacemaker cohort to date” showed that in propensity score–matched cohorts, the 3,276 patients who received the Micra leadless transcatheter pacemaker during routine management and were followed for 6 months had a 3.3% rate of total complications, compared with a 9.4% rate among 7,256 patients who received a conventional VVI pacemaker with a transvenous lead, a statistically significant 66% relative risk reduction, Jonathan P. Piccini, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19.

The 66% reduced rate of complications – both acutely and with further follow-up – was similar to the complication reductions seen with Micra, compared with historical controls who received transvenous single-chamber pacemakers in both the pivotal study for the device (Heart Rhythm. 2017 May 1;14[3]:702-9) and in a postapproval registry study (Heart Rhythm. 2018 Dec 1;15[12]:1800-7). However, the newly reported advantage came in a population that was notably older and had significantly more comorbidities than in the prior leadless pacemaker studies, said Dr. Piccini, a cardiac electrophysiologist at Duke University, Durham, N.C.

The new Medicare data “tell us that physicians are reaching for these devices [leadless pacemakers] in patients with more comorbidities and a higher risk for complications to give them a [device with] better safety profile,” he said during a press briefing. “At Duke, and I suspect at other centers, when a patients is eligible for a leadless pacemaker that’s the preferred option.”

However, Dr. Piccini cited three examples of the small proportion of patients who are appropriate for the type of pacing the leadless pacemaker supplies but would be better candidates for a device with a transvenous lead: patients who failed treatment with a initial leadless pacemaker and have no suitable alternative subcutaneous spot to place the replacement device in a stable way, those with severe right ventricular enlargement that interferes with optimal placement, and those who don’t currently meet criteria for biventricular pacing but appear likely to switch to that pacing mode in the near term.

The 66% relative reduction in complications was “impressive; I hope this will be a message,” commented Nassir F. Marrouche, MD, a cardiac electrophysiologist and professor of medicine at Tulane University, New Orleans. Importantly, this reduced complication rate occurred in a real-world population that was sicker than any patient group previously studied with the device, he noted as a designated discussant for the report.

But the report’s second designated discussant, Roderick Tung, MD, highlighted some caveats when interpreting the lower complication rate with the leadless device compared with historical controls. He cited the absence of any episodes of pneumothorax among the patients reviewed by Dr. Piccini who received a leadless pacemaker, compared with a 5% rate among the control patients who had received a device with a transvenous lead, a major driver of the overall difference in complication rates. This difference “may not be relevant to operators who use either an axillary extrathoracic vein route for lead placement or a cephalic vein approach,” said Dr. Tung, director of cardiac electrophysiology at the University of Chicago. “There should not be a 5% rate of pneumothorax when implanting a VVI device.” The results reported by Dr. Piccini have the advantages of coming from many patients and from real-world practice, he acknowledged, but interpretation is limited by the lack of a randomized control group and the outsized impact of pneumothorax complications on the safety comparison.

The other major component of the 6-month complication tally was device-related events, which were twice as common in the historical controls who received a transvenous lead at a rate of 3.4%. The sole 6-month event more common among the patients who received a leadless pacemaker was pericarditis, at a rate of 1.3% in the Micra group and 0.5% in the transvenous lead controls, Dr. Piccini reported. The 6-month rate of device revisions was 1.7% with the leadless device and 2.8% with transvenous lead pacemakers, a difference that was not statistically significant. The two treatment arms had virtually identical 6-month mortality rates.

The rate of acute complications during the first 30 days after implant was also virtually the same in the two study arms. Patient who received the leadless device had significantly more puncture-site events, at a rate of 1.2%, and significantly more cardiac effusions or perforations, at a rate of 0.8%. The historical control patients who received devices with transvenous leads had significantly more device-related complications after 30 days, a 2.5% rate.

The 30-day cohorts examined had larger numbers of patients than at 6 months, 5,746 leadless pacemaker recipients and 9,662 matched historical controls who had received a transvenous lead pacemaker. The clinical and demographic profile of the 30-day cohort who received the leadless pacemaker highlighted the sicker nature of these patients compared with earlier studies of the device. They were an average age of 79 years, compared with average ages of 76 years in the two prior Micra studies, and they also had double the prevalence of coronary disease, triple the prevalence of heart failure, more than twice the rate of chronic obstructive pulmonary disease, and almost twice the prevalence of diabetes.

During the period examined in this report from Micra CED (Longitudinal Coverage With Evidence Development Study on Micra Leadless Pacemakers), in 2017-2018, the leadless pacemaker’s initial approved indications were for a circumscribed portion of the overall patient population that needs pacing. Essentially, they were elderly patients with persistent atrial fibrillation who only need ventricular pacing, roughly 15% of the overall cohort of pacing candidates. In January 2020, the FDA added an indication for high-grade atrioventricular block, an expanded population of candidates that roughly tripled the number of potentially appropriate recipients, said Larry A. Chinitz, MD, a cardiac electrophysiologist and a coinvestigator on some of the studies that led to the new indication, in an interview at the time of the revised labeling.

The study was sponsored by Medtronic, which markets the Micra leadless pacemaker. Dr. Piccini has received honoraria from Medtronic and several other companies. Dr. Marrouche has been a consultant to Medtronic as well as to Biosense Webster, Biotronik, Cardiac Design, and Preventice, and has received research funding from Abbott, Biosense Webster, Boston Scientific, and GE Healthcare. Dr. Tung has been a speaker on behalf of Abbott, Boston Scientific, and Biosense Webster. Dr. Chinitz has received fees and fellowship support from Medtronic, and has also received fees from Abbott, Biosense Webster, Biotronik, and Pfizer.

[email protected]

SOURCE: Piccini JP et al. Heart Rhythm 2020, Abstract D-LBCT04-01.

It is time to broaden the definition of osteoporosis used in clinical guidelines, states an article published in Age and Ageing, the official journal of the British Geriatrics Society.

The authors recommend that the World Health Organization and the International Society for Clinical Densitometry consider a broader definition of osteoporosis, which encompasses clinical diagnosis, providing clear guidance on communicating bone mineral density (BMD) results to patients.

The WHO definition of osteoporosis, which is endorsed as a diagnostic threshold in current U.K. and European guidance, still relies purely on BMD testing (T score of −2.5 SD or more). The authors say this definition no longer relates to the population for whom osteoporosis drugs are recommended.

In the past 15 years, they write, there has been a change in the field of osteoporosis, namely to base osteoporosis management not just on absolute values of BMD but also on broader consideration of future fracture risk. This change has been underpinned by observations that the majority of patients with a fragility fracture do not have osteoporotic BMD.

Coauthor Zoe Paskins, MBChB, a senior lecturer at Keele (England) University and clinical lead for the osteoporosis service in North Staffordshire, argues that many people with osteoporosis do not receive the treatment they need because of inconsistencies in how the condition is diagnosed around the world, resulting in confusion for both clinicians and patients.

“We think it is time for the WHO to reconsider the definition of osteoporosis, which is now more than 25 years old. A new definition is needed to acknowledge that it is possible, in some circumstances, to give a clinical diagnosis of osteoporosis in those who have osteoporotic fractures. In our view, this would help address current confusion and improve uptake of treatments,” she said.

This article first appeared on Univadis.

It is time to broaden the definition of osteoporosis used in clinical guidelines, states an article published in Age and Ageing, the official journal of the British Geriatrics Society.

The authors recommend that the World Health Organization and the International Society for Clinical Densitometry consider a broader definition of osteoporosis, which encompasses clinical diagnosis, providing clear guidance on communicating bone mineral density (BMD) results to patients.

The WHO definition of osteoporosis, which is endorsed as a diagnostic threshold in current U.K. and European guidance, still relies purely on BMD testing (T score of −2.5 SD or more). The authors say this definition no longer relates to the population for whom osteoporosis drugs are recommended.

In the past 15 years, they write, there has been a change in the field of osteoporosis, namely to base osteoporosis management not just on absolute values of BMD but also on broader consideration of future fracture risk. This change has been underpinned by observations that the majority of patients with a fragility fracture do not have osteoporotic BMD.

Coauthor Zoe Paskins, MBChB, a senior lecturer at Keele (England) University and clinical lead for the osteoporosis service in North Staffordshire, argues that many people with osteoporosis do not receive the treatment they need because of inconsistencies in how the condition is diagnosed around the world, resulting in confusion for both clinicians and patients.

“We think it is time for the WHO to reconsider the definition of osteoporosis, which is now more than 25 years old. A new definition is needed to acknowledge that it is possible, in some circumstances, to give a clinical diagnosis of osteoporosis in those who have osteoporotic fractures. In our view, this would help address current confusion and improve uptake of treatments,” she said.

This article first appeared on Univadis.

It is time to broaden the definition of osteoporosis used in clinical guidelines, states an article published in Age and Ageing, the official journal of the British Geriatrics Society.

The authors recommend that the World Health Organization and the International Society for Clinical Densitometry consider a broader definition of osteoporosis, which encompasses clinical diagnosis, providing clear guidance on communicating bone mineral density (BMD) results to patients.

The WHO definition of osteoporosis, which is endorsed as a diagnostic threshold in current U.K. and European guidance, still relies purely on BMD testing (T score of −2.5 SD or more). The authors say this definition no longer relates to the population for whom osteoporosis drugs are recommended.

In the past 15 years, they write, there has been a change in the field of osteoporosis, namely to base osteoporosis management not just on absolute values of BMD but also on broader consideration of future fracture risk. This change has been underpinned by observations that the majority of patients with a fragility fracture do not have osteoporotic BMD.

Coauthor Zoe Paskins, MBChB, a senior lecturer at Keele (England) University and clinical lead for the osteoporosis service in North Staffordshire, argues that many people with osteoporosis do not receive the treatment they need because of inconsistencies in how the condition is diagnosed around the world, resulting in confusion for both clinicians and patients.

“We think it is time for the WHO to reconsider the definition of osteoporosis, which is now more than 25 years old. A new definition is needed to acknowledge that it is possible, in some circumstances, to give a clinical diagnosis of osteoporosis in those who have osteoporotic fractures. In our view, this would help address current confusion and improve uptake of treatments,” she said.

This article first appeared on Univadis.

A high-intensity exercise program, already shown effective in improving bone density and performance in women, is also effective in older men with low bone density, according to the LIFTMOR-M study, published in Bone. The protocol incorporates barbell-based weightlifting and impact training involving jumping chin-ups.

sbm Hotting/Fotolia.com

“When you’ve got a condition primarily in one of the sexes, the other sex often gets ignored, and that’s absolute the case with osteoporosis,” said lead author Belinda Beck, PhD, a professor at Griffith University, Gold Coast, Australia, in an interview.

In older adults with low bone density, when it comes to building bone and reducing fracture, a review of the literature suggests that exercise doesn’t work. That’s not really true though, according to Dr. Beck. An unpublished analysis of studies of high-intensity exercise only at her institution shows promise. “It looks like exercise doesn’t work. It’s not that, it’s that the wrong kind of exercise doesn’t work,” she stressed.

The original LIFTMOR trial, in women, was inspired by a collaboration with Lisa Weis, an Olympic weightlifter who specialized in training older women, who subsequently showed improvements on bone scans. “That’s what jump-started it, because just like every other scientist, I would have been too scared to do this kind of loading in this fragile population, and that’s the reason why people haven’t been doing it. They don’t want to break people,” said Dr. Beck.

The investigators “cherry-picked some of those exercises and tested them in the LIFTMOR trial. I was nervous about the study because the weights we were lifting were much heavier than most people had applied for people with osteoporosis. The risk was, we would cause the fractures we were trying to prevent,” said Dr. Beck. Her team tested a high-intensity resistance and impact (HiRIT) protocol in postmenopausal women with low bone mass (J Bone Miner Res. 2019 Mar;34[3]:572. Controls underwent a home-based, low-intensity exercise program. They found improvements in bone density and functional performance, compared with controls.

“The exercise was effective and safe for this population if practiced with proper technique under close supervision,” said Dr. Beck, but she emphasized that the exercises must be led by experienced coaches because of the potential for injury.

The investigators then looked at men. “There are still one in five men over 50 who are going to fracture,” Dr. Beck said.

Her team launched LIFTMOR-M, which enrolled 93 men (mean age, 67.1 years) with a lower than average proximal femur areal bone mineral density. Of them, 34 were randomized to HiRIT, 33 to supervised machine-based isometric axial compression (IAC) exercise training, and 26 were designated as controls and self-selected to usual activities.

The intervention included 8 months of twice-weekly, supervised, 30-minute HiRIT sessions, which included five sets of five repetitions, using more than 85% the weight of the single repetition maximum. The routine included the deadlift, squat, and overhead press. The impact component included five sets of five repetitions of jumping chin-ups followed by a firm, flat-footed landing.

After 8 months, there was no difference in compliance between the two intervention groups. Those in the HiRIT group had improved medial femoral neck cortical thickness, compared with controls (5.6% vs. –0.1%; P = .028) and IAC (5.6% vs. 0.7%; P = .044). Those in the HiRIT group maintained distal tibia trabecular area, while the control group experienced a loss (0.2% vs. –1.6%; P = .013). The IAC group did not show any improvement in bone strength in any of the sites examined, though some findings suggest it may counteract age-related loss in bone strength indices in the distal tibia and radius.

The program requires a fluid movement that maintains a neutral spine throughout. Dr. Beck has developed the Onero program (theboneclinic.com.au/onero/) based on the routine, and licenses it to physical therapists and exercise physiologists.

The study was funded by the Australian Research Foundation and the Australian Government Research Training Program. Dr. Beck owns the Bone Clinic, which sells licenses to the Onero program based on the exercise program used in the study.

SOURCE: Beck B et al. Bone. 2020 April 11. doi: 10.1016/j.bone.2020.115362.

A high-intensity exercise program, already shown effective in improving bone density and performance in women, is also effective in older men with low bone density, according to the LIFTMOR-M study, published in Bone. The protocol incorporates barbell-based weightlifting and impact training involving jumping chin-ups.

sbm Hotting/Fotolia.com

“When you’ve got a condition primarily in one of the sexes, the other sex often gets ignored, and that’s absolute the case with osteoporosis,” said lead author Belinda Beck, PhD, a professor at Griffith University, Gold Coast, Australia, in an interview.

In older adults with low bone density, when it comes to building bone and reducing fracture, a review of the literature suggests that exercise doesn’t work. That’s not really true though, according to Dr. Beck. An unpublished analysis of studies of high-intensity exercise only at her institution shows promise. “It looks like exercise doesn’t work. It’s not that, it’s that the wrong kind of exercise doesn’t work,” she stressed.

The original LIFTMOR trial, in women, was inspired by a collaboration with Lisa Weis, an Olympic weightlifter who specialized in training older women, who subsequently showed improvements on bone scans. “That’s what jump-started it, because just like every other scientist, I would have been too scared to do this kind of loading in this fragile population, and that’s the reason why people haven’t been doing it. They don’t want to break people,” said Dr. Beck.

The investigators “cherry-picked some of those exercises and tested them in the LIFTMOR trial. I was nervous about the study because the weights we were lifting were much heavier than most people had applied for people with osteoporosis. The risk was, we would cause the fractures we were trying to prevent,” said Dr. Beck. Her team tested a high-intensity resistance and impact (HiRIT) protocol in postmenopausal women with low bone mass (J Bone Miner Res. 2019 Mar;34[3]:572. Controls underwent a home-based, low-intensity exercise program. They found improvements in bone density and functional performance, compared with controls.

“The exercise was effective and safe for this population if practiced with proper technique under close supervision,” said Dr. Beck, but she emphasized that the exercises must be led by experienced coaches because of the potential for injury.

The investigators then looked at men. “There are still one in five men over 50 who are going to fracture,” Dr. Beck said.

Her team launched LIFTMOR-M, which enrolled 93 men (mean age, 67.1 years) with a lower than average proximal femur areal bone mineral density. Of them, 34 were randomized to HiRIT, 33 to supervised machine-based isometric axial compression (IAC) exercise training, and 26 were designated as controls and self-selected to usual activities.

The intervention included 8 months of twice-weekly, supervised, 30-minute HiRIT sessions, which included five sets of five repetitions, using more than 85% the weight of the single repetition maximum. The routine included the deadlift, squat, and overhead press. The impact component included five sets of five repetitions of jumping chin-ups followed by a firm, flat-footed landing.

After 8 months, there was no difference in compliance between the two intervention groups. Those in the HiRIT group had improved medial femoral neck cortical thickness, compared with controls (5.6% vs. –0.1%; P = .028) and IAC (5.6% vs. 0.7%; P = .044). Those in the HiRIT group maintained distal tibia trabecular area, while the control group experienced a loss (0.2% vs. –1.6%; P = .013). The IAC group did not show any improvement in bone strength in any of the sites examined, though some findings suggest it may counteract age-related loss in bone strength indices in the distal tibia and radius.

The program requires a fluid movement that maintains a neutral spine throughout. Dr. Beck has developed the Onero program (theboneclinic.com.au/onero/) based on the routine, and licenses it to physical therapists and exercise physiologists.

The study was funded by the Australian Research Foundation and the Australian Government Research Training Program. Dr. Beck owns the Bone Clinic, which sells licenses to the Onero program based on the exercise program used in the study.

SOURCE: Beck B et al. Bone. 2020 April 11. doi: 10.1016/j.bone.2020.115362.

A high-intensity exercise program, already shown effective in improving bone density and performance in women, is also effective in older men with low bone density, according to the LIFTMOR-M study, published in Bone. The protocol incorporates barbell-based weightlifting and impact training involving jumping chin-ups.

sbm Hotting/Fotolia.com

“When you’ve got a condition primarily in one of the sexes, the other sex often gets ignored, and that’s absolute the case with osteoporosis,” said lead author Belinda Beck, PhD, a professor at Griffith University, Gold Coast, Australia, in an interview.

In older adults with low bone density, when it comes to building bone and reducing fracture, a review of the literature suggests that exercise doesn’t work. That’s not really true though, according to Dr. Beck. An unpublished analysis of studies of high-intensity exercise only at her institution shows promise. “It looks like exercise doesn’t work. It’s not that, it’s that the wrong kind of exercise doesn’t work,” she stressed.

The original LIFTMOR trial, in women, was inspired by a collaboration with Lisa Weis, an Olympic weightlifter who specialized in training older women, who subsequently showed improvements on bone scans. “That’s what jump-started it, because just like every other scientist, I would have been too scared to do this kind of loading in this fragile population, and that’s the reason why people haven’t been doing it. They don’t want to break people,” said Dr. Beck.

The investigators “cherry-picked some of those exercises and tested them in the LIFTMOR trial. I was nervous about the study because the weights we were lifting were much heavier than most people had applied for people with osteoporosis. The risk was, we would cause the fractures we were trying to prevent,” said Dr. Beck. Her team tested a high-intensity resistance and impact (HiRIT) protocol in postmenopausal women with low bone mass (J Bone Miner Res. 2019 Mar;34[3]:572. Controls underwent a home-based, low-intensity exercise program. They found improvements in bone density and functional performance, compared with controls.

“The exercise was effective and safe for this population if practiced with proper technique under close supervision,” said Dr. Beck, but she emphasized that the exercises must be led by experienced coaches because of the potential for injury.

The investigators then looked at men. “There are still one in five men over 50 who are going to fracture,” Dr. Beck said.

Her team launched LIFTMOR-M, which enrolled 93 men (mean age, 67.1 years) with a lower than average proximal femur areal bone mineral density. Of them, 34 were randomized to HiRIT, 33 to supervised machine-based isometric axial compression (IAC) exercise training, and 26 were designated as controls and self-selected to usual activities.

The intervention included 8 months of twice-weekly, supervised, 30-minute HiRIT sessions, which included five sets of five repetitions, using more than 85% the weight of the single repetition maximum. The routine included the deadlift, squat, and overhead press. The impact component included five sets of five repetitions of jumping chin-ups followed by a firm, flat-footed landing.

After 8 months, there was no difference in compliance between the two intervention groups. Those in the HiRIT group had improved medial femoral neck cortical thickness, compared with controls (5.6% vs. –0.1%; P = .028) and IAC (5.6% vs. 0.7%; P = .044). Those in the HiRIT group maintained distal tibia trabecular area, while the control group experienced a loss (0.2% vs. –1.6%; P = .013). The IAC group did not show any improvement in bone strength in any of the sites examined, though some findings suggest it may counteract age-related loss in bone strength indices in the distal tibia and radius.

The program requires a fluid movement that maintains a neutral spine throughout. Dr. Beck has developed the Onero program (theboneclinic.com.au/onero/) based on the routine, and licenses it to physical therapists and exercise physiologists.

The study was funded by the Australian Research Foundation and the Australian Government Research Training Program. Dr. Beck owns the Bone Clinic, which sells licenses to the Onero program based on the exercise program used in the study.

SOURCE: Beck B et al. Bone. 2020 April 11. doi: 10.1016/j.bone.2020.115362.

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

New research shows that almost 5% of older British citizens have potentially serious brain abnormalities, including aneurysms, and about a third have blood test abnormalities. Knowing the expected prevalence of such incidental findings in the older general population is “extremely useful” for both researchers and clinicians, said study co-author Sarah Elisabeth Keuss, MBChB, clinical research associate, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK.

“In research, the knowledge helps to inform study protocols regarding how to manage incidental findings and enables study participants to be appropriately informed,” said Dr. Keuss. Greater awareness also helps clinicians make decisions about whether or not to scan a patient, she said, adding that imaging is increasingly available to them. It allows clinicians to counsel patients regarding the probability of an incidental finding and balance that risk against the potential benefits of having a test.

The research is being presented online as part of the American Academy of Neurology 2020 Science Highlights. The incidental findings also were published last year in BMJ Open.

The new findings are from the first wave of data collection for the Insight 46 study, a neuroimaging substudy of the MRC National Survey of Health and Development (NSHD) 1946 British birth cohort, a broadly representative sample of the population born in mainland Britain during 1946. The research uses detailed brain imaging, cognitive testing, and blood and other biomarkers to investigate genetic and life-course factors associated with Alzheimer’s disease and cerebrovascular disease.

The current study included 502 individuals, aged about 71 years at the time of the analysis, and 49% were women. Almost all (93.8%) participants underwent 1-day MRI scans. Some 4.5% of these participants had an incidental finding of brain abnormality as per a prespecified standardized protocol.

Suspected vascular malformations were present in 1.9%, and suspected intracranial mass lesions were present in 1.5%. The single most common vascular abnormality was a suspected cerebral aneurysm, which affected 1.1% of participants.

Suspected meningiomas were the most common intracranial lesion, affecting 0.6% of study participants.
 

Action plan

Participants and their primary care provider were informed of findings “that were deemed to be potentially serious, or life-threatening, or could have a major impact on quality of life,” said Dr. Keuss. Relevant experts “came up with a recommended clinical action plan to help the primary care provider decide what should be the next course of action with regard to investigation or referral to another specialist,” said Dr. Keuss.

The new results are important for clinical decision-making, said Dr. Keuss. “Clinicians should consider the possibility of detecting an incidental finding whenever they’re requesting a brain scan. They should balance that risk against the possible benefits of recommending a test.”

The prevalence of incidental findings on MRI reported in the literature varies because of different methods used to review scans. “However, comparing our study with similar studies, the prevalence of the key findings with regard to aneurysms and intracranial mass lesions are very similar,” said Dr. Keuss.

Dr. Keuss and colleagues do not recommend all elderly patients get a brain scan.

“We don’t know what the long-term consequences are of being informed you have an incidental finding of an abnormality; we don’t know if it improves their outcome, and it potentially could cause anxiety,” said Dr. Keuss.
 

Psychological impact

The researchers have not looked at the psychological impact of negative findings on study participants, but they could do so at a later date.

“It would be very important to look into that given the potential to cause anxiety,” said Dr. Keuss. “It’s important to find out the potential negative consequences to inform researchers in future about how best to manage these findings.”

From blood tests, the analysis found that more than a third (34.6%) of participants had at least one related abnormality. The most common of these were kidney impairment (about 9%), thyroid function abnormalities (between 4% and 5%), anemia (about 4%), and low vitamin B₁₂ levels (about 3%).

However, few of these reached the prespecified threshold for urgent action, and Dr. Keuss noted these findings were not the focus of her AAN presentation.

A strength of the study was that participants were almost the exact same age.
 

Important issue

Commenting on the research, David S. Liebeskind, MD, professor of neurology and director, Neurovascular Imaging Research Core, University of California, Los Angeles, said it raises “a very interesting” and “important” public health issue.

“The question is whether we do things based around individual symptomatic status, or at a larger level in terms of public health, screening the larger population to figure out who is at risk for any particular disease or disorder.”

From the standpoint of imaging technologies like MRI that show details about brain structures, experts debate whether the population should be screened “before something occurs,” said Dr. Liebeskind. “Imaging has the capacity to tell us a tremendous amount; whether this implies we should therefore image everybody is a larger public health question.”

The issue is “fraught with a lot of difficulty and complexity” as treatment paradigms tend to be “built around symptomatic status,” he said. “When we sit in the office or with a patient at the bedside, we usually focus on that individual patient and not necessarily on the larger public.”

Dr. Liebeskind noted that the question of whether to put the emphasis on the individual patient or the public at large is also being discussed during the current COVID-19 pandemic.

He wasn’t surprised that the study uncovered incidental findings in almost 5% of the sample. “If you take an 80-year-old and study their brain, a good chunk, if not half or more, will have some abnormality,” he said.

Drs. Keuss and Liebeskind have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Five leading bone health organizations have gotten together to provide new recommendations for managing patients with osteoporosis during the COVID-19 pandemic.

The joint guidance – released by the American Society for Bone and Mineral Research (ASBMR), the American Association of Clinical Endocrinologists, the Endocrine Society, the European Calcified Tissue Society, and the National Osteoporosis Foundation – offered both general and specific recommendations for patients whose osteoporosis treatment plan is either continuing or has been disrupted during the COVID-19 pandemic.

Among the general recommendations are to initiate oral bisphosphonate therapy over either the telephone or through a video visit, with no delays for patients at high risk of fracture. They also noted that, as elective procedures, bone mineral density examinations may need to be postponed.

For patients already on osteoporosis medications – such as oral and IV bisphosphonates, denosumab, estrogen, raloxifene, teriparatide, abaloparatide, and romosozumab – they recommend continuing treatment whenever possible. “There is no evidence that any osteoporosis therapy increases the risk or severity of COVID-19 infection or alters the disease course,” they wrote. They did add, however, that COVID-19 may increase the risk of hypercoagulable complications and so caution should be exercised when treating patients with estrogen or raloxifene.

Separately, in a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism (doi: 10.1210/clinem/dgaa254), Ruban Dhaliwal, MD, MPH, of the State University of New York, Syracuse, and coauthors concur in regard to raloxifene. They wrote that, because of the increased risk of thromboembolic events related to COVID-19, “it is best to discontinue raloxifene, which is also associated with such risk.”

The joint statement recognizes current social distancing policies and therefore recommends avoiding standard pretreatment labs prior to IV bisphosphonate and/or denosumab administration if previous labs were normal and the patient’s recent health has been deemed “stable.” Lab evaluation is recommended, however, for patients with fluctuating renal function and for those at higher risk of developing hypocalcemia.

The statement also provides potential alternative methods for delivering parenteral osteoporosis treatments, including off-site clinics, home delivery and administration, self-injection of denosumab and/or romosozumab, and drive-through administration of denosumab and/or romosozumab. They acknowledged the complications surrounding each alternative, including residents of “socioeconomically challenged communities” being unable to reach clinics if public transportation is not available and the “important medicolegal issues” to consider around self-injection.

For all patients whose treatments have been disrupted, the authors recommend frequent reevaluation “with the goal to resume the original osteoporosis treatment plan once circumstances allow.” As for specific recommendations, patients on denosumab who will not be treatable within 7 months of their previous injection should be transitioned to oral bisphosphonate if at all possible. For patients with underlying gastrointestinal disorders, they recommend monthly ibandronate or weekly/monthly risedronate; for patients with chronic renal insufficiency, they recommend an off-label regimen of lower dose oral bisphosphonate.

For patients on teriparatide or abaloparatide who will be unable to receive continued treatment, they recommend a delay in treatment. If that delay goes beyond several months, they recommend a temporary transition to oral bisphosphonate. For patients on romosozumab who will be unable to receive continued treatment, they also recommend a delay in treatment and a temporary transition to oral bisphosphonate. Finally, they expressed confidence that patients on IV bisphosphonates will not be harmed by treatment delays, even those of several months.

“I think we could fall into a trap during this era of the pandemic and fail to address patients’ underlying chronic conditions, even though those comorbidities will end up greatly affecting their overall health,” said incoming ASBMR president Suzanne Jan de Beur, MD, of the Johns Hopkins University, Baltimore. “As we continue to care for our patients, we need to keep chronic conditions like osteoporosis on the radar screen and not stop diagnosing people at risk or those who present with fractures. Even when we can’t perform full screening tests due to distancing policies, we need to be vigilant for those patients who need treatment and administer the treatments we have available as needed.”

The statement’s authors acknowledged the limitations of their recommendations, noting that “there is a paucity of data to provide clear guidance” and as such they were “based primarily on expert opinion.”

The authors from the five organizations did not disclose any conflicts of interest.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

Testosterone normally decreases with age in men beginning in their mid-30s, with a rate of decline averaging approximately 1.6% per year. Using a cutoff of a total testosterone less than 325 ng/dL, the incidence of low testosterone is approximately 20% after age 60 years, and 30% after age 70. While the change in labs values has been reasonably validated, there is some uncertainty about whether many of the symptoms that are sometimes attributed to testosterone deficiency, including fatigue and decreased muscle mass, are actually caused by low testosterone.

Additional potential symptoms of testosterone deficiency include changes in bone mineral density, decreased libido, depression, erectile dysfunction, loss of hair, and general weakness. Since the symptoms are nonspecific, it is often unclear if someone should be tested or treated for testosterone deficiency. To address this issue, the American College of Physicians commissioned a systematic review of the evidence on testosterone-replacement therapy for age-related testosterone deficiency.¹

The evidence review of testosterone replacement in men with age-related low testosterone found the following.

• Low-certainty evidence of improvement in quality of life
• Moderate-certainty evidence of a small improvement in sexual function
• Low-certainty evidence of a small improvement in erectile function
• Low-certainty evidence showing little to no improvement in physical function
• Low-certainty evidence of a small increase to no difference in adverse cardiovascular events
• Moderate-certainty evidence of no increase in the risk for serious adverse events

The trials were not powered to assess mortality, but pool analysis showed fewer deaths among patients treated with testosterone than those who received placebo (odds ratio, 0.47; 95% confidence interval, 0.25-0.89). There were no differences in cognitive function, and the improvement in vitality and fatigue was “less than a small amount.” Evidence from an observational trial showed no increased risk for mortality, cardiovascular events, prostate cancer, or pulmonary embolus or deep vein thrombosis. Of note, most studies excluded men with recent cardiovascular disease.

This evidence review led to the following recommendations.²

Recommendation 1a

Clinicians should have a discussion regarding the potential risk and benefits of treatment with the patients who have documented age-related low testosterone (testosterone levels less than 10.4 nmol/L or 300 ng/dL) and are suffering from sexual dysfunction or have a desire to enhance their sexual function.

This recommendation was based on evidence showing small improvement in sexual function and erectile dysfunction.

Recommendation 1b

For patients who opt for treatment based on recommendation 1a, clinicians should reevaluate the benefit of treatment within 12 months. If a patient is not receiving any benefit in sexual function by 12 months, it is recommended that treatment be stopped at that time.

The ACP recommendation to stop treatment if a patient lacks improvement of sexual function within 12 months stems from low or insufficient evidence regarding potential harm of treatment. If the treatment is not helping the target symptom then the benefit no longer outweighs the potential harm.

Recommendation 1c

For patients who opt for treatment based on recommendation 1a, intramuscular replacement therapy rather than transdermal replacement therapy is recommended because of substantial differences in the cost.

It is important to note that both intramuscular and transdermal testosterone applications have been associated with improvements in sexual function, without any significant differences noted in benefit or harm for the patients. This recommendation is based on a per-person per-year average cost of the intramuscular formulation – $156.32, compared with the transdermal formulation – $2,135.32.

Recommendation 2

The ACP does not endorse the use of testosterone treatment for age-related low testosterone in patients desiring improvement in physical function, mood, energy, or cognitive function.

This clear recommendation is critical, as this might be the most common reason for prescriptions of testosterone – a misplaced belief that testosterone will help general quality of life. The evidence simply does not support this effect of testosterone replacement for age-related testosterone deficiency.

The bottom line

Testosterone levels in men decrease steadily with age, with a great deal of variability. Testosterone replacement therapy may be considered for men with age-related testosterone deficiency and sexual dysfunction. Testosterone replacement therapy is not recommended as a treatment for general fatigue, weakness or with an expectation that it will improve physical function, mood, energy, or cognitive function.

Dr. Hansen is a third-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Hospital–Jefferson Health.

References

1. Diem SJ et al. Efficacy and safety of testosterone treatment in men: An evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0830.

2. Qaseem A et al. Testosterone treatment in adult men with age-related low testosterone: A clinical guideline from the American College of Physicians. Ann Intern Med. 2020 Jan 21. doi: 10.7326/M19-0882.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

In older patients undergoing hemiarthroplasty for repair of a hip fracture, cemented fixation reduces the risk of aseptic revisions, according to a large retrospective cohort analysis reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled due to COVID-19.

“These data suggest surgeons should consider cemented over uncemented femoral stem fixation in the absence of contraindications,” reported Kanu M. Okike, MD, an orthopedic surgeon with the Hawaii Permanente Medical Group, Kaiser Moanalua Medical Center, Honolulu.

The finding was drawn from a cohort analysis conducted in the United States. Several studies conducted in Europe and elsewhere, including randomized trials, have also favored cement.

“Cemented fixation is becoming a standard of care for elderly individuals outside of the U.S., but this study was conducted to evaluate the U.S. experience,” explained Dr. Okike in an interview.

Citing 2018 American Joint Replacement Registry data, Dr. Okike reported that more than half of hemiarthroplasties in the United States are still being fixed without cement.

The retrospective cohort analysis was undertaken with the Kaiser Permanente Hip Fracture Registry, selecting patients age 60 years or older who underwent hemiarthroplasty for hip fracture between 2009 and 2017. Of the 12,491 patients, 6,449 (51.6%) included cement fixation, and the remaining were uncemented.

After controlling for confounders, including age, sex, body mass index, and comorbidities, the incidence of aseptic revision 1 year after repair was 3.0% in the uncemented group and 1.3% in the cemented group. By hazard ratio (HR), the risk of aseptic revision, which was the primary endpoint, was increased by more than 75% (HR 1.77; 95% confidence interval, 1.43-2.19; P < .001).

Of the secondary outcomes evaluated, such as medical complications at 90 days or mortality at 1 year, none were significantly different between the two arms.

A post hoc analysis suggested that a higher risk of periprosthetic fracture explained the higher rates of aseptic revision in the uncemented group, according to Dr. Okike, whose data have now been published (JAMA. 2020;323:1077-84).

Surgeon preference was also evaluated in this study as an instrumental variable. When patients treated by a surgeon with a preference for cemented fixation were compared with those treated by a surgeon with a preference for cementless repair, the relative advantage of cement for the primary outcome was similar (HR, 1.74; P = .02).

These data are consistent with trials outside of the United States. For example, a randomized trial with 160 patients conducted in New Zealand associated cemented fixation with a lower risk of periprosthetic fracture (1 vs. 18) and superior Oxford hip scores (J Bone Joint Surg Am. 2012;94:577-83). Similarly, a randomized trial of 141 patients conducted in Sweden associated cemented fixation with lower rate of periprosthetic fracture (0 vs. 9) and improved outcomes on several instruments, including the Harris Hip Scale (Bone Joint J. 2015;97-B:1475-80).

Cemented fixation generally requires a slightly longer operating time, but it is not otherwise more difficult or more expensive, according to Dr. Okike. He believes these results encourage cemented fixation in older patients without contraindications. This is already specifically recommended in AAOS guidelines for the management of hip fractures in elderly patients.

An orthopedic surgeon who has published frequently on total hip arthroplasty, Emil van Haaren, MD, of Zuyderland Medical Center, Heerlen, the Netherlands, confirmed that cemented hemiarthroplasty is considered “the golden standard of care” at his institution. In one study for which he served as the senior author, survival was characterized as excellent in older patients receiving cemented hip arthroplasty that were followed for more than 10 years (J Arthroplasty. 2016;31:194-8).

“We routinely use cemented prosthesis in hip fracture management when an arthroplasty is indicated,” he reported, echoing the contention by Dr. Okike that this approach is dominant in many centers outside of the United States.

Dr. Okike reports no potential conflicts of interest.

SOURCE: Okiki KM et al. JAMA. 2020;323:1077-84.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.

Cognitively normal carriers of the apolipoprotein E epsilon-4 (APOE4) allele aged 60 years and older who also showed heterozygosity for the Klotho-VS allele had a significantly reduced risk of developing Alzheimer’s disease, according to data from 22 research groups including more than 20,000 adults.

The transmembrane protein known as klotho (KL) is part of a functional haplotype known as KL-VS. “Specifically, heterozygosity for KL-VS (KL-VS^HET+ status) has been shown to increase serum levels of KL and exert protective effects on healthy aging and longevity when compared with individuals who are homozygotes for the major or minor alleles (KL-VS^HET−),” wrote Michael E. Belloy, PhD, of Stanford (Calif.) University and colleagues. However, the possible role of KL-VS in protecting against neurodegenerative disorders such as Alzheimer’s disease (AD) remains unclear, they said.

In a study published in JAMA Neurology, the researchers reviewed data from 20,928 participants in case-control studies, as well as 3,008 participants in conversion studies, 556 in amyloid-beta (a-beta) cerebrospinal fluid regression analyses, and 251 in brain amyloid PET regression analyses. The participants were aged 60-80 years, and of non-Hispanic northern European ancestry and were identified as cognitively normal or having mild cognitive impairment (MCI) or AD.

Overall, individuals with the APOE4 allele who were cognitively normal and heterozygous for KL-VS had a significantly reduced risk for developing AD (odds ratio, 0.75).

In addition, cognitively normal carriers of APOE4 with KL-VS heterozygosity had significantly lower risk of developing either MCI or AD (hazard ratio, 0.64). Also, those persons with APOE4 and positive KL-VS heterozygosity had higher a-beta in cerebrospinal fluid (P = .03) and lower a-beta on PET scans (P = .04). However, no association with cognitive outcomes were noted among APOE4 noncarriers, the researchers noted.

“This suggests that KL-VS interacts with aspects of AD pathology that are more pronounced in those who carry APOE4, such as a-beta accumulation during the presymptomatic phases of the disease,” they said.

The study findings were limited by the variable age and diagnoses across the multiple cohorts, but strengthened by the meta- and mega-analyses and sensitivity analyses that yielded consistent results, the researchers noted.

“Our work paves the way for biological validation studies to elucidate the molecular pathways by which KL-VS and APOE interact,” they said.

“The specificity of KL-VS benefits on AD in individuals who carry APOE4 is striking and suggests a yet-unstudied interaction between biological pathways of the klotho and APOE4 proteins,” wrote Dena B. Dubal, MD, and Jennifer S. Yokoyama, PhD, of the University of California, San Francisco, in an accompanying editorial. Despite limitations, the study findings have implications for clinical neurology, as well as clinical and translational research, they said.

“For personalized genomics, KL-VS status should integrate into knowledge that both lifestyle and genetics can negate or at least mitigate harmful influences of APOE4,” they noted. “In light of this, we might consider an individual’s KLOTHO genotype when counseling individuals who carry APOE4 about their prognosis for AD. In clinical trials using APOE4 for trial enrichment, further selection of individuals who carry APOE4 without KL-VS could define a population more likely to convert to AD and thus increase detection of a therapeutic benefit. In translational research, understanding how klotho itself or its biological pathways may counter APOE4 could lead to monumental progress in the future treatment of AD,” they added.

“Applying our growing knowledge of klotho to APOE4 and AD could ultimately pave the path to novel therapeutics for individuals who carry APOE4,” they concluded.

The study was supported by the Iqbal Farrukh & Asad Jamal Center for Cognitive Health in Aging, the South Palm Beach County Foundation, and the National Institutes of Health. The researchers had no financial conflicts to disclose. Dr. Dubal disclosed holding a patent for Methods for Improving Cognition that includes klotho, as well as consulting for Unity Biotechnology and receiving research funding from the National Institutes of Health, the American Federation for Aging Research, Glenn Medical Foundation, Unity Biotechnology, and other philanthropic support for translational research. Dr. Yokoyama disclosed research funding from the National Institutes of Health, the Department of Defense, and other foundations and philanthropic donors.

SOURCE: Belloy ME et al. JAMA Neurol. 2020 Apr 13. doi: 10.1001/jamaneurol.2020.0414.