Neurology Reviews

The results of a large longitudinal study spanning several years support a decrease in the risk for dementia among older adults who regularly use the Internet for < 2 hours per day. 

Several cross-sectional and longitudinal studies (though with relatively short follow-up periods) suggest that regular Internet use helps maintain cognitive reserve, although some observers have voiced skepticism. This hypothesis is particularly relevant for older patients facing the potentially detrimental effects of brain aging. According to some studies, memory, cognitive performance, and verbal reasoning tend to be better preserved among Internet users.

Several factors come into play, including socioeconomic disparities, socio-educational level, and generational differences, since Internet usage varies qualitatively and quantitatively with age. Older patients theoretically have more limited Internet usage. Under these conditions, the effect on cognitive functions would likely be modest compared with generations who were immersed in digital technology early on and tend to overuse it. After a certain age, accelerated brain aging would weigh much more heavily than any potential positive effects of the Internet. It is worth noting that the negative effects of Internet use have mainly been studied in young subjects, thus there is a lack of data concerning older patients.

Nearly 20,000 Participants

These considerations highlight the significance of a longitudinal cohort study that included 18,154 adults aged 50-64.9 years who were free from any dementia at baseline. These adults were participating in the Health and Retirement Study. The median follow-up period was 7.9 years, and follow-up extended to 17.1 years in some cases. Given that adults with better cognitive health are likely to self-select as regular users, the propensity score method was employed to control for this nonrandom factor using inverse probability weighting.

The risk for dementia based on initial Internet use was estimated using the Cox proportional hazards model, incorporating potentially late entry into the workforce and several covariables. Interactions with education level, gender, generation, and ethnic origin were also considered. Cumulative Internet exposure in terms of regular periodic use throughout life was included in the statistical analysis, as well as the hours spent on this activity each day. The analyses were conducted from September 2021 to November 2022.

Risk Nearly Halved

Regular Internet use was associated with a reduced risk for dementia, compared with irregular use. The hazard ratio (HR) for dementia was estimated at 0.57. After adjustment for the nonrandom factor of self-selection, this association persisted, and the HR decreased to 0.54. Accounting for baseline cognitive decline did not substantially change these results and yielded an HR of 0.62. The difference in risk between regular and irregular users was not altered by considering potential confounding factors such as education level, ethnic origin, gender, or generation. The longer the cumulative exposure over life, the lower the risk for dementia during follow-up.

The relationship between dementia risk and daily Internet usage hours seems to follow a U-shaped curve, with the lowest risk observed for durations between 0.1 and 2 hours. However, these estimates did not reach statistical significance because of the small sample size analyzed.

The risk for dementia appears to be approximately twice as low among regular Internet users compared with nonusers. This hypothesis deserves serious consideration because of the large sample size and long follow-up duration, as well as careful consideration of as many potential confounding factors as possible. Potential negative effects remain to be clarified as the study was not designed to detect them. The results of previous studies suggest that Internet usage should be moderate for optimal benefit, with approximately 2 hours per day being the most suitable duration, regardless of age, until proven otherwise.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large longitudinal study spanning several years support a decrease in the risk for dementia among older adults who regularly use the Internet for < 2 hours per day. 

Several cross-sectional and longitudinal studies (though with relatively short follow-up periods) suggest that regular Internet use helps maintain cognitive reserve, although some observers have voiced skepticism. This hypothesis is particularly relevant for older patients facing the potentially detrimental effects of brain aging. According to some studies, memory, cognitive performance, and verbal reasoning tend to be better preserved among Internet users.

Several factors come into play, including socioeconomic disparities, socio-educational level, and generational differences, since Internet usage varies qualitatively and quantitatively with age. Older patients theoretically have more limited Internet usage. Under these conditions, the effect on cognitive functions would likely be modest compared with generations who were immersed in digital technology early on and tend to overuse it. After a certain age, accelerated brain aging would weigh much more heavily than any potential positive effects of the Internet. It is worth noting that the negative effects of Internet use have mainly been studied in young subjects, thus there is a lack of data concerning older patients.

Nearly 20,000 Participants

These considerations highlight the significance of a longitudinal cohort study that included 18,154 adults aged 50-64.9 years who were free from any dementia at baseline. These adults were participating in the Health and Retirement Study. The median follow-up period was 7.9 years, and follow-up extended to 17.1 years in some cases. Given that adults with better cognitive health are likely to self-select as regular users, the propensity score method was employed to control for this nonrandom factor using inverse probability weighting.

The risk for dementia based on initial Internet use was estimated using the Cox proportional hazards model, incorporating potentially late entry into the workforce and several covariables. Interactions with education level, gender, generation, and ethnic origin were also considered. Cumulative Internet exposure in terms of regular periodic use throughout life was included in the statistical analysis, as well as the hours spent on this activity each day. The analyses were conducted from September 2021 to November 2022.

Risk Nearly Halved

Regular Internet use was associated with a reduced risk for dementia, compared with irregular use. The hazard ratio (HR) for dementia was estimated at 0.57. After adjustment for the nonrandom factor of self-selection, this association persisted, and the HR decreased to 0.54. Accounting for baseline cognitive decline did not substantially change these results and yielded an HR of 0.62. The difference in risk between regular and irregular users was not altered by considering potential confounding factors such as education level, ethnic origin, gender, or generation. The longer the cumulative exposure over life, the lower the risk for dementia during follow-up.

The relationship between dementia risk and daily Internet usage hours seems to follow a U-shaped curve, with the lowest risk observed for durations between 0.1 and 2 hours. However, these estimates did not reach statistical significance because of the small sample size analyzed.

The risk for dementia appears to be approximately twice as low among regular Internet users compared with nonusers. This hypothesis deserves serious consideration because of the large sample size and long follow-up duration, as well as careful consideration of as many potential confounding factors as possible. Potential negative effects remain to be clarified as the study was not designed to detect them. The results of previous studies suggest that Internet usage should be moderate for optimal benefit, with approximately 2 hours per day being the most suitable duration, regardless of age, until proven otherwise.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The results of a large longitudinal study spanning several years support a decrease in the risk for dementia among older adults who regularly use the Internet for < 2 hours per day. 

Several cross-sectional and longitudinal studies (though with relatively short follow-up periods) suggest that regular Internet use helps maintain cognitive reserve, although some observers have voiced skepticism. This hypothesis is particularly relevant for older patients facing the potentially detrimental effects of brain aging. According to some studies, memory, cognitive performance, and verbal reasoning tend to be better preserved among Internet users.

Several factors come into play, including socioeconomic disparities, socio-educational level, and generational differences, since Internet usage varies qualitatively and quantitatively with age. Older patients theoretically have more limited Internet usage. Under these conditions, the effect on cognitive functions would likely be modest compared with generations who were immersed in digital technology early on and tend to overuse it. After a certain age, accelerated brain aging would weigh much more heavily than any potential positive effects of the Internet. It is worth noting that the negative effects of Internet use have mainly been studied in young subjects, thus there is a lack of data concerning older patients.

Nearly 20,000 Participants

These considerations highlight the significance of a longitudinal cohort study that included 18,154 adults aged 50-64.9 years who were free from any dementia at baseline. These adults were participating in the Health and Retirement Study. The median follow-up period was 7.9 years, and follow-up extended to 17.1 years in some cases. Given that adults with better cognitive health are likely to self-select as regular users, the propensity score method was employed to control for this nonrandom factor using inverse probability weighting.

The risk for dementia based on initial Internet use was estimated using the Cox proportional hazards model, incorporating potentially late entry into the workforce and several covariables. Interactions with education level, gender, generation, and ethnic origin were also considered. Cumulative Internet exposure in terms of regular periodic use throughout life was included in the statistical analysis, as well as the hours spent on this activity each day. The analyses were conducted from September 2021 to November 2022.

Risk Nearly Halved

Regular Internet use was associated with a reduced risk for dementia, compared with irregular use. The hazard ratio (HR) for dementia was estimated at 0.57. After adjustment for the nonrandom factor of self-selection, this association persisted, and the HR decreased to 0.54. Accounting for baseline cognitive decline did not substantially change these results and yielded an HR of 0.62. The difference in risk between regular and irregular users was not altered by considering potential confounding factors such as education level, ethnic origin, gender, or generation. The longer the cumulative exposure over life, the lower the risk for dementia during follow-up.

The relationship between dementia risk and daily Internet usage hours seems to follow a U-shaped curve, with the lowest risk observed for durations between 0.1 and 2 hours. However, these estimates did not reach statistical significance because of the small sample size analyzed.

The risk for dementia appears to be approximately twice as low among regular Internet users compared with nonusers. This hypothesis deserves serious consideration because of the large sample size and long follow-up duration, as well as careful consideration of as many potential confounding factors as possible. Potential negative effects remain to be clarified as the study was not designed to detect them. The results of previous studies suggest that Internet usage should be moderate for optimal benefit, with approximately 2 hours per day being the most suitable duration, regardless of age, until proven otherwise.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

A group of 16 Democratic legislators on the House Committee on Oversight and Reform has demanded in a letter that the drugmaker Pfizer present details on how the company is responding to shortages of the generic chemotherapy drugs carboplatin, cisplatin, and methotrexate.

In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.

A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”

What is the basis for concern?

All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.

What has the government done in response to the recent shortages?

The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.

What can the lawmakers expect to achieve with their letter?

By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”

Why did the committee target Pfizer specifically?

Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”

The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.

What is being demanded of Pfizer?

Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

TOPLINE:

The use of stimulant therapy by adolescents with attention-deficit/hyperactivity disorder (ADHD) was not associated with later prescription drug misuse (PDM), a new study showed. However, misuse of prescription stimulants during adolescence was associated with significantly higher odds of later PDM.

METHODOLOGY:

• Data came from 11,066 participants in the ongoing Monitoring the Future panel study (baseline cohort years 2005-2017), a multicohort US national longitudinal study of adolescents followed into adulthood, in which procedures and measures are kept consistent across time.
• Participants (ages 17 and 18 years, 51.7% female, 11.2% Black, 15.7% Hispanic, and 59.6% White) completed self-administered questionnaires, with biennial follow-up during young adulthood (ages 19-24 years).
• The questionnaires asked about the number of occasions (if any) in which respondents used a prescription drug (benzodiazepine, opioid, or stimulant) on their own, without a physician’s order.
• Baseline covariates included sex, race, ethnicity, grade point average during high school, parental education, past 2-week binge drinking, past-month cigarette use, and past-year marijuana use, as well as demographic factors.

TAKEAWAY:

• Overall, 9.9% of participants reported lifetime stimulant therapy for ADHD, and 18.6% reported lifetime prescription stimulant misuse at baseline.
• Adolescents who received stimulant therapy for ADHD were less likely to report past-year prescription stimulant misuse as young adults compared with their same-age peers who did not receive stimulant therapy (adjusted odds ratio, 0.71; 95% CI, 0.52-0.99).
• The researchers found no significant differences between adolescents with or without lifetime stimulants in later incidence or prevalence of past-year PDM during young adulthood.
• The most robust predictor of prescription stimulant misuse during young adulthood was prescription stimulant misuse during adolescence; similarly, the most robust predictors of prescription opioid and prescription benzodiazepine misuse during young adulthood were prescription opioid and prescription benzodiazepine misuse (respectively) during adolescence.

IN PRACTICE:

“These findings amplify accumulating evidence suggesting that careful monitoring and screening during adolescence could identify individuals who are at relatively greater risk for PDM and need more comprehensive substance use assessment,” the authors wrote.

SOURCE:

Sean Esteban McCabe, PhD, professor and director, Center for the Study of Drugs, Alcohol, Smoking and Health, University of Michigan School of Nursing, Ann Arbor, was the lead and corresponding author of the study. It was published online on February 7 in Psychiatric Sciences.

LIMITATIONS:

Some subpopulations with higher rates of substance use, including youths who left school before completion and institutionalized populations, were excluded from the study, which may have led to an underestimation of PDM. Moreover, some potential confounders (eg, comorbid psychiatric conditions) were not assessed.

DISCLOSURES:

This study was supported by a research award from the US Food and Drug Administration and research awards from the National Institute on Drug Abuse of the NIH. Dr. McCabe reported no relevant financial relationships. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

The use of stimulant therapy by adolescents with attention-deficit/hyperactivity disorder (ADHD) was not associated with later prescription drug misuse (PDM), a new study showed. However, misuse of prescription stimulants during adolescence was associated with significantly higher odds of later PDM.

METHODOLOGY:

• Data came from 11,066 participants in the ongoing Monitoring the Future panel study (baseline cohort years 2005-2017), a multicohort US national longitudinal study of adolescents followed into adulthood, in which procedures and measures are kept consistent across time.
• Participants (ages 17 and 18 years, 51.7% female, 11.2% Black, 15.7% Hispanic, and 59.6% White) completed self-administered questionnaires, with biennial follow-up during young adulthood (ages 19-24 years).
• The questionnaires asked about the number of occasions (if any) in which respondents used a prescription drug (benzodiazepine, opioid, or stimulant) on their own, without a physician’s order.
• Baseline covariates included sex, race, ethnicity, grade point average during high school, parental education, past 2-week binge drinking, past-month cigarette use, and past-year marijuana use, as well as demographic factors.

TAKEAWAY:

• Overall, 9.9% of participants reported lifetime stimulant therapy for ADHD, and 18.6% reported lifetime prescription stimulant misuse at baseline.
• Adolescents who received stimulant therapy for ADHD were less likely to report past-year prescription stimulant misuse as young adults compared with their same-age peers who did not receive stimulant therapy (adjusted odds ratio, 0.71; 95% CI, 0.52-0.99).
• The researchers found no significant differences between adolescents with or without lifetime stimulants in later incidence or prevalence of past-year PDM during young adulthood.
• The most robust predictor of prescription stimulant misuse during young adulthood was prescription stimulant misuse during adolescence; similarly, the most robust predictors of prescription opioid and prescription benzodiazepine misuse during young adulthood were prescription opioid and prescription benzodiazepine misuse (respectively) during adolescence.

IN PRACTICE:

“These findings amplify accumulating evidence suggesting that careful monitoring and screening during adolescence could identify individuals who are at relatively greater risk for PDM and need more comprehensive substance use assessment,” the authors wrote.

SOURCE:

Sean Esteban McCabe, PhD, professor and director, Center for the Study of Drugs, Alcohol, Smoking and Health, University of Michigan School of Nursing, Ann Arbor, was the lead and corresponding author of the study. It was published online on February 7 in Psychiatric Sciences.

LIMITATIONS:

Some subpopulations with higher rates of substance use, including youths who left school before completion and institutionalized populations, were excluded from the study, which may have led to an underestimation of PDM. Moreover, some potential confounders (eg, comorbid psychiatric conditions) were not assessed.

DISCLOSURES:

This study was supported by a research award from the US Food and Drug Administration and research awards from the National Institute on Drug Abuse of the NIH. Dr. McCabe reported no relevant financial relationships. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

The use of stimulant therapy by adolescents with attention-deficit/hyperactivity disorder (ADHD) was not associated with later prescription drug misuse (PDM), a new study showed. However, misuse of prescription stimulants during adolescence was associated with significantly higher odds of later PDM.

METHODOLOGY:

• Data came from 11,066 participants in the ongoing Monitoring the Future panel study (baseline cohort years 2005-2017), a multicohort US national longitudinal study of adolescents followed into adulthood, in which procedures and measures are kept consistent across time.
• Participants (ages 17 and 18 years, 51.7% female, 11.2% Black, 15.7% Hispanic, and 59.6% White) completed self-administered questionnaires, with biennial follow-up during young adulthood (ages 19-24 years).
• The questionnaires asked about the number of occasions (if any) in which respondents used a prescription drug (benzodiazepine, opioid, or stimulant) on their own, without a physician’s order.
• Baseline covariates included sex, race, ethnicity, grade point average during high school, parental education, past 2-week binge drinking, past-month cigarette use, and past-year marijuana use, as well as demographic factors.

TAKEAWAY:

• Overall, 9.9% of participants reported lifetime stimulant therapy for ADHD, and 18.6% reported lifetime prescription stimulant misuse at baseline.
• Adolescents who received stimulant therapy for ADHD were less likely to report past-year prescription stimulant misuse as young adults compared with their same-age peers who did not receive stimulant therapy (adjusted odds ratio, 0.71; 95% CI, 0.52-0.99).
• The researchers found no significant differences between adolescents with or without lifetime stimulants in later incidence or prevalence of past-year PDM during young adulthood.
• The most robust predictor of prescription stimulant misuse during young adulthood was prescription stimulant misuse during adolescence; similarly, the most robust predictors of prescription opioid and prescription benzodiazepine misuse during young adulthood were prescription opioid and prescription benzodiazepine misuse (respectively) during adolescence.

IN PRACTICE:

“These findings amplify accumulating evidence suggesting that careful monitoring and screening during adolescence could identify individuals who are at relatively greater risk for PDM and need more comprehensive substance use assessment,” the authors wrote.

SOURCE:

Sean Esteban McCabe, PhD, professor and director, Center for the Study of Drugs, Alcohol, Smoking and Health, University of Michigan School of Nursing, Ann Arbor, was the lead and corresponding author of the study. It was published online on February 7 in Psychiatric Sciences.

LIMITATIONS:

Some subpopulations with higher rates of substance use, including youths who left school before completion and institutionalized populations, were excluded from the study, which may have led to an underestimation of PDM. Moreover, some potential confounders (eg, comorbid psychiatric conditions) were not assessed.

DISCLOSURES:

This study was supported by a research award from the US Food and Drug Administration and research awards from the National Institute on Drug Abuse of the NIH. Dr. McCabe reported no relevant financial relationships. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

PHOENIX — Adding either argatroban or eptifibatide to thrombolytic therapy doesn’t improve function following an ischemic stroke, results of new research show. 

“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri. 

The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said. 

The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.

The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.” 

Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective. 

Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto. 

The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.

All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).

Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
 

Two Different Mechanisms

The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.

Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.

The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.

The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial. 

Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study. 

The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.

The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial. 

In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto. 
 

No Increased ICH Risk

The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.

The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug. 

Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase. 

Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.” 

But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence. 

“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.” 
 

Down the Rabbit Hole

Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful. 

“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.” 

He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.” 

Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

PHOENIX — Adding either argatroban or eptifibatide to thrombolytic therapy doesn’t improve function following an ischemic stroke, results of new research show. 

“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri. 

The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said. 

The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.

The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.” 

Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective. 

Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto. 

The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.

All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).

Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
 

Two Different Mechanisms

The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.

Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.

The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.

The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial. 

Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study. 

The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.

The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial. 

In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto. 
 

No Increased ICH Risk

The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.

The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug. 

Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase. 

Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.” 

But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence. 

“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.” 
 

Down the Rabbit Hole

Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful. 

“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.” 

He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.” 

Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

PHOENIX — Adding either argatroban or eptifibatide to thrombolytic therapy doesn’t improve function following an ischemic stroke, results of new research show. 

“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” said lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St. Louis, Missouri. 

The results were surprising and disappointing for Dr. Adeoye. “We went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said. 

The Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early because of futility following recommendations from the data and safety monitoring board.

The findings were presented at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.” 

Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Dr. Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective. 

Six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone.” These findings prompted the current phase 3 trial, said Dr. Barreto. 

The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers. In the study cohort the mean age was about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.

All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).

Study patients were also randomly assigned to receive placebo or either argatroban (100 mcg/kg bolus followed by 3 mcg/kg per minute for 12 hours) or eptifibatide (135 mcg/kg bolus followed by 0.75 mcg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
 

Two Different Mechanisms

The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.

Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.

The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.

The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial. 

Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study. 

The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.

The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial. 

In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Dr. Barreto. 
 

No Increased ICH Risk

The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.

The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Dr. Adeoye. For example, it had more all-cause deaths, although none were related to the study drug. 

Speculating on why the intervention didn’t work, Dr. Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase. 

Although the results were disappointing, Dr. Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.” 

But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence. 

“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.” 
 

Down the Rabbit Hole

Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, Lexington, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful. 

“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.” 

He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.” 

Dr. Adeoye and Dr. Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Dr. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Dr. Goldstein has no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Exercising for upwards of 30 minutes most days may help relieve pain in patients who’ve been diagnosed with cancer, according to a study of exercise and pain outcomes from more than 60,000 people, including 10,000 with a history of cancer. 

Study participants who’d been diagnosed with cancer and surpassed 150 minutes of moderate activity a week were 16% less likely to report pain than those who did not exercise or who exercised less. Exercise was particularly helpful for those with moderate to severe pain. In general, the more people exercised, the less pain they felt — and that was true for those with and without a history of cancer.

“This adds to a large evidence base regarding other benefits of exercise after cancer,” said lead study author Christopher Swain, PhD, a researcher at the University of Melbourne, Australia, who studies how physical activity can protect against cancer. “It would be great for physicians to encourage physical activity” for anyone who’s ever been diagnosed with cancer. 

The findings also add to mounting evidence — including observational and experimental studies — that physical activity may help ease people’s pain. One large cross-sectional study of Norwegian adults found that the prevalence of chronic pain was 10%-38% lower among people who exercised. Randomized trials suggest exercise could be an effective pain management tool for a range of conditions, including neck and low-back pain, osteoarthritis, myofascial pain, and fibromyalgia. 

Still, the analgesic effects of exercise are less established for cancer-related pain, the authors wrote in the recent study published in Cancer — even though cancer pain remains a common and critical issue. 

Cancer-related pain is unique, stemming from multiple potential causes, said Shakil Ahmed, MB, an anesthesiologist at Weill Cornell Medicine who specializes in treating cancer pain. (Dr. Ahmed was not involved in the study.) Patients “might be having pain from the tumor itself,” — such as a tumor pressing on nerves — “or as a result of treatment, including surgery, radiation, chemotherapy, or complications from long-term medications,” Dr. Ahmed said. Indeed, some 40% of patients have chronic pain post cancer diagnosis, and it›s often undertreated and underdiagnosed.
 

How Does Exercise Reduce Pain?

Researchers aren’t exactly sure how exercise modulates pain, but they have some theories.

A 2021 meta-analysis found that exercise training can raise a person›s pain threshold, particularly at the pain site, suggesting adaptations in central inhibition, a process in the central nervous system that suppresses the perception of pain. This echoes a 2017 review that suggests exercise may help relieve pain by activating central inhibitory pathways. 

“There’s definitely evidence that there is improvement in the pain-reduction chemicals and augmentation of the pain inhibitory process in the central nervous system,” said Dr. Ahmed. That is, exercise may induce chemical changes that alter how much pain the brain’s sensory neurons can detect. 

Regular exercise can also reduce inflammation and improve blood flow, noted William McCarthy, PhD, a public health researcher with UCLA Health — both effects that may help to reduce pain.

Psychological factors may be another part of it. “There’s a lot of psychological stress as a result of a cancer diagnosis, which can lower the pain threshold,” said Dr. Ahmed. Exercise may help boost mood and reduce stress, increasing pain tolerance.

“People who are physically active also tend to be more socially active,” Dr. McCarthy added. “Engaging in social networks that provide social support can often palliate a sense of constant battling with fatigue, pain, and other negative effects of cancer.” Social activity, in turn, may promote physical activity: Studies show that when sedentary people socialize with active people, they become more active themselves — often by joining in walks or sports.

 

Help Patients Reap the Pain-Relieving Benefits of Exercise 

For beginners, the key to establishing a long-term exercise routine is to start low and slow, said Dr. Ahmed. That is, start with low-intensity activities like walking (walking was the most common activity reported in the study) or using light weights. Then, build slowly from there. 

Keep in mind that some pain or stiffness is normal at first, as one’s muscles and joints get used to the new activity. But be sure to investigate any new pain, Dr. Ahmed said. “Especially for patients who have had cancer, you want to see if the patient has any recurrence of disease,” Dr. Ahmed said. “That has to be kept in mind when you recommend any kind of exercise. “ 

It’s worth acknowledging that pain can be a significant barrier to exercise. If appropriate, you may consider referring out to exercise or physical therapy professionals in your network. Emphasizing the benefits of exercise — like the pain relief — may help motivate patients as well. 

For Dr. Swain, encouraging exercise is less about prescribing specific quantities and more about helping patients find activities “that give them enjoyment, that they feel comfortable doing, and that they can sustain over time.”

“The field needs to consider the different ways of supporting physical activity after a cancer diagnosis and treatment,” Dr. Swain said. “We have a lot of great research that shows the benefit of physical activity but not as strong an understanding of how to encourage and support it.”

A version of this article appeared on Medscape.com.

Exercising for upwards of 30 minutes most days may help relieve pain in patients who’ve been diagnosed with cancer, according to a study of exercise and pain outcomes from more than 60,000 people, including 10,000 with a history of cancer. 

Study participants who’d been diagnosed with cancer and surpassed 150 minutes of moderate activity a week were 16% less likely to report pain than those who did not exercise or who exercised less. Exercise was particularly helpful for those with moderate to severe pain. In general, the more people exercised, the less pain they felt — and that was true for those with and without a history of cancer.

“This adds to a large evidence base regarding other benefits of exercise after cancer,” said lead study author Christopher Swain, PhD, a researcher at the University of Melbourne, Australia, who studies how physical activity can protect against cancer. “It would be great for physicians to encourage physical activity” for anyone who’s ever been diagnosed with cancer. 

The findings also add to mounting evidence — including observational and experimental studies — that physical activity may help ease people’s pain. One large cross-sectional study of Norwegian adults found that the prevalence of chronic pain was 10%-38% lower among people who exercised. Randomized trials suggest exercise could be an effective pain management tool for a range of conditions, including neck and low-back pain, osteoarthritis, myofascial pain, and fibromyalgia. 

Still, the analgesic effects of exercise are less established for cancer-related pain, the authors wrote in the recent study published in Cancer — even though cancer pain remains a common and critical issue. 

Cancer-related pain is unique, stemming from multiple potential causes, said Shakil Ahmed, MB, an anesthesiologist at Weill Cornell Medicine who specializes in treating cancer pain. (Dr. Ahmed was not involved in the study.) Patients “might be having pain from the tumor itself,” — such as a tumor pressing on nerves — “or as a result of treatment, including surgery, radiation, chemotherapy, or complications from long-term medications,” Dr. Ahmed said. Indeed, some 40% of patients have chronic pain post cancer diagnosis, and it›s often undertreated and underdiagnosed.
 

How Does Exercise Reduce Pain?

Researchers aren’t exactly sure how exercise modulates pain, but they have some theories.

A 2021 meta-analysis found that exercise training can raise a person›s pain threshold, particularly at the pain site, suggesting adaptations in central inhibition, a process in the central nervous system that suppresses the perception of pain. This echoes a 2017 review that suggests exercise may help relieve pain by activating central inhibitory pathways. 

“There’s definitely evidence that there is improvement in the pain-reduction chemicals and augmentation of the pain inhibitory process in the central nervous system,” said Dr. Ahmed. That is, exercise may induce chemical changes that alter how much pain the brain’s sensory neurons can detect. 

Regular exercise can also reduce inflammation and improve blood flow, noted William McCarthy, PhD, a public health researcher with UCLA Health — both effects that may help to reduce pain.

Psychological factors may be another part of it. “There’s a lot of psychological stress as a result of a cancer diagnosis, which can lower the pain threshold,” said Dr. Ahmed. Exercise may help boost mood and reduce stress, increasing pain tolerance.

“People who are physically active also tend to be more socially active,” Dr. McCarthy added. “Engaging in social networks that provide social support can often palliate a sense of constant battling with fatigue, pain, and other negative effects of cancer.” Social activity, in turn, may promote physical activity: Studies show that when sedentary people socialize with active people, they become more active themselves — often by joining in walks or sports.

 

Help Patients Reap the Pain-Relieving Benefits of Exercise 

For beginners, the key to establishing a long-term exercise routine is to start low and slow, said Dr. Ahmed. That is, start with low-intensity activities like walking (walking was the most common activity reported in the study) or using light weights. Then, build slowly from there. 

Keep in mind that some pain or stiffness is normal at first, as one’s muscles and joints get used to the new activity. But be sure to investigate any new pain, Dr. Ahmed said. “Especially for patients who have had cancer, you want to see if the patient has any recurrence of disease,” Dr. Ahmed said. “That has to be kept in mind when you recommend any kind of exercise. “ 

It’s worth acknowledging that pain can be a significant barrier to exercise. If appropriate, you may consider referring out to exercise or physical therapy professionals in your network. Emphasizing the benefits of exercise — like the pain relief — may help motivate patients as well. 

For Dr. Swain, encouraging exercise is less about prescribing specific quantities and more about helping patients find activities “that give them enjoyment, that they feel comfortable doing, and that they can sustain over time.”

“The field needs to consider the different ways of supporting physical activity after a cancer diagnosis and treatment,” Dr. Swain said. “We have a lot of great research that shows the benefit of physical activity but not as strong an understanding of how to encourage and support it.”

A version of this article appeared on Medscape.com.

Exercising for upwards of 30 minutes most days may help relieve pain in patients who’ve been diagnosed with cancer, according to a study of exercise and pain outcomes from more than 60,000 people, including 10,000 with a history of cancer. 

Study participants who’d been diagnosed with cancer and surpassed 150 minutes of moderate activity a week were 16% less likely to report pain than those who did not exercise or who exercised less. Exercise was particularly helpful for those with moderate to severe pain. In general, the more people exercised, the less pain they felt — and that was true for those with and without a history of cancer.

“This adds to a large evidence base regarding other benefits of exercise after cancer,” said lead study author Christopher Swain, PhD, a researcher at the University of Melbourne, Australia, who studies how physical activity can protect against cancer. “It would be great for physicians to encourage physical activity” for anyone who’s ever been diagnosed with cancer. 

The findings also add to mounting evidence — including observational and experimental studies — that physical activity may help ease people’s pain. One large cross-sectional study of Norwegian adults found that the prevalence of chronic pain was 10%-38% lower among people who exercised. Randomized trials suggest exercise could be an effective pain management tool for a range of conditions, including neck and low-back pain, osteoarthritis, myofascial pain, and fibromyalgia. 

Still, the analgesic effects of exercise are less established for cancer-related pain, the authors wrote in the recent study published in Cancer — even though cancer pain remains a common and critical issue. 

Cancer-related pain is unique, stemming from multiple potential causes, said Shakil Ahmed, MB, an anesthesiologist at Weill Cornell Medicine who specializes in treating cancer pain. (Dr. Ahmed was not involved in the study.) Patients “might be having pain from the tumor itself,” — such as a tumor pressing on nerves — “or as a result of treatment, including surgery, radiation, chemotherapy, or complications from long-term medications,” Dr. Ahmed said. Indeed, some 40% of patients have chronic pain post cancer diagnosis, and it›s often undertreated and underdiagnosed.
 

How Does Exercise Reduce Pain?

Researchers aren’t exactly sure how exercise modulates pain, but they have some theories.

A 2021 meta-analysis found that exercise training can raise a person›s pain threshold, particularly at the pain site, suggesting adaptations in central inhibition, a process in the central nervous system that suppresses the perception of pain. This echoes a 2017 review that suggests exercise may help relieve pain by activating central inhibitory pathways. 

“There’s definitely evidence that there is improvement in the pain-reduction chemicals and augmentation of the pain inhibitory process in the central nervous system,” said Dr. Ahmed. That is, exercise may induce chemical changes that alter how much pain the brain’s sensory neurons can detect. 

Regular exercise can also reduce inflammation and improve blood flow, noted William McCarthy, PhD, a public health researcher with UCLA Health — both effects that may help to reduce pain.

Psychological factors may be another part of it. “There’s a lot of psychological stress as a result of a cancer diagnosis, which can lower the pain threshold,” said Dr. Ahmed. Exercise may help boost mood and reduce stress, increasing pain tolerance.

“People who are physically active also tend to be more socially active,” Dr. McCarthy added. “Engaging in social networks that provide social support can often palliate a sense of constant battling with fatigue, pain, and other negative effects of cancer.” Social activity, in turn, may promote physical activity: Studies show that when sedentary people socialize with active people, they become more active themselves — often by joining in walks or sports.

 

Help Patients Reap the Pain-Relieving Benefits of Exercise 

For beginners, the key to establishing a long-term exercise routine is to start low and slow, said Dr. Ahmed. That is, start with low-intensity activities like walking (walking was the most common activity reported in the study) or using light weights. Then, build slowly from there. 

Keep in mind that some pain or stiffness is normal at first, as one’s muscles and joints get used to the new activity. But be sure to investigate any new pain, Dr. Ahmed said. “Especially for patients who have had cancer, you want to see if the patient has any recurrence of disease,” Dr. Ahmed said. “That has to be kept in mind when you recommend any kind of exercise. “ 

It’s worth acknowledging that pain can be a significant barrier to exercise. If appropriate, you may consider referring out to exercise or physical therapy professionals in your network. Emphasizing the benefits of exercise — like the pain relief — may help motivate patients as well. 

For Dr. Swain, encouraging exercise is less about prescribing specific quantities and more about helping patients find activities “that give them enjoyment, that they feel comfortable doing, and that they can sustain over time.”

“The field needs to consider the different ways of supporting physical activity after a cancer diagnosis and treatment,” Dr. Swain said. “We have a lot of great research that shows the benefit of physical activity but not as strong an understanding of how to encourage and support it.”

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Poor communication between physician and patient can cause a lot of harm, according to Joseph N. Cappella, PhD, Gerald R. Miller Professor Emeritus of Communication at the University of Pennsylvania in Philadelphia, and Richard N. Street Jr, PhD, professor of communication and media science at Texas A&M University in Houston, Texas. When a physician and patient talk past each other, it may impair the patient’s compliance with preventive measures, screening, and treatment; undermine the physician-patient relationship; exacerbate fears and concerns; and possibly lead patients to rely on misleading, incomplete, or simply incorrect information, turning away from evidence-based medicine.

Drs. Cappella and Street made these points in an essay recently published in JAMA. The essay marks the beginning of the JAMA series Communicating Medicine.

“Helping clinicians deliver accurate information more effectively can lead to better-informed patients,” wrote Anne R. Cappola, MD, professor of endocrinology, diabetes, and metabolism at the University of Pennsylvania, and Kirsten Bibbins-Domingo, MD, PhD, professor of medicine at the University of California, San Francisco, in an accompanying editorial. Drs. Cappola and Bibbins-Domingo also are editors of JAMA.

To establish a common understanding between physician and patient, Drs. Cappella and Street identified the following four responsibilities of the physician:

• Discover what the patient understands and why
• Provide accurate information in an understandable manner
• Promote the credibility of the information
• Verify whether the patient has understood.

“Research has shown that although medical facts need to be the basis for the clinician’s core message, those facts are more effectively communicated in a patient-clinician relationship characterized by trust and cooperation and when the information is presented in a manner that fosters patient understanding,” wrote Drs. Cappella and Street. This approach includes using interpreters for patients who do not fluently speak the physician’s language and supplementing explanations with simple written information, images, and videos.

Patients generally believe their physician’s information, and most patients view their physicians as a trustworthy source. Trust is based on the belief that the physician has the patient’s best interests at heart.

However, patients may be distrustful of their physician’s information if it contradicts their own belief system or personal experiences or because they inherently distrust the medical profession.

In addition, patients are less willing to accept explanations and recommendations if they feel misunderstood, judged, discriminated against, or rushed by the physician. The basis for effective communication is a relationship with patients that is built on trust and respect. Empirically supported strategies for expressing respect and building trust include the following:

• Affirming the patient’s values
• Anticipating and addressing false or misleading information
• Using simple, jargon-free language
• Embedding facts into a story, rather than presenting the scientific evidence dryly.

“Conveying factual material using these techniques makes facts more engaging and memorable,” wrote Drs. Cappella and Street. It is crucial to inquire about and consider the patient’s perspective, health beliefs, assumptions, concerns, needs, and stories in the conversation.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Bariatric surgery is associated with long-term improvements in cognition and brain structure in addition to general health benefits and expected weight loss, a large study found.

Among 133 adults with severe obesity who underwent bariatric surgery, roughly two in five showed > 20% improvement in global cognitive function at 24 months following the surgery. 

“Notably, the temporal cortex exhibited not only higher cortical thickness but also higher vascular efficiency after surgery,” reported Amanda Kiliaan, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues.

“These results highlight beneficial vascular responses occurring in conjunction with bariatric surgery,” the researchers wrote. 

They also suggested that weight-loss surgery may represent a treatment option for patients with obesity and dementia. 

The study was published online on February 9, 2024, in JAMA Network Open.

Obesity is associated with an increased risk of developing dementia. Bariatric surgery-induced weight loss has been associated with improvements in brain function and structure in some small cohort studies with short follow-up periods. However, long-term neurological outcomes associated with bariatric surgery are unclear. 

To investigate, Dr. Kiliaan and colleagues studied 133 adults with severe obesity (mean age, 46 years; 84% women) who underwent Roux-en-Y gastric bypass. The researchers collected relevant data from laboratory tests, cognitive tests, and MRI brain scans before surgery and at 6 and 24 months after surgery.

Overall, mean body weight, body mass index, waist circumference, and blood pressure were significantly lower at 6 and 24 months after surgery. At 24 months, significantly fewer patients were taking antihypertensive medication (17% vs 36% before surgery). 

Improvements in inflammatory markers, depressive symptoms, and physical activity were also evident after surgery. 
 

Cognitive Improvements 

Several cognitive domains showed significant improvement at 6 and 24 months after bariatric surgery. Based on the 20% change index, improvements in working memory, episodic memory, and verbal fluency were seen in 11%, 32%, and 24% of participants, respectively. 

Forty percent of patients showed improvement in their able to shift their attention, and 43% showed improvements in global cognition after surgery. 

Several changes in brain parameters were also noted. Despite lower cerebral blood flow (CBF) in several regions, volumes of hippocampus, nucleus accumbens, frontal cortex, white matter, and white matter hyperintensity remained stable after surgery. 

The temporal cortex showed a greater thickness (mean, 2.724 mm vs 2.761 mm; P = .007) and lower spatial coefficient of variation (sCOV; median, 4.41% vs 3.97%; P = .02) after surgery. 

Overall, the results suggest that cognitive improvements “begin shortly after bariatric surgery and are long lasting,” the authors wrote. 

Various factors may be involved including remission of comorbidities, higher physical activity, lower depressive symptoms, and lower inflammatory factors, they suggest. Stabilization of volume, CBF, and sCOV in brain regions, coupled with gains in cortical thickness and vascular efficiency in the temporal cortex could also play a role.
 

‘Remarkable’ Results

“Taken together, the research intimates bariatric surgery’s potential protective effects against dementia manifest through both weight-related brain changes and reducing cardiovascular risk factors,” Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who wasn’t involved in the study, told this news organization.

“These remarkable neurological transformations intimate this surgery represents a pivotal opportunity to combat the parallel public health crises of obesity and dementia threatening society,” he said. 

“In demonstrating a durable cognitive and brain boost out years beyond surgery, patients now have an emphatic answer — these aren’t short-lived benefits but rather profound improvements propelling them positively for the rest of life,” he added. 

This opens up questions on whether the new class of obesity medications targeting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide pathways, that can achieve weight loss approaching that of bariatric surgery, could have similar benefits. 

The use of GLP-1 drugs have also shown neuroprotective effects such as improvement in motor and cognitive deficits, reduction of neuroinflammation, prevention of neuronal loss, and possibly slowing of neurodegeneration across animal models of Parkinson’s disease, Alzheimer’s disease, and stroke, said Dr. Lakhan. However, the exact mechanisms and ability to cross the blood-brain barrier require further confirmation, especially in humans.

Large, long-term, randomized controlled trials looking into potential effects of semaglutide on early Alzheimer›s disease, including the EVOKE Plus trial, are currently underway, he noted. 

“These game-changing obesity drugs may hand us medicine’s holy grail — a pill to rival surgery’s brain benefits without the scalpel, allowing patients a more accessible path to protecting their brain,” Dr. Lakhan said.

The study had no funding from industry. Dr. Kiliaan and Dr. Lakhan had no relevant disclosures.

A version of this article first appeared on Medscape.com.

Bariatric surgery is associated with long-term improvements in cognition and brain structure in addition to general health benefits and expected weight loss, a large study found.

Among 133 adults with severe obesity who underwent bariatric surgery, roughly two in five showed > 20% improvement in global cognitive function at 24 months following the surgery. 

“Notably, the temporal cortex exhibited not only higher cortical thickness but also higher vascular efficiency after surgery,” reported Amanda Kiliaan, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues.

“These results highlight beneficial vascular responses occurring in conjunction with bariatric surgery,” the researchers wrote. 

They also suggested that weight-loss surgery may represent a treatment option for patients with obesity and dementia. 

The study was published online on February 9, 2024, in JAMA Network Open.

Obesity is associated with an increased risk of developing dementia. Bariatric surgery-induced weight loss has been associated with improvements in brain function and structure in some small cohort studies with short follow-up periods. However, long-term neurological outcomes associated with bariatric surgery are unclear. 

To investigate, Dr. Kiliaan and colleagues studied 133 adults with severe obesity (mean age, 46 years; 84% women) who underwent Roux-en-Y gastric bypass. The researchers collected relevant data from laboratory tests, cognitive tests, and MRI brain scans before surgery and at 6 and 24 months after surgery.

Overall, mean body weight, body mass index, waist circumference, and blood pressure were significantly lower at 6 and 24 months after surgery. At 24 months, significantly fewer patients were taking antihypertensive medication (17% vs 36% before surgery). 

Improvements in inflammatory markers, depressive symptoms, and physical activity were also evident after surgery. 
 

Cognitive Improvements 

Several cognitive domains showed significant improvement at 6 and 24 months after bariatric surgery. Based on the 20% change index, improvements in working memory, episodic memory, and verbal fluency were seen in 11%, 32%, and 24% of participants, respectively. 

Forty percent of patients showed improvement in their able to shift their attention, and 43% showed improvements in global cognition after surgery. 

Several changes in brain parameters were also noted. Despite lower cerebral blood flow (CBF) in several regions, volumes of hippocampus, nucleus accumbens, frontal cortex, white matter, and white matter hyperintensity remained stable after surgery. 

The temporal cortex showed a greater thickness (mean, 2.724 mm vs 2.761 mm; P = .007) and lower spatial coefficient of variation (sCOV; median, 4.41% vs 3.97%; P = .02) after surgery. 

Overall, the results suggest that cognitive improvements “begin shortly after bariatric surgery and are long lasting,” the authors wrote. 

Various factors may be involved including remission of comorbidities, higher physical activity, lower depressive symptoms, and lower inflammatory factors, they suggest. Stabilization of volume, CBF, and sCOV in brain regions, coupled with gains in cortical thickness and vascular efficiency in the temporal cortex could also play a role.
 

‘Remarkable’ Results

“Taken together, the research intimates bariatric surgery’s potential protective effects against dementia manifest through both weight-related brain changes and reducing cardiovascular risk factors,” Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who wasn’t involved in the study, told this news organization.

“These remarkable neurological transformations intimate this surgery represents a pivotal opportunity to combat the parallel public health crises of obesity and dementia threatening society,” he said. 

“In demonstrating a durable cognitive and brain boost out years beyond surgery, patients now have an emphatic answer — these aren’t short-lived benefits but rather profound improvements propelling them positively for the rest of life,” he added. 

This opens up questions on whether the new class of obesity medications targeting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide pathways, that can achieve weight loss approaching that of bariatric surgery, could have similar benefits. 

The use of GLP-1 drugs have also shown neuroprotective effects such as improvement in motor and cognitive deficits, reduction of neuroinflammation, prevention of neuronal loss, and possibly slowing of neurodegeneration across animal models of Parkinson’s disease, Alzheimer’s disease, and stroke, said Dr. Lakhan. However, the exact mechanisms and ability to cross the blood-brain barrier require further confirmation, especially in humans.

Large, long-term, randomized controlled trials looking into potential effects of semaglutide on early Alzheimer›s disease, including the EVOKE Plus trial, are currently underway, he noted. 

“These game-changing obesity drugs may hand us medicine’s holy grail — a pill to rival surgery’s brain benefits without the scalpel, allowing patients a more accessible path to protecting their brain,” Dr. Lakhan said.

The study had no funding from industry. Dr. Kiliaan and Dr. Lakhan had no relevant disclosures.

A version of this article first appeared on Medscape.com.

Bariatric surgery is associated with long-term improvements in cognition and brain structure in addition to general health benefits and expected weight loss, a large study found.

Among 133 adults with severe obesity who underwent bariatric surgery, roughly two in five showed > 20% improvement in global cognitive function at 24 months following the surgery. 

“Notably, the temporal cortex exhibited not only higher cortical thickness but also higher vascular efficiency after surgery,” reported Amanda Kiliaan, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, and colleagues.

“These results highlight beneficial vascular responses occurring in conjunction with bariatric surgery,” the researchers wrote. 

They also suggested that weight-loss surgery may represent a treatment option for patients with obesity and dementia. 

The study was published online on February 9, 2024, in JAMA Network Open.

Obesity is associated with an increased risk of developing dementia. Bariatric surgery-induced weight loss has been associated with improvements in brain function and structure in some small cohort studies with short follow-up periods. However, long-term neurological outcomes associated with bariatric surgery are unclear. 

To investigate, Dr. Kiliaan and colleagues studied 133 adults with severe obesity (mean age, 46 years; 84% women) who underwent Roux-en-Y gastric bypass. The researchers collected relevant data from laboratory tests, cognitive tests, and MRI brain scans before surgery and at 6 and 24 months after surgery.

Overall, mean body weight, body mass index, waist circumference, and blood pressure were significantly lower at 6 and 24 months after surgery. At 24 months, significantly fewer patients were taking antihypertensive medication (17% vs 36% before surgery). 

Improvements in inflammatory markers, depressive symptoms, and physical activity were also evident after surgery. 
 

Cognitive Improvements 

Several cognitive domains showed significant improvement at 6 and 24 months after bariatric surgery. Based on the 20% change index, improvements in working memory, episodic memory, and verbal fluency were seen in 11%, 32%, and 24% of participants, respectively. 

Forty percent of patients showed improvement in their able to shift their attention, and 43% showed improvements in global cognition after surgery. 

Several changes in brain parameters were also noted. Despite lower cerebral blood flow (CBF) in several regions, volumes of hippocampus, nucleus accumbens, frontal cortex, white matter, and white matter hyperintensity remained stable after surgery. 

The temporal cortex showed a greater thickness (mean, 2.724 mm vs 2.761 mm; P = .007) and lower spatial coefficient of variation (sCOV; median, 4.41% vs 3.97%; P = .02) after surgery. 

Overall, the results suggest that cognitive improvements “begin shortly after bariatric surgery and are long lasting,” the authors wrote. 

Various factors may be involved including remission of comorbidities, higher physical activity, lower depressive symptoms, and lower inflammatory factors, they suggest. Stabilization of volume, CBF, and sCOV in brain regions, coupled with gains in cortical thickness and vascular efficiency in the temporal cortex could also play a role.
 

‘Remarkable’ Results

“Taken together, the research intimates bariatric surgery’s potential protective effects against dementia manifest through both weight-related brain changes and reducing cardiovascular risk factors,” Shaheen Lakhan, MD, a neurologist and researcher based in Miami, who wasn’t involved in the study, told this news organization.

“These remarkable neurological transformations intimate this surgery represents a pivotal opportunity to combat the parallel public health crises of obesity and dementia threatening society,” he said. 

“In demonstrating a durable cognitive and brain boost out years beyond surgery, patients now have an emphatic answer — these aren’t short-lived benefits but rather profound improvements propelling them positively for the rest of life,” he added. 

This opens up questions on whether the new class of obesity medications targeting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide pathways, that can achieve weight loss approaching that of bariatric surgery, could have similar benefits. 

The use of GLP-1 drugs have also shown neuroprotective effects such as improvement in motor and cognitive deficits, reduction of neuroinflammation, prevention of neuronal loss, and possibly slowing of neurodegeneration across animal models of Parkinson’s disease, Alzheimer’s disease, and stroke, said Dr. Lakhan. However, the exact mechanisms and ability to cross the blood-brain barrier require further confirmation, especially in humans.

Large, long-term, randomized controlled trials looking into potential effects of semaglutide on early Alzheimer›s disease, including the EVOKE Plus trial, are currently underway, he noted. 

“These game-changing obesity drugs may hand us medicine’s holy grail — a pill to rival surgery’s brain benefits without the scalpel, allowing patients a more accessible path to protecting their brain,” Dr. Lakhan said.

The study had no funding from industry. Dr. Kiliaan and Dr. Lakhan had no relevant disclosures.

A version of this article first appeared on Medscape.com.