Federal Practitioner

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

Insufficient blood pressure measurement during medical consultation, use of an inadequate technique for its determination, and lack of validated automatic sphygmomanometers are three problems that convergently complicate the diagnosis and control of arterial hypertension in the Americas, a silent disease that affects 180 million people in the region and is the main risk factor for cardiovascular diseases, said the Pan American Health Organization.

Jarbas Barbosa, MD, MPH, PhD, director of PAHO, said in an interview: “We don’t have specific data for each of these scenarios, but unfortunately, all three doubtless work together to make the situation worse.

“Often, the staff members at our primary care clinics are not prepared to diagnose and treat hypertension, because there aren’t national protocols to raise awareness and prepare them to provide this care to the correct standard. Also, they are often unqualified to take blood pressure readings properly,” he added.

This concern is reflected in the theme the organization chose for World Hypertension Day, which was observed on May 17: Measure your blood pressure accurately, control it, live longer! “We shouldn’t underestimate the importance of taking blood pressure,” warned Silvana Luciani, chief of PAHO’s noncommunicable diseases, violence, and injury prevention unit. But, the experts stressed, it must be done correctly.
 

Time no problem

It’s important to raise awareness of the value of blood pressure measurement for the general population. However, as multiple studies have shown, one barrier to detecting and controlling hypertension is that doctors and other health care professionals measure blood pressure less frequently in clinic than expected, or they use inappropriate techniques or obsolete or uncalibrated measurement devices.

“The importance of clinic blood pressure measurement has been recognized for many decades, but adherence to guidelines on proper, standardized blood pressure measurement remains uncommon in clinical practice,” concluded a consensus document signed by 25 experts from 13 institutions in the United States, Australia, Germany, the United Kingdom, Canada, Italy, Belgium, and Greece.

The first problem lies in the low quantity of measurements. A recent study in Argentina of nearly 3,000 visits to the doctor’s office at nine health care centers showed that doctors took blood pressure readings in only once in every seven encounters. Even cardiologists, the specialists with the best performance, did so only half of the time.

“Several factors can come into play: lack of awareness, medical inertia, or lack of appropriate equipment. But it is not for lack of time. How long does it take to take blood pressure three times within a 1-minute interval, with the patient seated and their back supported, as indicated? Four minutes. That’s not very much,” said Judith Zilberman, MD, PhD, said in an interview. Dr. Zilberman leads the department of hypertension and the women’s cardiovascular disease area at the Argerich Hospital in Buenos Aires, and is the former chair of the Argentinian Society of Hypertension.

Patricio López-Jaramillo, MD, PhD, said in an interview that the greatest obstacle is the lack of awareness among physicians and other health care staff about the importance of taking proper blood pressure measurements. Dr. López-Jaramillo is president and scientific director of the MASIRA Research Institute at the University of Santander in Bucaramanga, Colombia, and first author of the Manual Práctico de Diagnóstico y Manejo de la Hipertensión Arterial (Practice Guidelines for Diagnosing and Managing Hypertension), published by the Latin American Hypertension Society.

“Medical schools are also responsible for this. They go over this topic very superficially during undergraduate and, even worse, postgraduate training. The lack of time to take correct measurements, or the lack of appropriate instruments, is secondary to this lack of awareness among most health care staff members,” added Dr. López-Jaramillo, who is one of the researchers of the PURE epidemiologic study. Since 2002, it has followed a cohort of 225,000 participants from 27 high-, mid-, and low-income countries.

Dr. Zilberman added that it would be good practice for all primary care physicians to take blood pressure readings regardless of the reason for the visit and whether patients have been diagnosed with hypertension or not. “If a woman goes to her gynecologist because she wants to get pregnant, her blood pressure should also be taken! And any other specialist should interview the patient, ascertain her history, what medications she’s on, and then ask if her blood pressure has been taken recently,” she recommended.
 

Measure well

The second factor to consider is that a correct technique should be used to take blood pressure readings in the doctor’s office or clinic so as not to produce inaccurate results that could lead to underdiagnosis, overdiagnosis, or a poor assessment of the patient’s response to prescribed treatments. An observational study performed in Uruguay in 2017 showed that only 5% of 302 blood pressure measurements followed appropriate procedures.

A new fact sheet from the PAHO lists the following eight requirements for obtaining an accurate reading: don’t have a conversation, support the arm at heart level, put the cuff on a bare arm, use the correct cuff size, support the feet, keep the legs uncrossed, ensure the patient has an empty bladder, and support the back.

Though most guidelines recommend taking three readings, the “pragmatic” focus proposed in the international consensus accepts at least two readings separated by a minimum of 30 seconds. The two readings should then be averaged out. There is evidence that simplified protocols can be used, at least for population screening.

The authors of the new document also recommend preparing the patient before taking the measurement. The patient should be asked not to smoke, exercise, or consume alcohol or caffeine for at least 30 minutes beforehand. He or she should rest for a period of 3-5 minutes without speaking or being spoken to before the measurement is taken.

Lastly, clinically validated automated measurement devices should be used, as called for by the PAHO HEARTS initiative in the Americas. “The sphygmomanometer or classic aneroid tensiometer for the auscultatory method, which is still used way too often at doctor’s office visits in the region, has many weaknesses – not only the device itself but also the way it’s used (human error). This produces a rounded, approximate reading,” stressed Dr. Zilberman.

Automated devices also minimize interactions with the patient by reducing distractions during the preparation and measurement phases and freeing up time for the health care professional. “To [check for a] fever, we use the appropriate thermometer in the appropriate location. We should do the same for blood pressure,” she added.

The STRIDE-BP database, which is affiliated with the European Society of Hypertension, the International Society of Hypertension, and the World Hypertension League, contains an updated list of validated devices for measuring blood pressure.

The signers of the consensus likewise recognized that, beyond taking blood pressure measurements during office visits, the best measurements are those taken at home outside the context of medical care (doctor’s office or clinic) and that the same recommendations are directly applicable. “Few diseases can be detected so easily as with a simple at-home assessment performed by the individual himself or herself. If after three consecutive measurements, readings above 140/90 mm Hg are obtained, the individual should see the doctor to set up a comprehensive treatment program,” said Pablo Rodríguez, MD, secretary of the Argentinian Society of Hypertension. From now through September 14 (Day for Patients With Hypertension), the society is conducting a campaign to take blood pressure measurements at different locations across the country.

Dr. Zilberman and Dr. López-Jiménez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

Insufficient blood pressure measurement during medical consultation, use of an inadequate technique for its determination, and lack of validated automatic sphygmomanometers are three problems that convergently complicate the diagnosis and control of arterial hypertension in the Americas, a silent disease that affects 180 million people in the region and is the main risk factor for cardiovascular diseases, said the Pan American Health Organization.

Jarbas Barbosa, MD, MPH, PhD, director of PAHO, said in an interview: “We don’t have specific data for each of these scenarios, but unfortunately, all three doubtless work together to make the situation worse.

“Often, the staff members at our primary care clinics are not prepared to diagnose and treat hypertension, because there aren’t national protocols to raise awareness and prepare them to provide this care to the correct standard. Also, they are often unqualified to take blood pressure readings properly,” he added.

This concern is reflected in the theme the organization chose for World Hypertension Day, which was observed on May 17: Measure your blood pressure accurately, control it, live longer! “We shouldn’t underestimate the importance of taking blood pressure,” warned Silvana Luciani, chief of PAHO’s noncommunicable diseases, violence, and injury prevention unit. But, the experts stressed, it must be done correctly.
 

Time no problem

It’s important to raise awareness of the value of blood pressure measurement for the general population. However, as multiple studies have shown, one barrier to detecting and controlling hypertension is that doctors and other health care professionals measure blood pressure less frequently in clinic than expected, or they use inappropriate techniques or obsolete or uncalibrated measurement devices.

“The importance of clinic blood pressure measurement has been recognized for many decades, but adherence to guidelines on proper, standardized blood pressure measurement remains uncommon in clinical practice,” concluded a consensus document signed by 25 experts from 13 institutions in the United States, Australia, Germany, the United Kingdom, Canada, Italy, Belgium, and Greece.

The first problem lies in the low quantity of measurements. A recent study in Argentina of nearly 3,000 visits to the doctor’s office at nine health care centers showed that doctors took blood pressure readings in only once in every seven encounters. Even cardiologists, the specialists with the best performance, did so only half of the time.

“Several factors can come into play: lack of awareness, medical inertia, or lack of appropriate equipment. But it is not for lack of time. How long does it take to take blood pressure three times within a 1-minute interval, with the patient seated and their back supported, as indicated? Four minutes. That’s not very much,” said Judith Zilberman, MD, PhD, said in an interview. Dr. Zilberman leads the department of hypertension and the women’s cardiovascular disease area at the Argerich Hospital in Buenos Aires, and is the former chair of the Argentinian Society of Hypertension.

Patricio López-Jaramillo, MD, PhD, said in an interview that the greatest obstacle is the lack of awareness among physicians and other health care staff about the importance of taking proper blood pressure measurements. Dr. López-Jaramillo is president and scientific director of the MASIRA Research Institute at the University of Santander in Bucaramanga, Colombia, and first author of the Manual Práctico de Diagnóstico y Manejo de la Hipertensión Arterial (Practice Guidelines for Diagnosing and Managing Hypertension), published by the Latin American Hypertension Society.

“Medical schools are also responsible for this. They go over this topic very superficially during undergraduate and, even worse, postgraduate training. The lack of time to take correct measurements, or the lack of appropriate instruments, is secondary to this lack of awareness among most health care staff members,” added Dr. López-Jaramillo, who is one of the researchers of the PURE epidemiologic study. Since 2002, it has followed a cohort of 225,000 participants from 27 high-, mid-, and low-income countries.

Dr. Zilberman added that it would be good practice for all primary care physicians to take blood pressure readings regardless of the reason for the visit and whether patients have been diagnosed with hypertension or not. “If a woman goes to her gynecologist because she wants to get pregnant, her blood pressure should also be taken! And any other specialist should interview the patient, ascertain her history, what medications she’s on, and then ask if her blood pressure has been taken recently,” she recommended.
 

Measure well

The second factor to consider is that a correct technique should be used to take blood pressure readings in the doctor’s office or clinic so as not to produce inaccurate results that could lead to underdiagnosis, overdiagnosis, or a poor assessment of the patient’s response to prescribed treatments. An observational study performed in Uruguay in 2017 showed that only 5% of 302 blood pressure measurements followed appropriate procedures.

A new fact sheet from the PAHO lists the following eight requirements for obtaining an accurate reading: don’t have a conversation, support the arm at heart level, put the cuff on a bare arm, use the correct cuff size, support the feet, keep the legs uncrossed, ensure the patient has an empty bladder, and support the back.

Though most guidelines recommend taking three readings, the “pragmatic” focus proposed in the international consensus accepts at least two readings separated by a minimum of 30 seconds. The two readings should then be averaged out. There is evidence that simplified protocols can be used, at least for population screening.

The authors of the new document also recommend preparing the patient before taking the measurement. The patient should be asked not to smoke, exercise, or consume alcohol or caffeine for at least 30 minutes beforehand. He or she should rest for a period of 3-5 minutes without speaking or being spoken to before the measurement is taken.

Lastly, clinically validated automated measurement devices should be used, as called for by the PAHO HEARTS initiative in the Americas. “The sphygmomanometer or classic aneroid tensiometer for the auscultatory method, which is still used way too often at doctor’s office visits in the region, has many weaknesses – not only the device itself but also the way it’s used (human error). This produces a rounded, approximate reading,” stressed Dr. Zilberman.

Automated devices also minimize interactions with the patient by reducing distractions during the preparation and measurement phases and freeing up time for the health care professional. “To [check for a] fever, we use the appropriate thermometer in the appropriate location. We should do the same for blood pressure,” she added.

The STRIDE-BP database, which is affiliated with the European Society of Hypertension, the International Society of Hypertension, and the World Hypertension League, contains an updated list of validated devices for measuring blood pressure.

The signers of the consensus likewise recognized that, beyond taking blood pressure measurements during office visits, the best measurements are those taken at home outside the context of medical care (doctor’s office or clinic) and that the same recommendations are directly applicable. “Few diseases can be detected so easily as with a simple at-home assessment performed by the individual himself or herself. If after three consecutive measurements, readings above 140/90 mm Hg are obtained, the individual should see the doctor to set up a comprehensive treatment program,” said Pablo Rodríguez, MD, secretary of the Argentinian Society of Hypertension. From now through September 14 (Day for Patients With Hypertension), the society is conducting a campaign to take blood pressure measurements at different locations across the country.

Dr. Zilberman and Dr. López-Jiménez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

Insufficient blood pressure measurement during medical consultation, use of an inadequate technique for its determination, and lack of validated automatic sphygmomanometers are three problems that convergently complicate the diagnosis and control of arterial hypertension in the Americas, a silent disease that affects 180 million people in the region and is the main risk factor for cardiovascular diseases, said the Pan American Health Organization.

Jarbas Barbosa, MD, MPH, PhD, director of PAHO, said in an interview: “We don’t have specific data for each of these scenarios, but unfortunately, all three doubtless work together to make the situation worse.

“Often, the staff members at our primary care clinics are not prepared to diagnose and treat hypertension, because there aren’t national protocols to raise awareness and prepare them to provide this care to the correct standard. Also, they are often unqualified to take blood pressure readings properly,” he added.

This concern is reflected in the theme the organization chose for World Hypertension Day, which was observed on May 17: Measure your blood pressure accurately, control it, live longer! “We shouldn’t underestimate the importance of taking blood pressure,” warned Silvana Luciani, chief of PAHO’s noncommunicable diseases, violence, and injury prevention unit. But, the experts stressed, it must be done correctly.
 

Time no problem

It’s important to raise awareness of the value of blood pressure measurement for the general population. However, as multiple studies have shown, one barrier to detecting and controlling hypertension is that doctors and other health care professionals measure blood pressure less frequently in clinic than expected, or they use inappropriate techniques or obsolete or uncalibrated measurement devices.

“The importance of clinic blood pressure measurement has been recognized for many decades, but adherence to guidelines on proper, standardized blood pressure measurement remains uncommon in clinical practice,” concluded a consensus document signed by 25 experts from 13 institutions in the United States, Australia, Germany, the United Kingdom, Canada, Italy, Belgium, and Greece.

The first problem lies in the low quantity of measurements. A recent study in Argentina of nearly 3,000 visits to the doctor’s office at nine health care centers showed that doctors took blood pressure readings in only once in every seven encounters. Even cardiologists, the specialists with the best performance, did so only half of the time.

“Several factors can come into play: lack of awareness, medical inertia, or lack of appropriate equipment. But it is not for lack of time. How long does it take to take blood pressure three times within a 1-minute interval, with the patient seated and their back supported, as indicated? Four minutes. That’s not very much,” said Judith Zilberman, MD, PhD, said in an interview. Dr. Zilberman leads the department of hypertension and the women’s cardiovascular disease area at the Argerich Hospital in Buenos Aires, and is the former chair of the Argentinian Society of Hypertension.

Patricio López-Jaramillo, MD, PhD, said in an interview that the greatest obstacle is the lack of awareness among physicians and other health care staff about the importance of taking proper blood pressure measurements. Dr. López-Jaramillo is president and scientific director of the MASIRA Research Institute at the University of Santander in Bucaramanga, Colombia, and first author of the Manual Práctico de Diagnóstico y Manejo de la Hipertensión Arterial (Practice Guidelines for Diagnosing and Managing Hypertension), published by the Latin American Hypertension Society.

“Medical schools are also responsible for this. They go over this topic very superficially during undergraduate and, even worse, postgraduate training. The lack of time to take correct measurements, or the lack of appropriate instruments, is secondary to this lack of awareness among most health care staff members,” added Dr. López-Jaramillo, who is one of the researchers of the PURE epidemiologic study. Since 2002, it has followed a cohort of 225,000 participants from 27 high-, mid-, and low-income countries.

Dr. Zilberman added that it would be good practice for all primary care physicians to take blood pressure readings regardless of the reason for the visit and whether patients have been diagnosed with hypertension or not. “If a woman goes to her gynecologist because she wants to get pregnant, her blood pressure should also be taken! And any other specialist should interview the patient, ascertain her history, what medications she’s on, and then ask if her blood pressure has been taken recently,” she recommended.
 

Measure well

The second factor to consider is that a correct technique should be used to take blood pressure readings in the doctor’s office or clinic so as not to produce inaccurate results that could lead to underdiagnosis, overdiagnosis, or a poor assessment of the patient’s response to prescribed treatments. An observational study performed in Uruguay in 2017 showed that only 5% of 302 blood pressure measurements followed appropriate procedures.

A new fact sheet from the PAHO lists the following eight requirements for obtaining an accurate reading: don’t have a conversation, support the arm at heart level, put the cuff on a bare arm, use the correct cuff size, support the feet, keep the legs uncrossed, ensure the patient has an empty bladder, and support the back.

Though most guidelines recommend taking three readings, the “pragmatic” focus proposed in the international consensus accepts at least two readings separated by a minimum of 30 seconds. The two readings should then be averaged out. There is evidence that simplified protocols can be used, at least for population screening.

The authors of the new document also recommend preparing the patient before taking the measurement. The patient should be asked not to smoke, exercise, or consume alcohol or caffeine for at least 30 minutes beforehand. He or she should rest for a period of 3-5 minutes without speaking or being spoken to before the measurement is taken.

Lastly, clinically validated automated measurement devices should be used, as called for by the PAHO HEARTS initiative in the Americas. “The sphygmomanometer or classic aneroid tensiometer for the auscultatory method, which is still used way too often at doctor’s office visits in the region, has many weaknesses – not only the device itself but also the way it’s used (human error). This produces a rounded, approximate reading,” stressed Dr. Zilberman.

Automated devices also minimize interactions with the patient by reducing distractions during the preparation and measurement phases and freeing up time for the health care professional. “To [check for a] fever, we use the appropriate thermometer in the appropriate location. We should do the same for blood pressure,” she added.

The STRIDE-BP database, which is affiliated with the European Society of Hypertension, the International Society of Hypertension, and the World Hypertension League, contains an updated list of validated devices for measuring blood pressure.

The signers of the consensus likewise recognized that, beyond taking blood pressure measurements during office visits, the best measurements are those taken at home outside the context of medical care (doctor’s office or clinic) and that the same recommendations are directly applicable. “Few diseases can be detected so easily as with a simple at-home assessment performed by the individual himself or herself. If after three consecutive measurements, readings above 140/90 mm Hg are obtained, the individual should see the doctor to set up a comprehensive treatment program,” said Pablo Rodríguez, MD, secretary of the Argentinian Society of Hypertension. From now through September 14 (Day for Patients With Hypertension), the society is conducting a campaign to take blood pressure measurements at different locations across the country.

Dr. Zilberman and Dr. López-Jiménez disclosed no relevant financial relationships.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

In late 2021, the Rome Proposal for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and grading their severity was published. The 2023 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (GOLD) Report has adopted the Rome Proposal criteria. Given that an endorsement by GOLD is tantamount to acceptance by clinicians, researchers, and policymakers alike, I guess we’re all using them now.

Anyone who’s ever cared for patients with COPD knows that treatment and reduction of exacerbations is how we improve outcomes. AECOPD are associated with considerable morbidity, greater health care utilization and costs, and a long-term decline in lung function. While we hope our pharmacotherapies improve symptoms, we know they reduce AECOPD. If our pharmacotherapies have any impact on mortality, it’s probably via AECOPD prevention.

Methods for reducing AECOPD are not controversial, but the approach to AECOPD treatment is, particularly decisions about who gets an antibiotic and who doesn’t. Since antibiotic indications are tied to severity, using the Rome Proposal criteria may affect management in unpredictable ways. As such, it’s worth reviewing the data on antibiotics for AECOPD.
 

What do the data reveal?

To start, it’s important to note that GOLD doesn’t equate having an AECOPD with needing an antibiotic. I myself have conflated the diagnosis with the indication and thereby overprescribed. The bar for diagnosis is quite low. In previous GOLD summaries, any “change in respiratory symptoms” would warrant the AECOPD label. Although the Rome Proposal definition is more specific, it leaves room for liberal interpretation. It’s likely to have a greater effect on research than on clinical practice. My guess is that AECOPD prevalence doesn’t change.

The antibiotic hurdle is slightly higher than that for diagnosis but is equally open to interpretation. In part, that’s related to the inherent subjectivity of judging symptoms, sputum production, and changes in color, but it’s also because the data are so poor. The meta-analyses that have been used to establish the indications include fewer than 1000 patients spread across 10 to 11 trials. Thus, the individual trials are small, and the sample size remains nominal even after adding them together. The addition of antibiotics – and it doesn’t seem to matter which class, type, or duration – will decrease mortality and hospital length of stay. One study says these effects are limited to inpatients while the other does not. After reading GOLD 2013, GOLD 2023, and both the meta-analyses they used to support their recommendations, I’m still not sure who benefits. Do you have to be hospitalized? Is some sort of ventilatory support required? Does C-reactive protein help or not?

In accordance with the classic Anthonisen criteria, GOLD relies on sputum volume and color as evidence of a bacterial infection. Soon after GOLD 2023 was published, a meta-analysis found that sputum color isn’t particularly accurate for detecting bacterial infection. Because it doesn’t seem to matter which antibiotic class is used, I always thought we were using antibiotics for their magical, pleiotropic anti-inflammatory effects anyway. I didn’t think the presence of an actual bacterial infection was important. If I saw an infiltrate on chest x-ray, I’d change my diagnosis from AECOPD to community-acquired pneumonia (CAP) and switch to CAP coverage. I’ve been doing this so long that I swear it’s in a guideline somewhere, though admittedly I couldn’t find said guideline while reading for this piece.
 

Key takeaways

In summary, I believe that the guidance reflects the data, which is muddy. The Rome Proposal should be seen as just that – a framework for moving forward with AECOPD classification and antibiotic indications that will need to be refined over time as better data become available. In fact, they allow for a more objective, point-of-care assessment of severity that can be validated and tied to antibiotic benefits. The Rome criteria aren’t evidence-based; they’re a necessary first step toward creating the evidence.

In the meantime, if your AECOPD patients are hospitalized, they probably warrant an antibiotic. If they’re not, sputum changes may be a reasonable surrogate for a bacterial infection. Considerable uncertainty remains.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported conflicts of interest with Metapharm, CHEST College, and WebMD.

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

In late 2021, the Rome Proposal for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and grading their severity was published. The 2023 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (GOLD) Report has adopted the Rome Proposal criteria. Given that an endorsement by GOLD is tantamount to acceptance by clinicians, researchers, and policymakers alike, I guess we’re all using them now.

Anyone who’s ever cared for patients with COPD knows that treatment and reduction of exacerbations is how we improve outcomes. AECOPD are associated with considerable morbidity, greater health care utilization and costs, and a long-term decline in lung function. While we hope our pharmacotherapies improve symptoms, we know they reduce AECOPD. If our pharmacotherapies have any impact on mortality, it’s probably via AECOPD prevention.

Methods for reducing AECOPD are not controversial, but the approach to AECOPD treatment is, particularly decisions about who gets an antibiotic and who doesn’t. Since antibiotic indications are tied to severity, using the Rome Proposal criteria may affect management in unpredictable ways. As such, it’s worth reviewing the data on antibiotics for AECOPD.
 

What do the data reveal?

To start, it’s important to note that GOLD doesn’t equate having an AECOPD with needing an antibiotic. I myself have conflated the diagnosis with the indication and thereby overprescribed. The bar for diagnosis is quite low. In previous GOLD summaries, any “change in respiratory symptoms” would warrant the AECOPD label. Although the Rome Proposal definition is more specific, it leaves room for liberal interpretation. It’s likely to have a greater effect on research than on clinical practice. My guess is that AECOPD prevalence doesn’t change.

The antibiotic hurdle is slightly higher than that for diagnosis but is equally open to interpretation. In part, that’s related to the inherent subjectivity of judging symptoms, sputum production, and changes in color, but it’s also because the data are so poor. The meta-analyses that have been used to establish the indications include fewer than 1000 patients spread across 10 to 11 trials. Thus, the individual trials are small, and the sample size remains nominal even after adding them together. The addition of antibiotics – and it doesn’t seem to matter which class, type, or duration – will decrease mortality and hospital length of stay. One study says these effects are limited to inpatients while the other does not. After reading GOLD 2013, GOLD 2023, and both the meta-analyses they used to support their recommendations, I’m still not sure who benefits. Do you have to be hospitalized? Is some sort of ventilatory support required? Does C-reactive protein help or not?

In accordance with the classic Anthonisen criteria, GOLD relies on sputum volume and color as evidence of a bacterial infection. Soon after GOLD 2023 was published, a meta-analysis found that sputum color isn’t particularly accurate for detecting bacterial infection. Because it doesn’t seem to matter which antibiotic class is used, I always thought we were using antibiotics for their magical, pleiotropic anti-inflammatory effects anyway. I didn’t think the presence of an actual bacterial infection was important. If I saw an infiltrate on chest x-ray, I’d change my diagnosis from AECOPD to community-acquired pneumonia (CAP) and switch to CAP coverage. I’ve been doing this so long that I swear it’s in a guideline somewhere, though admittedly I couldn’t find said guideline while reading for this piece.
 

Key takeaways

In summary, I believe that the guidance reflects the data, which is muddy. The Rome Proposal should be seen as just that – a framework for moving forward with AECOPD classification and antibiotic indications that will need to be refined over time as better data become available. In fact, they allow for a more objective, point-of-care assessment of severity that can be validated and tied to antibiotic benefits. The Rome criteria aren’t evidence-based; they’re a necessary first step toward creating the evidence.

In the meantime, if your AECOPD patients are hospitalized, they probably warrant an antibiotic. If they’re not, sputum changes may be a reasonable surrogate for a bacterial infection. Considerable uncertainty remains.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported conflicts of interest with Metapharm, CHEST College, and WebMD.

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

In late 2021, the Rome Proposal for diagnosing acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and grading their severity was published. The 2023 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (GOLD) Report has adopted the Rome Proposal criteria. Given that an endorsement by GOLD is tantamount to acceptance by clinicians, researchers, and policymakers alike, I guess we’re all using them now.

Anyone who’s ever cared for patients with COPD knows that treatment and reduction of exacerbations is how we improve outcomes. AECOPD are associated with considerable morbidity, greater health care utilization and costs, and a long-term decline in lung function. While we hope our pharmacotherapies improve symptoms, we know they reduce AECOPD. If our pharmacotherapies have any impact on mortality, it’s probably via AECOPD prevention.

Methods for reducing AECOPD are not controversial, but the approach to AECOPD treatment is, particularly decisions about who gets an antibiotic and who doesn’t. Since antibiotic indications are tied to severity, using the Rome Proposal criteria may affect management in unpredictable ways. As such, it’s worth reviewing the data on antibiotics for AECOPD.
 

What do the data reveal?

To start, it’s important to note that GOLD doesn’t equate having an AECOPD with needing an antibiotic. I myself have conflated the diagnosis with the indication and thereby overprescribed. The bar for diagnosis is quite low. In previous GOLD summaries, any “change in respiratory symptoms” would warrant the AECOPD label. Although the Rome Proposal definition is more specific, it leaves room for liberal interpretation. It’s likely to have a greater effect on research than on clinical practice. My guess is that AECOPD prevalence doesn’t change.

The antibiotic hurdle is slightly higher than that for diagnosis but is equally open to interpretation. In part, that’s related to the inherent subjectivity of judging symptoms, sputum production, and changes in color, but it’s also because the data are so poor. The meta-analyses that have been used to establish the indications include fewer than 1000 patients spread across 10 to 11 trials. Thus, the individual trials are small, and the sample size remains nominal even after adding them together. The addition of antibiotics – and it doesn’t seem to matter which class, type, or duration – will decrease mortality and hospital length of stay. One study says these effects are limited to inpatients while the other does not. After reading GOLD 2013, GOLD 2023, and both the meta-analyses they used to support their recommendations, I’m still not sure who benefits. Do you have to be hospitalized? Is some sort of ventilatory support required? Does C-reactive protein help or not?

In accordance with the classic Anthonisen criteria, GOLD relies on sputum volume and color as evidence of a bacterial infection. Soon after GOLD 2023 was published, a meta-analysis found that sputum color isn’t particularly accurate for detecting bacterial infection. Because it doesn’t seem to matter which antibiotic class is used, I always thought we were using antibiotics for their magical, pleiotropic anti-inflammatory effects anyway. I didn’t think the presence of an actual bacterial infection was important. If I saw an infiltrate on chest x-ray, I’d change my diagnosis from AECOPD to community-acquired pneumonia (CAP) and switch to CAP coverage. I’ve been doing this so long that I swear it’s in a guideline somewhere, though admittedly I couldn’t find said guideline while reading for this piece.
 

Key takeaways

In summary, I believe that the guidance reflects the data, which is muddy. The Rome Proposal should be seen as just that – a framework for moving forward with AECOPD classification and antibiotic indications that will need to be refined over time as better data become available. In fact, they allow for a more objective, point-of-care assessment of severity that can be validated and tied to antibiotic benefits. The Rome criteria aren’t evidence-based; they’re a necessary first step toward creating the evidence.

In the meantime, if your AECOPD patients are hospitalized, they probably warrant an antibiotic. If they’re not, sputum changes may be a reasonable surrogate for a bacterial infection. Considerable uncertainty remains.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/sleep and critical care medicine physician at MedStar Washington Hospital Center in Washington. He reported conflicts of interest with Metapharm, CHEST College, and WebMD.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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

Dapagliflozin (Farxiga) appears to be no more effective than the “thiazide-like” diuretic metolazone at improving pulmonary congestion and fluid status in patients with acute heart failure (AHF), suggests a new randomized trial. The drugs were given to the study’s loop diuretic–resistant patients on top of furosemide.

Changes in volume status and measures of pulmonary congestion and risk for serious adverse events were similar for those assigned to take dapagliflozin, an SGLT2 inhibitor, or metolazone, a quinazoline diuretic. Those on dapagliflozin zone ultimately received a larger cumulative furosemide dose in the 61-patient trial, called DAPA-RESIST.

“The next steps are to assess whether a strategy of using SGLT2 inhibitors up front in patients with HF reduces the incidence of diuretic resistance, and to test further combinations of diuretics such as thiazide or thiazide-like diuretics, compared with acetazolamide, when used in addition to an IV loop diuretic and SGLT2 inhibitors together,” Ross T. Campbell, MBChB, PhD, University of Glasgow and Queen Elizabeth University Hospital, also in Glasgow, said in an interview.

Dr. Campbell presented the findings at the annual meeting of the Heart Failure Association of the European Society of Cardiology and is senior author on its simultaneous publication in the European Heart Journal.

The multicenter trial randomly assigned 61 patients with AHF to receive dapagliflozin at a fixed dose of 10 mg once daily or metolazone 5 mg or 10 mg (starting dosage at physician discretion) once daily for 3 days of treatment on an open-label basis.

Patients had entered the trial on furosemide at a mean daily dosage of 260 mg in the dapagliflozin group and 229 mg for those assigned metolazone; dosages for the loop diuretic in the trial weren’t prespecified.

Their median age was 79 and 54% were women; 44% had HF with reduced ejection fraction. Their mean glomerular filtration rate was below 30 mL/min per 1.73 m² in 26%, 90% had chronic kidney disease, 98% had peripheral edema, and 46% had diabetes.

The mean cumulative furosemide dose was significantly higher among the dapagliflozin group’s 31 patients, 976 mg versus 704 mg for the 30 on acetazolamide (P < .05), 96 hours after the start of randomized therapy. However, patients on dapagliflozin experienced a lesser increase in creatinine (P < .05) and in blood urea (P < .01), a greater change in serum sodium (P < .05), and a smaller reduction in serum potassium (P < .01).

Although the trial wasn’t powered for those outcomes, Dr. Campbell said, “less biochemical upset could be associated with better outcomes in terms of less medium- to long-term renal impairment, and in the short-term length of stay.”

The mean decrease in weight at 96 hours, the primary endpoint, reached 3 kg on dapagliflozin, compared with 3.6 kg with metolazone (P = .082), a difference that fell short of significance.

Loop diuretic efficiency, that is weight change in kg per 40 mg furosemide, “was smaller with dapagliflozin than with metolazone at each time point after randomization, although the difference was only significant at 24 hours,” the published report states.

Changes in pulmonary congestion (by lung ultrasound) and fluid volume were similar between the groups.

“This trial further adds to the evidence base and safety profile for using SGLT2 inhibitors in patients with acute heart failure,” and “gives further confidence to clinicians that this class can be started in ‘sicker’ patients with HF who also have diuretic resistance,” Dr. Campbell said.

Asked during his presentation’s question and answer whether dapagliflozin might have shown a greater effect had the dosage been higher, Dr. Campbell explained that the drug was investigational when the trial started. Adding a higher-dose dapagliflozin arm, he said, would have made for an excessively complex study. But “that’s a great research question for another trial.”

DAPA-RESIST was funded by AstraZeneca. Dr. Campbell disclosed receiving honoraria from AstraZeneca for speaking and from Bayer for serving on an advisory board.

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

Dapagliflozin (Farxiga) appears to be no more effective than the “thiazide-like” diuretic metolazone at improving pulmonary congestion and fluid status in patients with acute heart failure (AHF), suggests a new randomized trial. The drugs were given to the study’s loop diuretic–resistant patients on top of furosemide.

Changes in volume status and measures of pulmonary congestion and risk for serious adverse events were similar for those assigned to take dapagliflozin, an SGLT2 inhibitor, or metolazone, a quinazoline diuretic. Those on dapagliflozin zone ultimately received a larger cumulative furosemide dose in the 61-patient trial, called DAPA-RESIST.

“The next steps are to assess whether a strategy of using SGLT2 inhibitors up front in patients with HF reduces the incidence of diuretic resistance, and to test further combinations of diuretics such as thiazide or thiazide-like diuretics, compared with acetazolamide, when used in addition to an IV loop diuretic and SGLT2 inhibitors together,” Ross T. Campbell, MBChB, PhD, University of Glasgow and Queen Elizabeth University Hospital, also in Glasgow, said in an interview.

Dr. Campbell presented the findings at the annual meeting of the Heart Failure Association of the European Society of Cardiology and is senior author on its simultaneous publication in the European Heart Journal.

The multicenter trial randomly assigned 61 patients with AHF to receive dapagliflozin at a fixed dose of 10 mg once daily or metolazone 5 mg or 10 mg (starting dosage at physician discretion) once daily for 3 days of treatment on an open-label basis.

Patients had entered the trial on furosemide at a mean daily dosage of 260 mg in the dapagliflozin group and 229 mg for those assigned metolazone; dosages for the loop diuretic in the trial weren’t prespecified.

Their median age was 79 and 54% were women; 44% had HF with reduced ejection fraction. Their mean glomerular filtration rate was below 30 mL/min per 1.73 m² in 26%, 90% had chronic kidney disease, 98% had peripheral edema, and 46% had diabetes.

The mean cumulative furosemide dose was significantly higher among the dapagliflozin group’s 31 patients, 976 mg versus 704 mg for the 30 on acetazolamide (P < .05), 96 hours after the start of randomized therapy. However, patients on dapagliflozin experienced a lesser increase in creatinine (P < .05) and in blood urea (P < .01), a greater change in serum sodium (P < .05), and a smaller reduction in serum potassium (P < .01).

Although the trial wasn’t powered for those outcomes, Dr. Campbell said, “less biochemical upset could be associated with better outcomes in terms of less medium- to long-term renal impairment, and in the short-term length of stay.”

The mean decrease in weight at 96 hours, the primary endpoint, reached 3 kg on dapagliflozin, compared with 3.6 kg with metolazone (P = .082), a difference that fell short of significance.

Loop diuretic efficiency, that is weight change in kg per 40 mg furosemide, “was smaller with dapagliflozin than with metolazone at each time point after randomization, although the difference was only significant at 24 hours,” the published report states.

Changes in pulmonary congestion (by lung ultrasound) and fluid volume were similar between the groups.

“This trial further adds to the evidence base and safety profile for using SGLT2 inhibitors in patients with acute heart failure,” and “gives further confidence to clinicians that this class can be started in ‘sicker’ patients with HF who also have diuretic resistance,” Dr. Campbell said.

Asked during his presentation’s question and answer whether dapagliflozin might have shown a greater effect had the dosage been higher, Dr. Campbell explained that the drug was investigational when the trial started. Adding a higher-dose dapagliflozin arm, he said, would have made for an excessively complex study. But “that’s a great research question for another trial.”

DAPA-RESIST was funded by AstraZeneca. Dr. Campbell disclosed receiving honoraria from AstraZeneca for speaking and from Bayer for serving on an advisory board.

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

Dapagliflozin (Farxiga) appears to be no more effective than the “thiazide-like” diuretic metolazone at improving pulmonary congestion and fluid status in patients with acute heart failure (AHF), suggests a new randomized trial. The drugs were given to the study’s loop diuretic–resistant patients on top of furosemide.

Changes in volume status and measures of pulmonary congestion and risk for serious adverse events were similar for those assigned to take dapagliflozin, an SGLT2 inhibitor, or metolazone, a quinazoline diuretic. Those on dapagliflozin zone ultimately received a larger cumulative furosemide dose in the 61-patient trial, called DAPA-RESIST.

“The next steps are to assess whether a strategy of using SGLT2 inhibitors up front in patients with HF reduces the incidence of diuretic resistance, and to test further combinations of diuretics such as thiazide or thiazide-like diuretics, compared with acetazolamide, when used in addition to an IV loop diuretic and SGLT2 inhibitors together,” Ross T. Campbell, MBChB, PhD, University of Glasgow and Queen Elizabeth University Hospital, also in Glasgow, said in an interview.

Dr. Campbell presented the findings at the annual meeting of the Heart Failure Association of the European Society of Cardiology and is senior author on its simultaneous publication in the European Heart Journal.

The multicenter trial randomly assigned 61 patients with AHF to receive dapagliflozin at a fixed dose of 10 mg once daily or metolazone 5 mg or 10 mg (starting dosage at physician discretion) once daily for 3 days of treatment on an open-label basis.

Patients had entered the trial on furosemide at a mean daily dosage of 260 mg in the dapagliflozin group and 229 mg for those assigned metolazone; dosages for the loop diuretic in the trial weren’t prespecified.

Their median age was 79 and 54% were women; 44% had HF with reduced ejection fraction. Their mean glomerular filtration rate was below 30 mL/min per 1.73 m² in 26%, 90% had chronic kidney disease, 98% had peripheral edema, and 46% had diabetes.

The mean cumulative furosemide dose was significantly higher among the dapagliflozin group’s 31 patients, 976 mg versus 704 mg for the 30 on acetazolamide (P < .05), 96 hours after the start of randomized therapy. However, patients on dapagliflozin experienced a lesser increase in creatinine (P < .05) and in blood urea (P < .01), a greater change in serum sodium (P < .05), and a smaller reduction in serum potassium (P < .01).

Although the trial wasn’t powered for those outcomes, Dr. Campbell said, “less biochemical upset could be associated with better outcomes in terms of less medium- to long-term renal impairment, and in the short-term length of stay.”

The mean decrease in weight at 96 hours, the primary endpoint, reached 3 kg on dapagliflozin, compared with 3.6 kg with metolazone (P = .082), a difference that fell short of significance.

Loop diuretic efficiency, that is weight change in kg per 40 mg furosemide, “was smaller with dapagliflozin than with metolazone at each time point after randomization, although the difference was only significant at 24 hours,” the published report states.

Changes in pulmonary congestion (by lung ultrasound) and fluid volume were similar between the groups.

“This trial further adds to the evidence base and safety profile for using SGLT2 inhibitors in patients with acute heart failure,” and “gives further confidence to clinicians that this class can be started in ‘sicker’ patients with HF who also have diuretic resistance,” Dr. Campbell said.

Asked during his presentation’s question and answer whether dapagliflozin might have shown a greater effect had the dosage been higher, Dr. Campbell explained that the drug was investigational when the trial started. Adding a higher-dose dapagliflozin arm, he said, would have made for an excessively complex study. But “that’s a great research question for another trial.”

DAPA-RESIST was funded by AstraZeneca. Dr. Campbell disclosed receiving honoraria from AstraZeneca for speaking and from Bayer for serving on an advisory board.

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

Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.

“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.

“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.

“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.


 

Links between gout and neurodegenerative diseases debated in earlier studies

Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.

Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
 

A novel approach that analyzes brain structure and genetics

In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.

Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
 

MRI shows brain changes in patients with gout

In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.

They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.

Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.

Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).

In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.

Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
 

Genetic analyses reinforce MRI results

Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.

They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.

In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.

Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
 

A novel approach that suggests further related research

Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.

Dr. Khanna, who was not involved in the study, said she would like to know more about the role that horizontal pleiotropy – one genetic variant having independent effects on multiple traits – plays in this disease process, and about the impact of the antioxidative properties of urate in maintaining neuroprotection.

“[The] U.K. Biobank is an excellent database to look at questions of association,” John D. FitzGerald, MD, PhD, MPH, MBA, professor and clinical chief of rheumatology at the University of California, Los Angeles, said in an interview.

Early diagnosis benefits patients

Dr. Khanna and Dr. FitzGerald joined the authors in advising doctors to monitor their gout patients for cognitive and motor symptoms of neurodegenerative disease.

“It is clearly important to pay close attention to the neurologic exam and history in gout, especially because it is a disease of the aging population,” Dr. Khanna advised. “Addressing dementia when gout is diagnosed can lead to prompt mitigation strategies that can hugely impact patients.”

Dr. Topiwala and her colleagues would like to investigate why the dementia risk was time-dependent. “Is this because of the acute inflammatory response in gout, or could it just be that patients with gout visit their doctors more frequently, so any cognitive problems are picked up sooner?” she asked.

The authors, and Dr. Khanna and Dr. FitzGerald, report no relevant financial relationships. The Wellcome Trust; the U.K. Medical Research Council; the European Commission Horizon 2020 research and innovation program; the British Heart Foundation; the U.S. National Institutes of Health; the Engineering and Physical Sciences Research Council; and the National Institute for Health and Care Research funded the study.

Patients with gout may have smaller brain volumes and higher brain iron markers than people without gout, and also be more likely to develop Parkinson’s disease, probable essential tremor, and dementia, researchers in the United Kingdom report.

“We were surprised about the regions of the brain affected by gout, several of which are important for motor function. The other intriguing finding was that the risk of dementia amongst gout patients was strongly time-dependent: highest in the first 3 years after their gout diagnosis,” lead study author Anya Topiwala, BMBCh, DPhil, said in an interview.

“Our combination of traditional and genetic approaches increases the confidence that gout is causing the brain findings,” said Dr. Topiwala, a clinical research fellow and consultant psychiatrist in the Nuffield Department of Population Health at the University of Oxford, England.

“We suggest that clinicians be vigilant for cognitive and motor problems after gout diagnosis, particularly in the early stages,” she added.


 

Links between gout and neurodegenerative diseases debated in earlier studies

Gout, the most common inflammatory arthritis, affects around 1%-4% of people, the authors wrote, with monosodium urate crystal deposits causing acute flares of pain and swelling in joints and periarticular tissues.

Whether and how gout may affect the brain has been debated in the literature. Gout and hyperuricemia have been linked with elevated stroke risk; and although observational studies have linked hyperuricemia with lower dementia risk, especially Alzheimer’s disease, Mendelian randomization studies have had conflicting results in Alzheimer’s disease.
 

A novel approach that analyzes brain structure and genetics

In a study published in Nature Communications, Dr. Topiwala and her colleagues combined observational and Mendelian randomization techniques to explore relationships between gout and neurodegenerative diseases. They analyzed data from over 303,000 volunteer participants between 40 and 69 years of age recruited between 2006 and 2010 to contribute their detailed genetic and health information to the U.K. Biobank, a large-scale biomedical database and research resource.

Patients with gout tended to be older and male. At baseline, all participants’ serum urate levels were measured, and 30.8% of patients with gout reported that they currently used urate-lowering therapy.
 

MRI shows brain changes in patients with gout

In what the authors said is the first investigation of neuroimaging markers in patients with gout, they compared differences in gray matter volumes found in the 1,165 participants with gout and the 32,202 controls without gout who had MRI data.

They found no marked sex differences in associations. Urate was inversely linked with global brain volume and with gray and white matter volumes, and gout appeared to age global gray matter by 2 years.

Patients with gout and higher urate showed significant differences in regional gray matter volumes, especially in the cerebellum, pons, and midbrain, as well as subcortical differences in the nucleus accumbens, putamen, and caudate. They also showed significant differences in white matter tract microstructure in the fornix.

Patients with gout were more likely to develop dementia (average hazard ratio [HR] over study = 1.60), especially in the first 3 years after gout diagnosis (HR = 7.40). They were also at higher risk for vascular dementia (average HR = 2.41), compared with all-cause dementia, but not for Alzheimer’s disease (average HR = 1.62).

In asymptomatic participants though, urate and dementia were inversely linked (HR = 0.85), with no time dependence.

Gout was linked with higher incidence of Parkinson’s disease (HR = 1.43) and probable essential tremor (HR = 6.75). In asymptomatic participants, urate and Parkinson’s disease (HR = 0.89), but not probable essential tremor, were inversely linked.
 

Genetic analyses reinforce MRI results

Using Mendelian randomization estimates, the authors found that genetic links generally reflected their observational findings. Both genetically predicted gout and serum urate were significantly linked with regional gray matter volumes, including cerebellar, midbrain, pons, and brainstem.

They also found significant links with higher magnetic susceptibility in the putamen and caudate, markers of higher iron. But while genetically predicted gout was significantly linked with global gray matter volume, urate was not.

In males, but not in females, urate was positively linked with alcohol intake and lower socioeconomic status.

Dr. Topiwala acknowledged several limitations to the study, writing that “the results from the volunteer participants may not apply to other populations; the cross-sectional serum urate measurements may not reflect chronic exposure; and Parkinson’s disease and essential tremor may have been diagnostically confounded.”
 

A novel approach that suggests further related research

Asked to comment on the study, Puja Khanna, MD, MPH, a rheumatologist and clinical associate professor of medicine at the University of Michigan, Ann Arbor, called its novel use of neuroimaging interesting.