CAD & Atherosclerosis

Increased intake of meat was linked to the risk of coronary heart disease, and substituting plant protein for red or processed meat appeared to reduce that risk, in a study from pooled cohorts totaling more than a million persons.

Fuse/Thinkstock

“We know that red and processed meat intake has been associated with higher risks of fatal coronary heart disease,” said Laila Al-Shaar, PhD, of Penn State University, Hershey. However, very few studies have evaluated substitution of alternative protein sources for red and processed meat in relation to fatal CHD risk, she said.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, Dr. Al-Shaar and colleagues reviewed individual-level data from the Pooling Project of Prospective Studies of Diet and Cancer, which included 16 prospective cohorts totaling 1,364,211 participants. The average age of the participants was 57 years, and 40% were men. Individuals with a history of cancer or cardiovascular disease were excluded. The participants were followed for 7-32 years. Diet was assessed in each cohort using baselines questionnaires, and cases were identified through medical records.

Total red meat included processed meat and unprocessed red meat; animal protein sources included seafood, poultry, eggs, and low- and high-fat dairy products; and plant protein sources included nuts and beans.

The researchers identified 51,176 fatal CHD cases during the study period. After controlling for dietary and nondietary factors, they found that an increase of 100 g per day of total red meat intake was associated with a 7% increased risk of fatal coronary heart disease (relative risk, 1.07).

However, substituting 200 calories (kcal) per day from nuts, low- and high-fat dairy products, and poultry for 200 calories per day from total red meat was associated with a 6%-14% lower risk of fatal CHD, Dr. Al-Shaar added at the meeting sponsored by the American Heart Association.

These associations were stronger when substituting the alternative protein sources for processed meat, especially among women; risk was reduced by 17%-24%, on the basis of 14,888 cases.

The researchers also found that substituting 200 calories per day from eggs for 200 calories per day for total red meat and unprocessed red meat was associated with 8% and 14% higher risk of fatal CHD, respectively; but this substitution of eggs for processed meat was not significant (4%).

“When we did the association by gender, the results were even stronger in women,” said Dr. Al-Shaar. However, “these are very preliminary results” that should be interpreted with caution, and more analysis is needed, she said. “We are planning to include other cohorts with other protein sources such as soy protein,” she noted. However, the results provide additional evidence that consumption of red and processed meat contributes to an increased risk of coronary heart disease, and that substituting some red and processed meat with nuts, dairy products, or poultry may reduce this risk, she concluded.
 

Women especially benefit from red meat reduction

The study is important because of the continuing interest in various sources of dietary protein intake, Linda Van Horn, PhD, RD, of Northwestern University, Chicago, said in an interview.

“The investigators studied associations of substituting other animal and plant protein sources for total red meat, unprocessed red meat, and processed meat in relation to risk of fatal CHD,” she said.

The researchers found that swapping as little as 200 calories per day of total red meat for nuts, low- or high-fat dairy products, or poultry were associated with a 6%-14% reduced risk of fatal CHD, said Dr. Van Horn. “Alternatively, if those 200 calories per day for red meat were substituted with eggs, they saw as much as 14% higher risk of fatal CHD,” she noted.

The message for both consumers and clinicians is that the findings from this large study support recommendations for plant-based and lean animal sources of protein instead of red and processed meat or eggs, as these sources “offer significantly lower risk for CHD mortality,” Dr. Van Horn said. “This may be especially true for women, but the total population is likely to benefit from this approach,” she said.

Additional research is needed, Dr. Van Horn emphasized. “Prospective lifetime data, starting in utero and over the life course, are needed to better establish recommended dietary patterns at every age and among all ethnicities and diverse socioeconomic groups,” she said.

Dr. Al-Shaar had no financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Increased intake of meat was linked to the risk of coronary heart disease, and substituting plant protein for red or processed meat appeared to reduce that risk, in a study from pooled cohorts totaling more than a million persons.

Fuse/Thinkstock

“We know that red and processed meat intake has been associated with higher risks of fatal coronary heart disease,” said Laila Al-Shaar, PhD, of Penn State University, Hershey. However, very few studies have evaluated substitution of alternative protein sources for red and processed meat in relation to fatal CHD risk, she said.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, Dr. Al-Shaar and colleagues reviewed individual-level data from the Pooling Project of Prospective Studies of Diet and Cancer, which included 16 prospective cohorts totaling 1,364,211 participants. The average age of the participants was 57 years, and 40% were men. Individuals with a history of cancer or cardiovascular disease were excluded. The participants were followed for 7-32 years. Diet was assessed in each cohort using baselines questionnaires, and cases were identified through medical records.

Total red meat included processed meat and unprocessed red meat; animal protein sources included seafood, poultry, eggs, and low- and high-fat dairy products; and plant protein sources included nuts and beans.

The researchers identified 51,176 fatal CHD cases during the study period. After controlling for dietary and nondietary factors, they found that an increase of 100 g per day of total red meat intake was associated with a 7% increased risk of fatal coronary heart disease (relative risk, 1.07).

However, substituting 200 calories (kcal) per day from nuts, low- and high-fat dairy products, and poultry for 200 calories per day from total red meat was associated with a 6%-14% lower risk of fatal CHD, Dr. Al-Shaar added at the meeting sponsored by the American Heart Association.

These associations were stronger when substituting the alternative protein sources for processed meat, especially among women; risk was reduced by 17%-24%, on the basis of 14,888 cases.

The researchers also found that substituting 200 calories per day from eggs for 200 calories per day for total red meat and unprocessed red meat was associated with 8% and 14% higher risk of fatal CHD, respectively; but this substitution of eggs for processed meat was not significant (4%).

“When we did the association by gender, the results were even stronger in women,” said Dr. Al-Shaar. However, “these are very preliminary results” that should be interpreted with caution, and more analysis is needed, she said. “We are planning to include other cohorts with other protein sources such as soy protein,” she noted. However, the results provide additional evidence that consumption of red and processed meat contributes to an increased risk of coronary heart disease, and that substituting some red and processed meat with nuts, dairy products, or poultry may reduce this risk, she concluded.
 

Women especially benefit from red meat reduction

The study is important because of the continuing interest in various sources of dietary protein intake, Linda Van Horn, PhD, RD, of Northwestern University, Chicago, said in an interview.

“The investigators studied associations of substituting other animal and plant protein sources for total red meat, unprocessed red meat, and processed meat in relation to risk of fatal CHD,” she said.

The researchers found that swapping as little as 200 calories per day of total red meat for nuts, low- or high-fat dairy products, or poultry were associated with a 6%-14% reduced risk of fatal CHD, said Dr. Van Horn. “Alternatively, if those 200 calories per day for red meat were substituted with eggs, they saw as much as 14% higher risk of fatal CHD,” she noted.

The message for both consumers and clinicians is that the findings from this large study support recommendations for plant-based and lean animal sources of protein instead of red and processed meat or eggs, as these sources “offer significantly lower risk for CHD mortality,” Dr. Van Horn said. “This may be especially true for women, but the total population is likely to benefit from this approach,” she said.

Additional research is needed, Dr. Van Horn emphasized. “Prospective lifetime data, starting in utero and over the life course, are needed to better establish recommended dietary patterns at every age and among all ethnicities and diverse socioeconomic groups,” she said.

Dr. Al-Shaar had no financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Increased intake of meat was linked to the risk of coronary heart disease, and substituting plant protein for red or processed meat appeared to reduce that risk, in a study from pooled cohorts totaling more than a million persons.

Fuse/Thinkstock

“We know that red and processed meat intake has been associated with higher risks of fatal coronary heart disease,” said Laila Al-Shaar, PhD, of Penn State University, Hershey. However, very few studies have evaluated substitution of alternative protein sources for red and processed meat in relation to fatal CHD risk, she said.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, Dr. Al-Shaar and colleagues reviewed individual-level data from the Pooling Project of Prospective Studies of Diet and Cancer, which included 16 prospective cohorts totaling 1,364,211 participants. The average age of the participants was 57 years, and 40% were men. Individuals with a history of cancer or cardiovascular disease were excluded. The participants were followed for 7-32 years. Diet was assessed in each cohort using baselines questionnaires, and cases were identified through medical records.

Total red meat included processed meat and unprocessed red meat; animal protein sources included seafood, poultry, eggs, and low- and high-fat dairy products; and plant protein sources included nuts and beans.

The researchers identified 51,176 fatal CHD cases during the study period. After controlling for dietary and nondietary factors, they found that an increase of 100 g per day of total red meat intake was associated with a 7% increased risk of fatal coronary heart disease (relative risk, 1.07).

However, substituting 200 calories (kcal) per day from nuts, low- and high-fat dairy products, and poultry for 200 calories per day from total red meat was associated with a 6%-14% lower risk of fatal CHD, Dr. Al-Shaar added at the meeting sponsored by the American Heart Association.

These associations were stronger when substituting the alternative protein sources for processed meat, especially among women; risk was reduced by 17%-24%, on the basis of 14,888 cases.

The researchers also found that substituting 200 calories per day from eggs for 200 calories per day for total red meat and unprocessed red meat was associated with 8% and 14% higher risk of fatal CHD, respectively; but this substitution of eggs for processed meat was not significant (4%).

“When we did the association by gender, the results were even stronger in women,” said Dr. Al-Shaar. However, “these are very preliminary results” that should be interpreted with caution, and more analysis is needed, she said. “We are planning to include other cohorts with other protein sources such as soy protein,” she noted. However, the results provide additional evidence that consumption of red and processed meat contributes to an increased risk of coronary heart disease, and that substituting some red and processed meat with nuts, dairy products, or poultry may reduce this risk, she concluded.
 

Women especially benefit from red meat reduction

The study is important because of the continuing interest in various sources of dietary protein intake, Linda Van Horn, PhD, RD, of Northwestern University, Chicago, said in an interview.

“The investigators studied associations of substituting other animal and plant protein sources for total red meat, unprocessed red meat, and processed meat in relation to risk of fatal CHD,” she said.

The researchers found that swapping as little as 200 calories per day of total red meat for nuts, low- or high-fat dairy products, or poultry were associated with a 6%-14% reduced risk of fatal CHD, said Dr. Van Horn. “Alternatively, if those 200 calories per day for red meat were substituted with eggs, they saw as much as 14% higher risk of fatal CHD,” she noted.

The message for both consumers and clinicians is that the findings from this large study support recommendations for plant-based and lean animal sources of protein instead of red and processed meat or eggs, as these sources “offer significantly lower risk for CHD mortality,” Dr. Van Horn said. “This may be especially true for women, but the total population is likely to benefit from this approach,” she said.

Additional research is needed, Dr. Van Horn emphasized. “Prospective lifetime data, starting in utero and over the life course, are needed to better establish recommended dietary patterns at every age and among all ethnicities and diverse socioeconomic groups,” she said.

Dr. Al-Shaar had no financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

The improved Los Angeles medical dispatch system prompted more callers with limited English proficiency to initiate telecommunicator-assisted cardiopulmonary resuscitation (T-CPR), compared with the previous system, a new study shows.

Chalabala/iStock/Getty Images Plus

The Los Angeles Tiered Dispatch System (LA-TDS), adopted in late 2014, used simplified questions aimed at identifying cardiac arrest, compared with the city’s earlier Medical Priority Dispatch System (MPDS).

The result was substantially decreased call processing times, decreased “undertriage” of out-of-hospital cardiac arrest (OHCA), and improved overall T-CPR rates (Resuscitation. 2020 Oct;155:74-81).

But now, a secondary analysis of the data shows there was a much higher jump in T-CPR rates among a small subset of callers with limited English proficiency, compared with those proficient in English (JAMA Network Open. 2021;4[6]:e216827).

“This was an unanticipated, significant, and disproportionate change, but fortunately a very good change,” lead author Stephen Sanko, MD, said in an interview.

While the T-CPR rate among English-proficient callers increased from 55% with the MPDS to 67% with the LA-TDS (odds ratio, 1.66; P = .007), it rose from 28% to 69% (OR, 5.66; P = .003) among callers with limited English proficiency. In the adjusted analysis, the new LA-TDS was associated with a 69% higher prevalence of T-CPR among English-proficient callers, compared with a 350% greater prevalence among callers with limited English proficiency.

“The emergency communication process between a caller and 911 telecommunicator is more complex than we thought, and likely constitutes a unique subsubspecialty that interacts with fields as diverse as medicine, health equity, linguistics, sociology, consumer behavior and others,” said Dr. Sanko, who is from the division of emergency medical services at the University of Southern California in Los Angeles.

“Yet in spite of this complexity, we’re starting to be able to reproducibly classify elements of the emergency conversation that we believe are tied to outcomes we all care about. ... Modulators of health disparities are present as early as the dispatch conversation, and, importantly, they can be intervened upon to promote improved outcomes,” he continued.

The retrospective cohort study was a predefined secondary analysis of a previously published study comparing telecommunicator management of out-of-hospital cardiac arrest over 3 months with the MPDS versus 3 months with the LA-TDS. The primary outcome was the number of patients who received telecommunicator-assisted chest compressions from callers with limited English proficiency.

Of the 597 emergency calls that met the inclusion criteria, 289 (48%) were in the MPDS cohort and 308 (52%) were in the LA-TDS cohort. In the MPDS cohort, 263 callers had English proficiency and 26 had limited proficiency; in the latter cohort, those figures were 273 and 35, respectively.

There were no significant differences between cohorts in the use of real-time translation services, which were employed 27%-31% of the time.

The reason for the overall T-CPR improvement is likely that the LA-TDS was tailored to the community needs, said Dr. Sanko. “Most people, including doctors, think of 911 dispatch as something simple and straightforward, like ordering a pizza or calling a ride share. [But] LA-TDS is a ‘home grown’ dispatch system whose structure, questions, and emergency instructions were all developed by EMS medical directors and telecommunicators with extensive experience in our community.”

That being said, the researchers acknowledge that the reason behind the bigger T-CPR boost in LEP callers remains unclear. Although the link between language and system was statistically significant, they noted “it was not an a priori hypothesis and appeared to be largely attributable to the low T-CPR rates for callers with limited English proficiency using MPDS.” Additionally, such callers were “remarkably under-represented” in the sample, “which included approximately 600 calls over two quarters in a large city,” said Dr Sanko.

“We hypothesize that a more direct structure, earlier commitment to treating patients with abnormal life status indicators as being suspected cardiac arrest cases, and earlier reassurance may have improved caller confidence that telecommunicators knew what they were doing. This in turn may have translated into an increased likelihood of bystander caller willingness to perform immediate life-saving maneuvers.”

Despite a number of limitations, “the study is important and highlights instructive topics for discussion that suggest potential next-step opportunities,” noted Richard Chocron, MD, PhD, Miranda Lewis, MD, and Thomas Rea, MD, MPH, in an invited commentary that accompanied the publication. Dr. Chocron is from the Paris University, Paris Research Cardiovascular Center, INSERM; Dr. Lewis is from the Georges Pompidou European Hospital in Paris; and Dr. Rea is from the Division of Emergency Medical Services, Public Health–Seattle & King County. Both Dr. Lewis and Dr. Rea are also at the University of Washington, Seattle.

“Sanko et al. found that approximately 10% of all emergency calls were classified as limited English proficiency calls in a community in which 19% of the population was considered to have limited English proficiency,” they added. “This finding suggests the possibility that populations with limited English proficiency are less likely to activate 911 for incidence of cardiac arrest. If true, this finding would compound the health disparity observed among those with limited English proficiency. This topic is important in that it transcends the role of EMS personnel and engages a broad spectrum of societal stakeholders. We must listen, learn, and ultimately deliver public safety resources to groups who have not been well served by conventional approaches.”

None of the authors or editorialists reported any conflicts of interest.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Taking more steps each day, in short spurts or longer bouts, was associated with a longer life in women older than 60 years, according to data from more than 16,000 participants in the ongoing Women’s Health Study.

The American Heart Association recommends at least 150 minutes per week of moderate physical activity, 75 minutes of vigorous physical activity, or a combination of both as fitness guidelines for adults. Walking is a safe and easy way for many adults to follow these guidelines, according to Christopher C. Moore, MS, a PhD candidate at the University of North Carolina at Chapel Hill.

The popularity of step counts reflect that they are simple and objective, and “focusing on steps can help promote an active lifestyle,” he said. Data on the impact of sporadic steps accumulated outside of longer bouts of activity on health outcomes are limited; however, technology advances in the form of fitness apps and wearable devices make it possible for researchers to track and measure the benefits of short periods of activity as well as longer periods.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the AHA, Mr. Moore and colleagues assessed data from women older than 60 years who used wearable step-counting devices to measure their daily steps and walking patterns.

The study population included 16,732 women enrolled in the Women’s Health Study, a longstanding study of heart disease, cancer, and disease prevention among women in the United States. The participants wore waist step counters 4-7 days a week during 2011-2015. The average of the women was 72 years; 96% were non-Hispanic White, and the average BMI was 26 kg/m².

The researchers divided the total number of steps for each study participant into two groups: “bouted” steps, defined as 10 minutes or longer bouts of walking with few interruptions; and “sporadic” steps, defined as short spurts of walking during regular daily activities such as housework, taking the stairs, or walking to or from a car.

A total of 804 deaths occurred during an average of 6 years of follow-up. Each initial increase of 1,000 steps including sporadic or bouted steps was associated with a 28% decrease in death, compared with no daily steps (hazard ratio, 0.72).

Each increasing quartile of sporadic steps was linked with higher total steps per day, Mr. Moore said. “Initial increase in sporadic steps corresponded to the greatest reductions in mortality,” with a HR of 0.69 per additional sporadic steps below 3,200 per day, and the impact on reduced mortality plateaued at about 4,500 sporadic steps per day.

In further analysis, the researchers also found a roughly 32% decrease in death in participants who took more than 2,000 steps daily in uninterrupted bouts (HR, 0.69).

The study findings were limited by several factors, including the relatively short follow-up period and number of events, the assessment of steps at a single time point, and the mostly homogeneous population, Mr. Moore noted. Additional research is needed to assess whether the results are generalizable to men, younger women, and diverse racial and ethnic groups.

However, the results may have implications for public health messaging, he emphasized. The message is that, to impact longevity, the total volume of steps is more important than the type of activity through which they are accumulated.

“You can accumulate your steps through longer bouts of purposeful activity or through everyday behaviors such as walking to your car, taking the stairs, and doing housework,” Mr. Moore concluded.

Find a friend, both of you benefit

On the basis of this study and other available evidence, more steps daily are recommended for everyone, Nieca Goldberg, MD, a cardiologist at New York University Langone Health, said in an interview.

“You can increase minutes of walking and frequency of walking,” she said.

Dr. Goldberg emphasized that you don’t need a fancy app or wearable device to up your steps. She offered some tips to help overcome barriers to putting one foot in front of the other. “Take the steps instead of the elevator. Park your car farther from your destination so you can walk.” Also, you can help yourself and help a friend to better health. “Get a walking buddy so you can encourage each other to walk,” Dr. Goldberg added.

Mr. Moore and Dr. Goldberg had no financial conflicts to disclose. The Women’s Health Study is funded by Brigham and Women’s Hospital; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Mr. Moore was funded by a grant from the NHLBI but had no other financial conflicts to disclose.

Taking more steps each day, in short spurts or longer bouts, was associated with a longer life in women older than 60 years, according to data from more than 16,000 participants in the ongoing Women’s Health Study.

The American Heart Association recommends at least 150 minutes per week of moderate physical activity, 75 minutes of vigorous physical activity, or a combination of both as fitness guidelines for adults. Walking is a safe and easy way for many adults to follow these guidelines, according to Christopher C. Moore, MS, a PhD candidate at the University of North Carolina at Chapel Hill.

The popularity of step counts reflect that they are simple and objective, and “focusing on steps can help promote an active lifestyle,” he said. Data on the impact of sporadic steps accumulated outside of longer bouts of activity on health outcomes are limited; however, technology advances in the form of fitness apps and wearable devices make it possible for researchers to track and measure the benefits of short periods of activity as well as longer periods.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the AHA, Mr. Moore and colleagues assessed data from women older than 60 years who used wearable step-counting devices to measure their daily steps and walking patterns.

The study population included 16,732 women enrolled in the Women’s Health Study, a longstanding study of heart disease, cancer, and disease prevention among women in the United States. The participants wore waist step counters 4-7 days a week during 2011-2015. The average of the women was 72 years; 96% were non-Hispanic White, and the average BMI was 26 kg/m².

The researchers divided the total number of steps for each study participant into two groups: “bouted” steps, defined as 10 minutes or longer bouts of walking with few interruptions; and “sporadic” steps, defined as short spurts of walking during regular daily activities such as housework, taking the stairs, or walking to or from a car.

A total of 804 deaths occurred during an average of 6 years of follow-up. Each initial increase of 1,000 steps including sporadic or bouted steps was associated with a 28% decrease in death, compared with no daily steps (hazard ratio, 0.72).

Each increasing quartile of sporadic steps was linked with higher total steps per day, Mr. Moore said. “Initial increase in sporadic steps corresponded to the greatest reductions in mortality,” with a HR of 0.69 per additional sporadic steps below 3,200 per day, and the impact on reduced mortality plateaued at about 4,500 sporadic steps per day.

In further analysis, the researchers also found a roughly 32% decrease in death in participants who took more than 2,000 steps daily in uninterrupted bouts (HR, 0.69).

The study findings were limited by several factors, including the relatively short follow-up period and number of events, the assessment of steps at a single time point, and the mostly homogeneous population, Mr. Moore noted. Additional research is needed to assess whether the results are generalizable to men, younger women, and diverse racial and ethnic groups.

However, the results may have implications for public health messaging, he emphasized. The message is that, to impact longevity, the total volume of steps is more important than the type of activity through which they are accumulated.

“You can accumulate your steps through longer bouts of purposeful activity or through everyday behaviors such as walking to your car, taking the stairs, and doing housework,” Mr. Moore concluded.

Find a friend, both of you benefit

On the basis of this study and other available evidence, more steps daily are recommended for everyone, Nieca Goldberg, MD, a cardiologist at New York University Langone Health, said in an interview.

“You can increase minutes of walking and frequency of walking,” she said.

Dr. Goldberg emphasized that you don’t need a fancy app or wearable device to up your steps. She offered some tips to help overcome barriers to putting one foot in front of the other. “Take the steps instead of the elevator. Park your car farther from your destination so you can walk.” Also, you can help yourself and help a friend to better health. “Get a walking buddy so you can encourage each other to walk,” Dr. Goldberg added.

Mr. Moore and Dr. Goldberg had no financial conflicts to disclose. The Women’s Health Study is funded by Brigham and Women’s Hospital; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Mr. Moore was funded by a grant from the NHLBI but had no other financial conflicts to disclose.

Taking more steps each day, in short spurts or longer bouts, was associated with a longer life in women older than 60 years, according to data from more than 16,000 participants in the ongoing Women’s Health Study.

The American Heart Association recommends at least 150 minutes per week of moderate physical activity, 75 minutes of vigorous physical activity, or a combination of both as fitness guidelines for adults. Walking is a safe and easy way for many adults to follow these guidelines, according to Christopher C. Moore, MS, a PhD candidate at the University of North Carolina at Chapel Hill.

The popularity of step counts reflect that they are simple and objective, and “focusing on steps can help promote an active lifestyle,” he said. Data on the impact of sporadic steps accumulated outside of longer bouts of activity on health outcomes are limited; however, technology advances in the form of fitness apps and wearable devices make it possible for researchers to track and measure the benefits of short periods of activity as well as longer periods.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the AHA, Mr. Moore and colleagues assessed data from women older than 60 years who used wearable step-counting devices to measure their daily steps and walking patterns.

The study population included 16,732 women enrolled in the Women’s Health Study, a longstanding study of heart disease, cancer, and disease prevention among women in the United States. The participants wore waist step counters 4-7 days a week during 2011-2015. The average of the women was 72 years; 96% were non-Hispanic White, and the average BMI was 26 kg/m².

The researchers divided the total number of steps for each study participant into two groups: “bouted” steps, defined as 10 minutes or longer bouts of walking with few interruptions; and “sporadic” steps, defined as short spurts of walking during regular daily activities such as housework, taking the stairs, or walking to or from a car.

A total of 804 deaths occurred during an average of 6 years of follow-up. Each initial increase of 1,000 steps including sporadic or bouted steps was associated with a 28% decrease in death, compared with no daily steps (hazard ratio, 0.72).

Each increasing quartile of sporadic steps was linked with higher total steps per day, Mr. Moore said. “Initial increase in sporadic steps corresponded to the greatest reductions in mortality,” with a HR of 0.69 per additional sporadic steps below 3,200 per day, and the impact on reduced mortality plateaued at about 4,500 sporadic steps per day.

In further analysis, the researchers also found a roughly 32% decrease in death in participants who took more than 2,000 steps daily in uninterrupted bouts (HR, 0.69).

The study findings were limited by several factors, including the relatively short follow-up period and number of events, the assessment of steps at a single time point, and the mostly homogeneous population, Mr. Moore noted. Additional research is needed to assess whether the results are generalizable to men, younger women, and diverse racial and ethnic groups.

However, the results may have implications for public health messaging, he emphasized. The message is that, to impact longevity, the total volume of steps is more important than the type of activity through which they are accumulated.

“You can accumulate your steps through longer bouts of purposeful activity or through everyday behaviors such as walking to your car, taking the stairs, and doing housework,” Mr. Moore concluded.

Find a friend, both of you benefit

On the basis of this study and other available evidence, more steps daily are recommended for everyone, Nieca Goldberg, MD, a cardiologist at New York University Langone Health, said in an interview.

“You can increase minutes of walking and frequency of walking,” she said.

Dr. Goldberg emphasized that you don’t need a fancy app or wearable device to up your steps. She offered some tips to help overcome barriers to putting one foot in front of the other. “Take the steps instead of the elevator. Park your car farther from your destination so you can walk.” Also, you can help yourself and help a friend to better health. “Get a walking buddy so you can encourage each other to walk,” Dr. Goldberg added.

Mr. Moore and Dr. Goldberg had no financial conflicts to disclose. The Women’s Health Study is funded by Brigham and Women’s Hospital; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Mr. Moore was funded by a grant from the NHLBI but had no other financial conflicts to disclose.

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

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

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

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

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

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

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

People with prediabetes, defined by having a hemoglobin A1c of 5.7%-6.4%, had a significantly increased rate of atherosclerotic cardiovascular disease events and incident chronic kidney disease in a study of nearly 337,000 people included in the UK Biobank database.

The findings suggest that people with prediabetes have “heightened risk even without progression to type 2 diabetes,” Michael C. Honigberg, MD, said at the annual scientific sessions of the American College of Cardiology.

“Hemoglobin A1c may be better considered as a continuous measure of risk rather than dichotomized” as either less than 6.5%, or 6.5% or higher, the usual threshold defining people with type 2 diabetes, said Dr. Honigberg, a cardiologist at Massachusetts General Hospital in Boston.
 

‘Prediabetes is not a benign entity’

“Our findings reinforce the notion that A1c represents a continuum of risk, with elevated risks observed, especially for atherosclerotic cardiovascular disease [ASCVD], at levels where some clinicians wouldn’t think twice about them. Prediabetes is not a benign entity in the middle-aged population we studied,” Dr. Honigberg said in an interview. “Risks are higher in individuals with type 2 diabetes,” he stressed, “however, prediabetes is so much more common that it appears to confer similar cardio, renal, and metabolic risks at a population level.”

Results from prior observational studies also showed elevated incidence rate of cardiovascular disease events in people with prediabetes, including a 2010 report based on data from about 11,000 U.S. residents, and in a more recent meta-analysis of 129 studies involving more than 10 million people. The new report by Dr. Honigberg “is the first to comprehensively evaluate diverse cardio-renal-metabolic outcomes across a range of A1c levels using a very large, contemporary database,” he noted. In addition, most prior reports did not include chronic kidney disease as an examined outcome.

The primary endpoint examined in the new analysis was the combined incidence during a median follow-up of just over 11 years of ASCVD events (coronary artery disease, ischemic stroke, or peripheral artery disease), CKD, or heart failure among 336,709 adults in the UK Biobank who at baseline had none of these conditions nor type 1 diabetes.

The vast majority, 82%, were normoglycemic at baseline, based on having an A1c of less than 5.7%; 14% had prediabetes, with an A1c of 5.7%-6.4%; and 4% had type 2 diabetes based on an A1c of at least 6.5% or on insulin treatment. Patients averaged about 57 years of age, slightly more than half were women, and average body mass index was in the overweight category except for those with type 2 diabetes.

The primary endpoint, the combined incidence of ASCVD, CKD, and heart failure, was 24% among those with type 2 diabetes, 14% in those with prediabetes, and 8% in those who were normoglycemic at entry. Concurrently with the report, the results appeared online. Most of these events involved ASCVD, which occurred in 11% of those in the prediabetes subgroup (roughly four-fifths of the events in this subgroup), and in 17% of those with type 2 diabetes (nearly three-quarters of the events in this subgroup).

In an analysis that adjusted for more than a dozen demographic and clinical factors, the presence of prediabetes linked with significant increases in the incidence rate of all three outcomes compared with people who were normoglycemic at baseline. The analysis also identified an A1c level of 5.0% as linked with the lowest incidence of each of the three adverse outcomes. And a very granular analysis suggested that a significantly elevated risk for ASCVD first appeared when A1c levels were in the range of 5.4%-5.7%; a significantly increased incidence of CKD became apparent once A1c was in the range of 6.2%-6.5%; and a significantly increased incidence of heart failure began to manifest once A1c levels reached at least 7.0%.

Need for comprehensive cardiometabolic risk management

The findings “highlight the importance of identifying and comprehensively managing cardiometabolic risk in people with prediabetes, including dietary modification, exercise, weight loss and obesity management, smoking cessation, and attention to hypertension and hypercholesterolemia,” Dr. Honigberg said. While these data cannot address the appropriateness of using novel drug interventions in people with prediabetes, they suggest that people with prediabetes should be the focus of future prevention trials testing agents such as sodium-glucose cotransporter 2 inhibitors.

“These data help us discuss risk with patients [with prediabetes], and reemphasize the importance of guideline-directed preventive care,” said Vijay Nambi, MD, PhD, a preventive cardiologist and lipid specialist at Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, who was not involved with the study.

An additional analysis reported by Dr. Honigberg examined the risk among people with prediabetes who also were current or former smokers and in the top tertile of the prediabetes study population for systolic blood pressure, high non-HDL cholesterol, and C-reactive protein (a marker of inflammation). This very high-risk subgroup of people with prediabetes had incidence rates for ASCVD events and for heart failure that tracked identically to those with type 2 diabetes. However. the incidence rate for CKD in these high-risk people with prediabetes remained below that of patients with type 2 diabetes.

Dr. Honigberg had no disclosures. Dr. Nambi has received research funding from Amgen, Merck, and Roche.

[email protected]

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

New data show for the first time that combining the DASH (Dietary Approaches to Stop Hypertension) diet with sodium restriction decreases myocardial injury and cardiac strain, which are associated with subclinical cardiac damage and long-term cardiovascular risk.

“The benefits of healthy eating are swift and direct. High sodium is not just about taste, it causes heart strain,” Stephen Juraschek, MD, PhD, from Beth Israel Deaconess Medical Center, Boston, said in an interview.

“We should consciously follow a diet enriched with fruit and vegetables and low in sodium. Collectively, we should think about how foods are promoted in society and what is an acceptable amount of sodium for food supplies,” said Dr. Juraschek.

The findings, from a secondary analysis of the DASH-Sodium trial, were published the Journal of the American College of Cardiology.
 

Renewed focus on diet

“These data should spur a renewed focus on the critical need for widespread adoption of the DASH–low-sodium diet in the United States,” wrote the coauthors of a linked editorial.

“The challenge remains moving the DASH–low-sodium diet from the research world into the real world, where its significant health benefits can be fully realized,” they added.

The researchers evaluated the impact of the DASH diet and sodium restriction, individually and combined, on biomarkers of cardiac injury (high-sensitivity cardiac troponin I [hs-cTnI]), cardiac strain (N-terminal of the prohormone brain natriuretic peptide [NT-proBNP]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]).

The DASH-Sodium trial was a controlled feeding study that enrolled 412 adults (mean age, 48 years; 56% women, 56% Black) with untreated systolic blood pressure between 120 and 159 mm Hg and diastolic blood pressure between 80 and 95 mm Hg. Mean baseline BP was 135/86 mm Hg.

Participants were randomly allocated to a typical American diet (control) or the heart-healthy DASH diet. Further, participants in both groups were assigned to each of three sodium intake levels: low (0.5 mg/kcal), medium (1.1 mg/kcal) or high (1.6 mg/kcal) for 30 days using a crossover design with washout periods in between.

Compared with the control diet, the DASH diet reduced hs-cTnI by 18% and hs-CRP by 13% with no impact on NT-proBNP.

In contrast, lowering sodium from high to low levels reduced NT-proBNP independent of diet by 19%, but did not alter hs-cTnI and mildly increased hs-CRP (9%).

Combining the DASH diet with sodium reduction lowered hs-cTnI by 20% and NT-proBNP by 23%, with no significant change in hs-CRP, compared with the high-sodium-control diet.

“Together, these findings imply that two distinct dietary strategies might improve two key pathways of subclinical cardiac damage: injury and strain,” Dr. Juraschek and colleagues wrote.

“These findings should strengthen public resolve for public policies that promote the DASH dietary pattern and lower sodium intake in the United States and globally,” they concluded.

“We need to talk about DASH more. Most adults in the U.S. have never heard of it,” Dr. Juraschek said in an interview.

“We need to promote nutrition literacy with regard to nutrition facts. Labeling is not very transparent and hard to understand. Many people don’t know where salt is hiding in their diet,” he added.

It will also be important to address disparities in access to healthy foods and food insecurity, Dr. Juraschek said.

“If we don’t address food costs and access, disparities in healthy eating will persist. Greater equity is key. We should also be mindful about populations dependent on others for meal preparation [children in schools or older adults on meal plans]. This might be regulated in ways that promote healthier eating population wide, but for these patients, they may not have autonomy to choose what they eat,” Dr. Juraschek said.

In their editorial, Neha J. Pagidipati, MD, and Laura P. Svetkey, MD, from Duke University and Duke Clinical Research Institute, Durham, N.C., said an important caveat is that the beneficial effects of diet and sodium restriction on cardiac injury and strain occurred in people without any clinical evidence of coronary artery disease or heart failure at baseline, “suggesting that this dietary combination can improve subclinical metrics of cardiac health.”

“Further, the impact on these markers was seen within weeks, indicating a relatively rapid impact on cardiac damage,” they added.

The measurement of cardiac biomarkers was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute. The original DASH trial was supported by the NHLBI, the Office of Research on Minority Health, and the National Center for Research Resources. Dr. Juraschek and coauthors disclosed no relevant conflicts of interest. Dr. Pagidipati has received research support to the institution from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, and Verily Life Sciences; and has received consultation fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr. Svetkey has no relevant disclosures.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

[email protected]