User login
Walking intensity and step count are linked to health benefits
Each additional 2,000 steps per day – up to 10,000 – was associated with 8% to 11% fewer deaths and less heart disease and cancer, the researchers found. Walking quickly had an even stronger link to lower health risks.
The findings were reported in JAMA Internal Medicine. In a separate paper, published in JAMA Neurology, the researchers reported associations between walking and reduced risk of dementia.
Moving faster provides a health ‘bonus’
The findings expand on evidence in smaller studies of middle-aged individuals and older women that suggested health benefits from covering less than the widely promoted target of 10,000 steps a day.
The new study supports the ideas that “every step counts” and moving faster provides a health “bonus,” said one of its co-lead authors, Borja del Pozo Cruz, PhD, an associate professor at the University of Southern Denmark, Odense, and a senior researcher in health at the University of Cadiz, Spain.
Dr. Del Pozo Cruz and his coauthors analyzed median daily step counts for 78,500 adults aged 40-79 years in the U.K. Biobank database who agreed to wear an accelerometer for 1 week. Participants’ average age was 61. Fifty-five percent were women and 97% were White.
Steps were categorized as “incidental,” defined as a pace of less than 40 per minute, and “purposeful,” ones taken at the pace of 40 or more per minute. Researchers also calculated peak 30-minute cadence, the average of an individual’s 30 most active minutes in a day.
Participants’ health records were reviewed after 7 years. Each additional 2,000 steps taken was associated with lower all-cause mortality (mean rate of change [MRC] in the hazard ratio, –0.08; 95% confidence interval, –0.11 to –0.06); cardiovascular mortality (MRC, –0.10; 95% CI, –0.15 to –0.06), and cancer mortality (MRC, –0.11; 95% CI, –0.15 to –0.06).
Similar incremental reductions were observed in the incidence of heart disease, defined as fatal and nonfatal coronary heart disease, stroke, and heart failure; and a composite cancer outcome of 13 sites shown to be associated with low physical activity.
Both incidental and purposeful steps were linked to lower rates of mortality and disease. Particularly encouraging, the researchers said, was the benefit associated with incidental steps, which might be more feasible for some individuals than a planned walk.
The association with better outcomes was especially strong for peak-30 cadence, with individuals in the top fifth of intensity having a 34% lower mortality rate compared with those in the bottom fifth – an observation that researchers wrote “reflects the importance of the natural best effort relative to the individual’s capability.”
The analysis adjusted for a variety of factors including age, sex, race, smoking, alcohol use, fruit and vegetable consumption, medication use, family history of cardiovascular disease or cancer, and sleep quality. It also excluded participants who had deaths and illnesses within 2 years of a step assessment to minimize the problem of reverse causation, in which existing health problems cause participants to move less.
Data contribute evidence toward step count recommendations
The data are observational and do not prove cause and effect, the researchers noted. Still, the authors said the study “contributes critical evidence toward step count–based recommendations” for physical activity.
Guidelines of the United States and the World Health Organization recommend 150 minutes of moderately intense activity or 75 minutes of vigorous activity weekly plus strength training twice a week.
Given the proliferation of activity trackers in phones and watches, recommendations based on steps could be especially useful for individuals who don’t intentionally record their physical activity, the researchers wrote.
“It’s nice to have a study that puts some science behind steps counts,” cardiologist Nieca Goldberg, MD, a clinical associate professor of medicine at New York University, and a spokesperson for the American Heart Association, said of the findings.
Particularly important, said Dr. Goldberg, who was not involved in the study, is the lack of a minimum threshold for health benefits, since the 10,000-step target may be daunting for some individuals.
Only one in five participants in this latest study achieved 10,000 steps per day, according to the paper.
The authors wrote that promotion of lower step targets “may provide a more realistic and achievable goal for the general adult population,” and longevity gains “may be maximized simply by shifting away from the least-active end of the step-count distribution.”
Dr. Goldberg put it this way: “Take a walk. Try to aspire to 10,000 steps. But if you can only do 6,000 or 8,000, you get benefit there, too.”
Cathy Handy Marshall, MD, MPH, an assistant professor of oncology at Johns Hopkins University, Baltimore, who was not involved in the new study, said the findings can be used to guide “exercise prescriptions,” but more research is needed to tailor recommendations, particularly for individuals who cannot achieve high step counts.
Dr. Del Pozo Cruz said the findings need to be replicated in other populations.
The study authors, Dr. Goldberg, and Dr. Handy Marshall reported no relevant competing interests.
Each additional 2,000 steps per day – up to 10,000 – was associated with 8% to 11% fewer deaths and less heart disease and cancer, the researchers found. Walking quickly had an even stronger link to lower health risks.
The findings were reported in JAMA Internal Medicine. In a separate paper, published in JAMA Neurology, the researchers reported associations between walking and reduced risk of dementia.
Moving faster provides a health ‘bonus’
The findings expand on evidence in smaller studies of middle-aged individuals and older women that suggested health benefits from covering less than the widely promoted target of 10,000 steps a day.
The new study supports the ideas that “every step counts” and moving faster provides a health “bonus,” said one of its co-lead authors, Borja del Pozo Cruz, PhD, an associate professor at the University of Southern Denmark, Odense, and a senior researcher in health at the University of Cadiz, Spain.
Dr. Del Pozo Cruz and his coauthors analyzed median daily step counts for 78,500 adults aged 40-79 years in the U.K. Biobank database who agreed to wear an accelerometer for 1 week. Participants’ average age was 61. Fifty-five percent were women and 97% were White.
Steps were categorized as “incidental,” defined as a pace of less than 40 per minute, and “purposeful,” ones taken at the pace of 40 or more per minute. Researchers also calculated peak 30-minute cadence, the average of an individual’s 30 most active minutes in a day.
Participants’ health records were reviewed after 7 years. Each additional 2,000 steps taken was associated with lower all-cause mortality (mean rate of change [MRC] in the hazard ratio, –0.08; 95% confidence interval, –0.11 to –0.06); cardiovascular mortality (MRC, –0.10; 95% CI, –0.15 to –0.06), and cancer mortality (MRC, –0.11; 95% CI, –0.15 to –0.06).
Similar incremental reductions were observed in the incidence of heart disease, defined as fatal and nonfatal coronary heart disease, stroke, and heart failure; and a composite cancer outcome of 13 sites shown to be associated with low physical activity.
Both incidental and purposeful steps were linked to lower rates of mortality and disease. Particularly encouraging, the researchers said, was the benefit associated with incidental steps, which might be more feasible for some individuals than a planned walk.
The association with better outcomes was especially strong for peak-30 cadence, with individuals in the top fifth of intensity having a 34% lower mortality rate compared with those in the bottom fifth – an observation that researchers wrote “reflects the importance of the natural best effort relative to the individual’s capability.”
The analysis adjusted for a variety of factors including age, sex, race, smoking, alcohol use, fruit and vegetable consumption, medication use, family history of cardiovascular disease or cancer, and sleep quality. It also excluded participants who had deaths and illnesses within 2 years of a step assessment to minimize the problem of reverse causation, in which existing health problems cause participants to move less.
Data contribute evidence toward step count recommendations
The data are observational and do not prove cause and effect, the researchers noted. Still, the authors said the study “contributes critical evidence toward step count–based recommendations” for physical activity.
Guidelines of the United States and the World Health Organization recommend 150 minutes of moderately intense activity or 75 minutes of vigorous activity weekly plus strength training twice a week.
Given the proliferation of activity trackers in phones and watches, recommendations based on steps could be especially useful for individuals who don’t intentionally record their physical activity, the researchers wrote.
“It’s nice to have a study that puts some science behind steps counts,” cardiologist Nieca Goldberg, MD, a clinical associate professor of medicine at New York University, and a spokesperson for the American Heart Association, said of the findings.
Particularly important, said Dr. Goldberg, who was not involved in the study, is the lack of a minimum threshold for health benefits, since the 10,000-step target may be daunting for some individuals.
Only one in five participants in this latest study achieved 10,000 steps per day, according to the paper.
The authors wrote that promotion of lower step targets “may provide a more realistic and achievable goal for the general adult population,” and longevity gains “may be maximized simply by shifting away from the least-active end of the step-count distribution.”
Dr. Goldberg put it this way: “Take a walk. Try to aspire to 10,000 steps. But if you can only do 6,000 or 8,000, you get benefit there, too.”
Cathy Handy Marshall, MD, MPH, an assistant professor of oncology at Johns Hopkins University, Baltimore, who was not involved in the new study, said the findings can be used to guide “exercise prescriptions,” but more research is needed to tailor recommendations, particularly for individuals who cannot achieve high step counts.
Dr. Del Pozo Cruz said the findings need to be replicated in other populations.
The study authors, Dr. Goldberg, and Dr. Handy Marshall reported no relevant competing interests.
Each additional 2,000 steps per day – up to 10,000 – was associated with 8% to 11% fewer deaths and less heart disease and cancer, the researchers found. Walking quickly had an even stronger link to lower health risks.
The findings were reported in JAMA Internal Medicine. In a separate paper, published in JAMA Neurology, the researchers reported associations between walking and reduced risk of dementia.
Moving faster provides a health ‘bonus’
The findings expand on evidence in smaller studies of middle-aged individuals and older women that suggested health benefits from covering less than the widely promoted target of 10,000 steps a day.
The new study supports the ideas that “every step counts” and moving faster provides a health “bonus,” said one of its co-lead authors, Borja del Pozo Cruz, PhD, an associate professor at the University of Southern Denmark, Odense, and a senior researcher in health at the University of Cadiz, Spain.
Dr. Del Pozo Cruz and his coauthors analyzed median daily step counts for 78,500 adults aged 40-79 years in the U.K. Biobank database who agreed to wear an accelerometer for 1 week. Participants’ average age was 61. Fifty-five percent were women and 97% were White.
Steps were categorized as “incidental,” defined as a pace of less than 40 per minute, and “purposeful,” ones taken at the pace of 40 or more per minute. Researchers also calculated peak 30-minute cadence, the average of an individual’s 30 most active minutes in a day.
Participants’ health records were reviewed after 7 years. Each additional 2,000 steps taken was associated with lower all-cause mortality (mean rate of change [MRC] in the hazard ratio, –0.08; 95% confidence interval, –0.11 to –0.06); cardiovascular mortality (MRC, –0.10; 95% CI, –0.15 to –0.06), and cancer mortality (MRC, –0.11; 95% CI, –0.15 to –0.06).
Similar incremental reductions were observed in the incidence of heart disease, defined as fatal and nonfatal coronary heart disease, stroke, and heart failure; and a composite cancer outcome of 13 sites shown to be associated with low physical activity.
Both incidental and purposeful steps were linked to lower rates of mortality and disease. Particularly encouraging, the researchers said, was the benefit associated with incidental steps, which might be more feasible for some individuals than a planned walk.
The association with better outcomes was especially strong for peak-30 cadence, with individuals in the top fifth of intensity having a 34% lower mortality rate compared with those in the bottom fifth – an observation that researchers wrote “reflects the importance of the natural best effort relative to the individual’s capability.”
The analysis adjusted for a variety of factors including age, sex, race, smoking, alcohol use, fruit and vegetable consumption, medication use, family history of cardiovascular disease or cancer, and sleep quality. It also excluded participants who had deaths and illnesses within 2 years of a step assessment to minimize the problem of reverse causation, in which existing health problems cause participants to move less.
Data contribute evidence toward step count recommendations
The data are observational and do not prove cause and effect, the researchers noted. Still, the authors said the study “contributes critical evidence toward step count–based recommendations” for physical activity.
Guidelines of the United States and the World Health Organization recommend 150 minutes of moderately intense activity or 75 minutes of vigorous activity weekly plus strength training twice a week.
Given the proliferation of activity trackers in phones and watches, recommendations based on steps could be especially useful for individuals who don’t intentionally record their physical activity, the researchers wrote.
“It’s nice to have a study that puts some science behind steps counts,” cardiologist Nieca Goldberg, MD, a clinical associate professor of medicine at New York University, and a spokesperson for the American Heart Association, said of the findings.
Particularly important, said Dr. Goldberg, who was not involved in the study, is the lack of a minimum threshold for health benefits, since the 10,000-step target may be daunting for some individuals.
Only one in five participants in this latest study achieved 10,000 steps per day, according to the paper.
The authors wrote that promotion of lower step targets “may provide a more realistic and achievable goal for the general adult population,” and longevity gains “may be maximized simply by shifting away from the least-active end of the step-count distribution.”
Dr. Goldberg put it this way: “Take a walk. Try to aspire to 10,000 steps. But if you can only do 6,000 or 8,000, you get benefit there, too.”
Cathy Handy Marshall, MD, MPH, an assistant professor of oncology at Johns Hopkins University, Baltimore, who was not involved in the new study, said the findings can be used to guide “exercise prescriptions,” but more research is needed to tailor recommendations, particularly for individuals who cannot achieve high step counts.
Dr. Del Pozo Cruz said the findings need to be replicated in other populations.
The study authors, Dr. Goldberg, and Dr. Handy Marshall reported no relevant competing interests.
FROM JAMA INTERNAL MEDICINE
Two states aim to curb diet pill sales to minors
California and New York are on the cusp of going further than the Food and Drug Administration in restricting the sale of nonprescription diet pills to minors as pediatricians and public health advocates try to protect kids from extreme weight-loss gimmicks online.
A bill before Gov. Gavin Newsom would bar anyone under 18 in California from buying over-the-counter weight-loss supplements – whether online or in shops – without a prescription. A similar bill passed by New York lawmakers is on Gov. Kathy Hochul’s desk. Neither Democrat has indicated how he or she will act.
If both bills are signed into law, proponents hope the momentum will build to restrict diet pill sales to children in more states. Massachusetts, New Jersey, and Missouri have introduced similar bills and backers plan to continue their push next year.
Nearly 30 million people in the United States will have an eating disorder in their lifetime; 95% of them are aged between 12 and 25, according to Johns Hopkins All Children’s Hospital. The hospital added that eating disorders pose the highest risk of mortality of any mental health disorder. And it has become easier than ever for minors to get pills that are sold online or on drugstore shelves. All dietary supplements, which include those for weight loss, accounted for nearly 35% of the $63 billion over-the-counter health products industry in 2021, according to Vision Research Reports, a market research firm.
Dietary supplements, which encompass a broad range of vitamins, herbs, and minerals, are classified by the FDA as food and don’t undergo scientific and safety testing as prescription drugs and over-the-counter medicines do.
Public health advocates want to keep weight-loss products – with ads that may promise to “Drop 5 pounds a week!” and pill names like Slim Sense – away from young people, particularly girls, since some research has linked some products to eating disorders. A study in the American Journal of Public Health, which followed more than 10,000 women aged 14-36 over 15 years, found that “those who used diet pills had more than 5 times higher adjusted odds of receiving an eating disorder diagnosis from a health care provider within 1-3 years than those who did not.”
Many pills have been found tainted with banned and dangerous ingredients that may cause cancer, heart attacks, strokes, and other ailments. For example, the FDA advised the public to avoid Slim Sense by Dr. Reade because it contains lorcaserin, which has been found to cause psychiatric disturbances and impairments in attention or memory. The FDA ordered it discontinued and the company couldn’t be reached for comment.
“Unscrupulous manufacturers are willing to take risks with consumers’ health – and they are lacing their products with illegal pharmaceuticals, banned pharmaceuticals, steroids, excessive stimulants, even experimental stimulants,” said S. Bryn Austin, ScD, founding director of the Strategic Training Initiative for the Prevention of Eating Disorders, or STRIPED, which supports the restrictions. “Consumers have no idea that this is what’s in these types of products.”
STRIPED is a public health initiative based at the Harvard School of Public Health, Boston, and Boston Children’s Hospital.
An industry trade group, the Natural Products Association, disputes that diet pills cause eating disorders, citing the lack of consumer complaints to the FDA of adverse events from their members’ products. “According to FDA data, there is no association between the two,” said Kyle Turk, the association’s director of government affairs.
The association contends that its members adhere to safe manufacturing processes, random product testing, and appropriate marketing guidelines. Representatives also worry that if minors can’t buy supplements over the counter, they may buy them from “crooks” on the black market and undermine the integrity of the industry. Under the bills, minors purchasing weight-loss products must show identification along with a prescription.
Not all business groups oppose the ban. The American Herbal Products Association, a trade group representing dietary supplement manufacturers and retailers, dropped its opposition to California’s bill once it was amended to remove ingredient categories that are found in non-diet supplements and vitamins, according to Robert Marriott, director of regulatory affairs.
Children’s advocates have found worrisome trends among young people who envision their ideal body type based on what they see on social media. According to a study commissioned by Fairplay, a nonprofit that seeks to stop harmful marketing practices targeting children, kids as young as 9 were found to be following three or more eating disorder accounts on Instagram, while the median age was 19. The authors called it a “pro–eating disorder bubble.”
Meta, which owns Instagram and Facebook, said the report lacks nuance, such as recognizing the human need to share life’s difficult moments. The company argues that blanket censorship isn’t the answer. “Experts and safety organizations have told us it’s important to strike a balance and allow people to share their personal stories while removing any content that encourages or promotes eating disorders,” Liza Crenshaw, a Meta spokesperson, said in an email.
Jason Nagata, MD, a pediatrician who cares for children and young adults with life-threatening eating disorders, believes that easy access to diet pills contributes to his patients’ conditions at UCSF Benioff Children’s Hospital in San Francisco. That was the case for one of his patients, an emaciated 11-year-old girl.
“She had basically entered a starvation state because she was not getting enough nutrition,” said Dr. Nagata, who provided supporting testimony for the California bill. “She was taking these pills and using other kinds of extreme behaviors to lose weight.”
Dr. Nagata said the number of patients he sees with eating disorders has tripled since the pandemic began. They are desperate to get diet pills, some with modest results. “We’ve had patients who have been so dependent on these products that they will be hospitalized and they’re still ordering these products on Amazon,” he said.
Public health advocates turned to state legislatures in response to the federal government’s limited authority to regulate diet pills. Under a 1994 federal law known as the Dietary Supplement Health and Education Act, the FDA “cannot step in until after there is a clear issue of harm to consumers,” said Dr. Austin.
No match for the supplement industry’s heavy lobbying on Capitol Hill, public health advocates shifted to a state-by-state approach.
There is, however, a push for the FDA to improve oversight of what goes into diet pills. Sen. Dick Durbin (D-Ill.) in April introduced a bill that would require dietary supplement manufacturers to register their products – along with the ingredients – with the regulator.
Proponents say the change is needed because manufacturers have been known to include dangerous ingredients. C. Michael White, PharmD, of the University of Connecticut, Storrs, found 35% of tainted health products came from weight-loss supplements in a review of a health fraud database.
A few ingredients have been banned, including sibutramine, a stimulant. “It was a very commonly used weight-loss supplement that ended up being removed from the U.S. market because of its elevated risk of causing things like heart attacks, strokes, and arrhythmias,” Dr. White said.
Another ingredient was phenolphthalein, which was used in laxatives until it was identified as a suspected carcinogen and banned in 1999. “To think,” he said, “that that product would still be on the U.S. market is just unconscionable.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
California and New York are on the cusp of going further than the Food and Drug Administration in restricting the sale of nonprescription diet pills to minors as pediatricians and public health advocates try to protect kids from extreme weight-loss gimmicks online.
A bill before Gov. Gavin Newsom would bar anyone under 18 in California from buying over-the-counter weight-loss supplements – whether online or in shops – without a prescription. A similar bill passed by New York lawmakers is on Gov. Kathy Hochul’s desk. Neither Democrat has indicated how he or she will act.
If both bills are signed into law, proponents hope the momentum will build to restrict diet pill sales to children in more states. Massachusetts, New Jersey, and Missouri have introduced similar bills and backers plan to continue their push next year.
Nearly 30 million people in the United States will have an eating disorder in their lifetime; 95% of them are aged between 12 and 25, according to Johns Hopkins All Children’s Hospital. The hospital added that eating disorders pose the highest risk of mortality of any mental health disorder. And it has become easier than ever for minors to get pills that are sold online or on drugstore shelves. All dietary supplements, which include those for weight loss, accounted for nearly 35% of the $63 billion over-the-counter health products industry in 2021, according to Vision Research Reports, a market research firm.
Dietary supplements, which encompass a broad range of vitamins, herbs, and minerals, are classified by the FDA as food and don’t undergo scientific and safety testing as prescription drugs and over-the-counter medicines do.
Public health advocates want to keep weight-loss products – with ads that may promise to “Drop 5 pounds a week!” and pill names like Slim Sense – away from young people, particularly girls, since some research has linked some products to eating disorders. A study in the American Journal of Public Health, which followed more than 10,000 women aged 14-36 over 15 years, found that “those who used diet pills had more than 5 times higher adjusted odds of receiving an eating disorder diagnosis from a health care provider within 1-3 years than those who did not.”
Many pills have been found tainted with banned and dangerous ingredients that may cause cancer, heart attacks, strokes, and other ailments. For example, the FDA advised the public to avoid Slim Sense by Dr. Reade because it contains lorcaserin, which has been found to cause psychiatric disturbances and impairments in attention or memory. The FDA ordered it discontinued and the company couldn’t be reached for comment.
“Unscrupulous manufacturers are willing to take risks with consumers’ health – and they are lacing their products with illegal pharmaceuticals, banned pharmaceuticals, steroids, excessive stimulants, even experimental stimulants,” said S. Bryn Austin, ScD, founding director of the Strategic Training Initiative for the Prevention of Eating Disorders, or STRIPED, which supports the restrictions. “Consumers have no idea that this is what’s in these types of products.”
STRIPED is a public health initiative based at the Harvard School of Public Health, Boston, and Boston Children’s Hospital.
An industry trade group, the Natural Products Association, disputes that diet pills cause eating disorders, citing the lack of consumer complaints to the FDA of adverse events from their members’ products. “According to FDA data, there is no association between the two,” said Kyle Turk, the association’s director of government affairs.
The association contends that its members adhere to safe manufacturing processes, random product testing, and appropriate marketing guidelines. Representatives also worry that if minors can’t buy supplements over the counter, they may buy them from “crooks” on the black market and undermine the integrity of the industry. Under the bills, minors purchasing weight-loss products must show identification along with a prescription.
Not all business groups oppose the ban. The American Herbal Products Association, a trade group representing dietary supplement manufacturers and retailers, dropped its opposition to California’s bill once it was amended to remove ingredient categories that are found in non-diet supplements and vitamins, according to Robert Marriott, director of regulatory affairs.
Children’s advocates have found worrisome trends among young people who envision their ideal body type based on what they see on social media. According to a study commissioned by Fairplay, a nonprofit that seeks to stop harmful marketing practices targeting children, kids as young as 9 were found to be following three or more eating disorder accounts on Instagram, while the median age was 19. The authors called it a “pro–eating disorder bubble.”
Meta, which owns Instagram and Facebook, said the report lacks nuance, such as recognizing the human need to share life’s difficult moments. The company argues that blanket censorship isn’t the answer. “Experts and safety organizations have told us it’s important to strike a balance and allow people to share their personal stories while removing any content that encourages or promotes eating disorders,” Liza Crenshaw, a Meta spokesperson, said in an email.
Jason Nagata, MD, a pediatrician who cares for children and young adults with life-threatening eating disorders, believes that easy access to diet pills contributes to his patients’ conditions at UCSF Benioff Children’s Hospital in San Francisco. That was the case for one of his patients, an emaciated 11-year-old girl.
“She had basically entered a starvation state because she was not getting enough nutrition,” said Dr. Nagata, who provided supporting testimony for the California bill. “She was taking these pills and using other kinds of extreme behaviors to lose weight.”
Dr. Nagata said the number of patients he sees with eating disorders has tripled since the pandemic began. They are desperate to get diet pills, some with modest results. “We’ve had patients who have been so dependent on these products that they will be hospitalized and they’re still ordering these products on Amazon,” he said.
Public health advocates turned to state legislatures in response to the federal government’s limited authority to regulate diet pills. Under a 1994 federal law known as the Dietary Supplement Health and Education Act, the FDA “cannot step in until after there is a clear issue of harm to consumers,” said Dr. Austin.
No match for the supplement industry’s heavy lobbying on Capitol Hill, public health advocates shifted to a state-by-state approach.
There is, however, a push for the FDA to improve oversight of what goes into diet pills. Sen. Dick Durbin (D-Ill.) in April introduced a bill that would require dietary supplement manufacturers to register their products – along with the ingredients – with the regulator.
Proponents say the change is needed because manufacturers have been known to include dangerous ingredients. C. Michael White, PharmD, of the University of Connecticut, Storrs, found 35% of tainted health products came from weight-loss supplements in a review of a health fraud database.
A few ingredients have been banned, including sibutramine, a stimulant. “It was a very commonly used weight-loss supplement that ended up being removed from the U.S. market because of its elevated risk of causing things like heart attacks, strokes, and arrhythmias,” Dr. White said.
Another ingredient was phenolphthalein, which was used in laxatives until it was identified as a suspected carcinogen and banned in 1999. “To think,” he said, “that that product would still be on the U.S. market is just unconscionable.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
California and New York are on the cusp of going further than the Food and Drug Administration in restricting the sale of nonprescription diet pills to minors as pediatricians and public health advocates try to protect kids from extreme weight-loss gimmicks online.
A bill before Gov. Gavin Newsom would bar anyone under 18 in California from buying over-the-counter weight-loss supplements – whether online or in shops – without a prescription. A similar bill passed by New York lawmakers is on Gov. Kathy Hochul’s desk. Neither Democrat has indicated how he or she will act.
If both bills are signed into law, proponents hope the momentum will build to restrict diet pill sales to children in more states. Massachusetts, New Jersey, and Missouri have introduced similar bills and backers plan to continue their push next year.
Nearly 30 million people in the United States will have an eating disorder in their lifetime; 95% of them are aged between 12 and 25, according to Johns Hopkins All Children’s Hospital. The hospital added that eating disorders pose the highest risk of mortality of any mental health disorder. And it has become easier than ever for minors to get pills that are sold online or on drugstore shelves. All dietary supplements, which include those for weight loss, accounted for nearly 35% of the $63 billion over-the-counter health products industry in 2021, according to Vision Research Reports, a market research firm.
Dietary supplements, which encompass a broad range of vitamins, herbs, and minerals, are classified by the FDA as food and don’t undergo scientific and safety testing as prescription drugs and over-the-counter medicines do.
Public health advocates want to keep weight-loss products – with ads that may promise to “Drop 5 pounds a week!” and pill names like Slim Sense – away from young people, particularly girls, since some research has linked some products to eating disorders. A study in the American Journal of Public Health, which followed more than 10,000 women aged 14-36 over 15 years, found that “those who used diet pills had more than 5 times higher adjusted odds of receiving an eating disorder diagnosis from a health care provider within 1-3 years than those who did not.”
Many pills have been found tainted with banned and dangerous ingredients that may cause cancer, heart attacks, strokes, and other ailments. For example, the FDA advised the public to avoid Slim Sense by Dr. Reade because it contains lorcaserin, which has been found to cause psychiatric disturbances and impairments in attention or memory. The FDA ordered it discontinued and the company couldn’t be reached for comment.
“Unscrupulous manufacturers are willing to take risks with consumers’ health – and they are lacing their products with illegal pharmaceuticals, banned pharmaceuticals, steroids, excessive stimulants, even experimental stimulants,” said S. Bryn Austin, ScD, founding director of the Strategic Training Initiative for the Prevention of Eating Disorders, or STRIPED, which supports the restrictions. “Consumers have no idea that this is what’s in these types of products.”
STRIPED is a public health initiative based at the Harvard School of Public Health, Boston, and Boston Children’s Hospital.
An industry trade group, the Natural Products Association, disputes that diet pills cause eating disorders, citing the lack of consumer complaints to the FDA of adverse events from their members’ products. “According to FDA data, there is no association between the two,” said Kyle Turk, the association’s director of government affairs.
The association contends that its members adhere to safe manufacturing processes, random product testing, and appropriate marketing guidelines. Representatives also worry that if minors can’t buy supplements over the counter, they may buy them from “crooks” on the black market and undermine the integrity of the industry. Under the bills, minors purchasing weight-loss products must show identification along with a prescription.
Not all business groups oppose the ban. The American Herbal Products Association, a trade group representing dietary supplement manufacturers and retailers, dropped its opposition to California’s bill once it was amended to remove ingredient categories that are found in non-diet supplements and vitamins, according to Robert Marriott, director of regulatory affairs.
Children’s advocates have found worrisome trends among young people who envision their ideal body type based on what they see on social media. According to a study commissioned by Fairplay, a nonprofit that seeks to stop harmful marketing practices targeting children, kids as young as 9 were found to be following three or more eating disorder accounts on Instagram, while the median age was 19. The authors called it a “pro–eating disorder bubble.”
Meta, which owns Instagram and Facebook, said the report lacks nuance, such as recognizing the human need to share life’s difficult moments. The company argues that blanket censorship isn’t the answer. “Experts and safety organizations have told us it’s important to strike a balance and allow people to share their personal stories while removing any content that encourages or promotes eating disorders,” Liza Crenshaw, a Meta spokesperson, said in an email.
Jason Nagata, MD, a pediatrician who cares for children and young adults with life-threatening eating disorders, believes that easy access to diet pills contributes to his patients’ conditions at UCSF Benioff Children’s Hospital in San Francisco. That was the case for one of his patients, an emaciated 11-year-old girl.
“She had basically entered a starvation state because she was not getting enough nutrition,” said Dr. Nagata, who provided supporting testimony for the California bill. “She was taking these pills and using other kinds of extreme behaviors to lose weight.”
Dr. Nagata said the number of patients he sees with eating disorders has tripled since the pandemic began. They are desperate to get diet pills, some with modest results. “We’ve had patients who have been so dependent on these products that they will be hospitalized and they’re still ordering these products on Amazon,” he said.
Public health advocates turned to state legislatures in response to the federal government’s limited authority to regulate diet pills. Under a 1994 federal law known as the Dietary Supplement Health and Education Act, the FDA “cannot step in until after there is a clear issue of harm to consumers,” said Dr. Austin.
No match for the supplement industry’s heavy lobbying on Capitol Hill, public health advocates shifted to a state-by-state approach.
There is, however, a push for the FDA to improve oversight of what goes into diet pills. Sen. Dick Durbin (D-Ill.) in April introduced a bill that would require dietary supplement manufacturers to register their products – along with the ingredients – with the regulator.
Proponents say the change is needed because manufacturers have been known to include dangerous ingredients. C. Michael White, PharmD, of the University of Connecticut, Storrs, found 35% of tainted health products came from weight-loss supplements in a review of a health fraud database.
A few ingredients have been banned, including sibutramine, a stimulant. “It was a very commonly used weight-loss supplement that ended up being removed from the U.S. market because of its elevated risk of causing things like heart attacks, strokes, and arrhythmias,” Dr. White said.
Another ingredient was phenolphthalein, which was used in laxatives until it was identified as a suspected carcinogen and banned in 1999. “To think,” he said, “that that product would still be on the U.S. market is just unconscionable.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
New ESC guidelines for cutting CV risk in noncardiac surgery
The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.
They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.
Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.
The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).
It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.
In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:
First, recommendations for preoperative ECG and biomarkers are more specific, he noted.
The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:
- It is recommended to obtain a preoperative 12-lead ECG (class I).
- It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
- It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).
However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).
Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.
Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”
Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”
“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
More preoperative recommendations
In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.
If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).
Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).
“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “
“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
Patients with specific types of CVD
Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.
Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”
“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”
Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).
Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).
Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”
Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”
Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
Postoperative cardiovascular complications
The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.
“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”
“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.
The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”
Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.
“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”
In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).
Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.
The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.
The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
Noncardiac surgery risk categories
The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:
- Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
- Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
- High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.
The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.
A version of this article first appeared on Medscape.com.
The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.
They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.
Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.
The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).
It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.
In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:
First, recommendations for preoperative ECG and biomarkers are more specific, he noted.
The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:
- It is recommended to obtain a preoperative 12-lead ECG (class I).
- It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
- It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).
However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).
Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.
Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”
Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”
“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
More preoperative recommendations
In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.
If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).
Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).
“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “
“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
Patients with specific types of CVD
Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.
Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”
“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”
Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).
Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).
Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”
Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”
Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
Postoperative cardiovascular complications
The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.
“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”
“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.
The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”
Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.
“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”
In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).
Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.
The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.
The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
Noncardiac surgery risk categories
The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:
- Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
- Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
- High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.
The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.
A version of this article first appeared on Medscape.com.
The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.
They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.
Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.
The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).
It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.
In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:
First, recommendations for preoperative ECG and biomarkers are more specific, he noted.
The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:
- It is recommended to obtain a preoperative 12-lead ECG (class I).
- It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
- It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).
However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).
Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.
Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”
Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”
“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
More preoperative recommendations
In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.
If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).
Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).
“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “
“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
Patients with specific types of CVD
Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.
Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”
“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”
Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).
Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).
Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”
Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”
Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
Postoperative cardiovascular complications
The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.
“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”
“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.
The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”
Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.
“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”
In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).
Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.
The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.
The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
Noncardiac surgery risk categories
The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:
- Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
- Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
- High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.
The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
Artificial sweeteners linked to higher CV event risk
Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.
In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.
The study was published online in the BMJ.
The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.
“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.
Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.
“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.
“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.
“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”
But another leading researcher in the field urges caution in interpreting these results.
John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.
“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
Risk increased by 9%
The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.
Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).
The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.
“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.
“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.
The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.
Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
Study strengths
Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.
And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.
Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.
“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”
Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.
“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
Different artificial sweeteners may be better?
Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.
“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.
Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.
“The comparator matters as no food is consumed in a vacuum,” he said.
To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.
On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.
“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.
His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.
“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.
The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.
In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.
The study was published online in the BMJ.
The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.
“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.
Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.
“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.
“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.
“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”
But another leading researcher in the field urges caution in interpreting these results.
John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.
“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
Risk increased by 9%
The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.
Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).
The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.
“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.
“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.
The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.
Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
Study strengths
Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.
And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.
Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.
“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”
Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.
“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
Different artificial sweeteners may be better?
Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.
“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.
Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.
“The comparator matters as no food is consumed in a vacuum,” he said.
To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.
On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.
“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.
His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.
“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.
The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.
In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.
The study was published online in the BMJ.
The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.
“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.
Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.
“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.
“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.
“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”
But another leading researcher in the field urges caution in interpreting these results.
John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.
“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
Risk increased by 9%
The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.
Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).
The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.
“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.
“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.
The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.
Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
Study strengths
Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.
And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.
Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.
“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”
Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.
“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
Different artificial sweeteners may be better?
Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.
“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.
Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.
“The comparator matters as no food is consumed in a vacuum,” he said.
To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.
On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.
“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.
His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.
“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.
The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ
Warfarin associated with higher upper GI bleeding rates, compared with DOACs
Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.
In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.
“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.
“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.
“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing bleed rates
Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.
Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.
Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.
In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.
Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.
Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.
Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.
“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.
Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.
“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
Considering future research
In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.
“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.
Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.
In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.
“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”
Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.
“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”
The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.
In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.
“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.
“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.
“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing bleed rates
Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.
Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.
Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.
In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.
Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.
Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.
Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.
“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.
Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.
“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
Considering future research
In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.
“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.
Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.
In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.
“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”
Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.
“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”
The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.
In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.
“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.
“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.
“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.
The study was published online in Clinical Gastroenterology and Hepatology.
Analyzing bleed rates
Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.
Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.
Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.
In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.
Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.
Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.
Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.
“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.
Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.
“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
Considering future research
In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.
“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.
Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.
In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.
“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”
Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.
“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”
The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Influenza vaccine may offer much more than flu prevention
in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.
“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.
“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”
The study was published online in Neurology.
‘Not a spurious association’
While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.
In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.
Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).
Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).
Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).
The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.
The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.
Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).
“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
Anti-inflammatory effect?
Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.
The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.
“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.
In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.
“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
‘More than just flu prevention’
In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.
“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.
Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.
“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”
Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”
The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.
A version of this article first appeared on Medscape.com.
in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.
“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.
“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”
The study was published online in Neurology.
‘Not a spurious association’
While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.
In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.
Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).
Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).
Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).
The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.
The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.
Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).
“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
Anti-inflammatory effect?
Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.
The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.
“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.
In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.
“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
‘More than just flu prevention’
In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.
“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.
Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.
“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”
Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”
The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.
A version of this article first appeared on Medscape.com.
in new findings that suggest the vaccine itself, and not just avoidance of the virus, may be beneficial.
“We postulate that influenza vaccination may have a protective effect against stroke that may be partly independent of influenza prevention,” study investigator Francisco J. de Abajo, MD, PhD, MPH, of the University of Alcalá, Madrid, said in an interview.
“Although the study is observational and this finding can also be explained by unmeasured confounding factors, we feel that a direct biological effect of vaccine cannot be ruled out and this finding opens new avenues for investigation.”
The study was published online in Neurology.
‘Not a spurious association’
While there is a well-established link between seasonal influenza and increased ischemic stroke risk, the role of flu vaccination in stroke prevention is unclear.
In the nested case-control study, researchers evaluated data from primary care practices in Spain between 2001 and 2015. They identified 14,322 patients with first-time ischemic stroke. Of these, 9,542 had noncardioembolic stroke and 4,780 had cardioembolic stroke.
Each case was matched with five controls from the population of age- and sex-matched controls without stroke (n = 71,610).
Those in the stroke group had a slightly higher rate of flu vaccination than controls, at 41.4% versus 40.5% (odds ratio, 1.05).
Adjusted analysis revealed those who received flu vaccination were less likely to experience ischemic stroke within 15-30 days of vaccination (OR, 0.79) and, to a lesser degree, over up to 150 days (OR, 0.92).
The reduced risk associated with the flu vaccine was observed with both types of ischemic stroke and appeared to offer stroke protection outside of flu season.
The reduced risk was also found in subgroup comparisons in men, women, those aged over and under 65 years, and those with intermediate and high vascular risk.
Importantly, a separate analysis of pneumococcal vaccination did not show a similar reduction in stroke risk (adjusted OR, 1.08).
“The lack of protection found with the pneumococcal vaccine actually reinforces the hypothesis that the protection of influenza vaccine is not a spurious association, as both vaccines might share the same biases and confounding factors,” Dr. de Abajo said.
Anti-inflammatory effect?
Influenza infection is known to induce a systemic inflammatory response that “can precipitate atheroma plaque rupture mediated by elevated concentrations of reactive proteins and cytokines,” the investigators noted, and so, avoiding infection could prevent those effects.
The results are consistent with other studies that have shown similar findings, including recent data from the INTERSTROKE trial. However, the reduced risk observed in the current study even in years without a flu epidemic expands on previous findings.
“This finding suggests that other mechanisms different from the prevention of influenza infection – e.g., a direct biological effect – could account for the risk reduction found,” the investigators wrote.
In terms of the nature of that effect, Dr. de Abajo noted that, “at this stage, we can only speculate.
“Having said that, there are some pieces of evidence that suggest influenza vaccination may release anti-inflammatory mediators that can stabilize the atheroma plaque. This is an interesting hypothesis that should be addressed in the near future,” he added.
‘More than just flu prevention’
In an accompanying editorial, Dixon Yang, MD, and Mitchell S.V. Elkind, MD, agree that the findings point to intriguing potential unexpected benefits of the vaccine.
“This case-control study ... importantly suggests the influenza vaccine is more than just about preventing the flu,” they wrote.
Dr. Elkind said in an interview that the mechanism could indeed involve an anti-inflammatory effect.
“There is some evidence that antibiotics also have anti-inflammatory properties that might reduce risk of stroke or the brain damage from a stroke,” he noted. “So, it is plausible that some of the effect of the vaccine on reducing risk of stroke may be through a reduction in inflammation.”
Dr. Elkind noted that the magnitude of the reduction observed with the vaccine, though not substantial, is important. “The magnitude of effect for any one individual may be modest, but it is in the ballpark of the effect of other commonly used approaches to stroke prevention, such as taking an aspirin a day, which reduces risk of stroke by about 20%. But because influenza is so common, the impact of even a small effect for an individual can have a large impact at the population level. So, the results are of public health significance.”
The study received support from the Biomedical Research Foundation of the Prince of Asturias University Hospital and the Institute of Health Carlos III in Madrid. Dr. Elkind has reported receiving ancillary funding but no personal compensation from Roche for a federally funded trial of stroke prevention.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Low physical function tied to cardiac events in older adults
including coronary heart disease (CHD), stroke, and heart failure (HF) in older adults, according to new observational data from the Atherosclerosis Risk in Communities (ARIC) study.
“We found that physical function in older adults predicts future cardiovascular disease (CVD) beyond traditional heart disease risk factors, regardless of whether an individual has a history of cardiovascular disease,” senior author Kunihiro Matsushita, MD, PhD, division of cardiology, Johns Hopkins University, Baltimore, said in a news release.
The study was published online in the Journal of the American Heart Association.
Keeping fit with age
The researchers analyzed health data collected between 2011 and 2013 for 5,570 ARIC participants (mean age, 75 years; 58% women, 22% Black persons). They assessed physical function using the Short Physical Performance Battery (SPPB), which measures walking speed, leg strength, and balance.
On the basis of the results, participants were categorized into three physical function groups: low (score, 0-6; 13% of the cohort), intermediate (score, 7-9; 30%) and high (score, 10-12; 57%).
During a median follow up of 7 years, there were 930 composite CVD events (386 CHD, 251 stroke, and 529 HF).
Adults with lower SPPB scores had a higher cumulative incidence of composite CVD outcomes.
The 5-year cumulative incidence of the composite CVD outcome in the low- and intermediate-SPPB categories was about three times (23.4%) and two times (15.3%) higher than in the high-SPPB category (8.6%), the researchers reported.
In addition, continuous SPPB scores showed significant associations with composite and individual CVD outcomes in all models. A 1-point lower SPPB score was associated with 6%-10% higher risk for CVD events after adjusting for potential confounders.
In the fully adjusted model, the risk for composite CVD outcomes was 47% higher (hazard ratio, 1.47; 95% confidence interval, 1.20-1.79) in those with low physical function and 25% higher in those with intermediate physical function (HR, 1.25; 95% CI, 1.07-1.46) compared with peers with high physical function.
For the individual outcomes, low physical function was associated with higher risk for stroke (HR, 1.81; 95% CI, 1.24-2.64) and HF (HR, 1.33; 95% CI, 1.02-1.73), whereas the association for CHD was not significant.
The associations were largely consistent across subgroups, including those with CVD at baseline.
The addition of SPPB scores significantly improved risk prediction of CVD events beyond traditional CVD risk factors in adults regardless of prior CVD history, suggesting that this tool may be useful for classifying CVD risk in older adults, the researchers said.
Meaningful impact on care?
“Our findings highlight the value of assessing the physical function level of older adults in clinical practice,” lead author Xiao Hu, MHS, with the department of epidemiology at Johns Hopkins, said in the news release. “In addition to heart health, older adults are at higher risk for falls and disability. The assessment of physical function may also inform the risk of these concerning conditions in older adults.”
Weighing in on the study, Jonathan Halperin, MD, cardiologist at Mount Sinai Heart and professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai, both in New York, said that “It’s known that cardiorespiratory fitness is an important predictor of cardiovascular risk, but it is one of the few physiological risk factors that are subjectively queried but not objectively assessed in routine clinical practice.”
In this study, Dr. Halperin noted, the investigators found that a battery of physical performance assessments, including a walk test, chair standing, and balance testing, improved cardiovascular risk prediction.
Dr. Halperin cautioned, however, that “since even the short sequence of tests takes time to perform and interpret, and is not currently reimbursed under most health insurance policies, it is not clear whether the report will have a meaningful impact on patient care.”
This research was funded by the National Institutes of Health. Dr. Matsushita and Dr. Halperin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
including coronary heart disease (CHD), stroke, and heart failure (HF) in older adults, according to new observational data from the Atherosclerosis Risk in Communities (ARIC) study.
“We found that physical function in older adults predicts future cardiovascular disease (CVD) beyond traditional heart disease risk factors, regardless of whether an individual has a history of cardiovascular disease,” senior author Kunihiro Matsushita, MD, PhD, division of cardiology, Johns Hopkins University, Baltimore, said in a news release.
The study was published online in the Journal of the American Heart Association.
Keeping fit with age
The researchers analyzed health data collected between 2011 and 2013 for 5,570 ARIC participants (mean age, 75 years; 58% women, 22% Black persons). They assessed physical function using the Short Physical Performance Battery (SPPB), which measures walking speed, leg strength, and balance.
On the basis of the results, participants were categorized into three physical function groups: low (score, 0-6; 13% of the cohort), intermediate (score, 7-9; 30%) and high (score, 10-12; 57%).
During a median follow up of 7 years, there were 930 composite CVD events (386 CHD, 251 stroke, and 529 HF).
Adults with lower SPPB scores had a higher cumulative incidence of composite CVD outcomes.
The 5-year cumulative incidence of the composite CVD outcome in the low- and intermediate-SPPB categories was about three times (23.4%) and two times (15.3%) higher than in the high-SPPB category (8.6%), the researchers reported.
In addition, continuous SPPB scores showed significant associations with composite and individual CVD outcomes in all models. A 1-point lower SPPB score was associated with 6%-10% higher risk for CVD events after adjusting for potential confounders.
In the fully adjusted model, the risk for composite CVD outcomes was 47% higher (hazard ratio, 1.47; 95% confidence interval, 1.20-1.79) in those with low physical function and 25% higher in those with intermediate physical function (HR, 1.25; 95% CI, 1.07-1.46) compared with peers with high physical function.
For the individual outcomes, low physical function was associated with higher risk for stroke (HR, 1.81; 95% CI, 1.24-2.64) and HF (HR, 1.33; 95% CI, 1.02-1.73), whereas the association for CHD was not significant.
The associations were largely consistent across subgroups, including those with CVD at baseline.
The addition of SPPB scores significantly improved risk prediction of CVD events beyond traditional CVD risk factors in adults regardless of prior CVD history, suggesting that this tool may be useful for classifying CVD risk in older adults, the researchers said.
Meaningful impact on care?
“Our findings highlight the value of assessing the physical function level of older adults in clinical practice,” lead author Xiao Hu, MHS, with the department of epidemiology at Johns Hopkins, said in the news release. “In addition to heart health, older adults are at higher risk for falls and disability. The assessment of physical function may also inform the risk of these concerning conditions in older adults.”
Weighing in on the study, Jonathan Halperin, MD, cardiologist at Mount Sinai Heart and professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai, both in New York, said that “It’s known that cardiorespiratory fitness is an important predictor of cardiovascular risk, but it is one of the few physiological risk factors that are subjectively queried but not objectively assessed in routine clinical practice.”
In this study, Dr. Halperin noted, the investigators found that a battery of physical performance assessments, including a walk test, chair standing, and balance testing, improved cardiovascular risk prediction.
Dr. Halperin cautioned, however, that “since even the short sequence of tests takes time to perform and interpret, and is not currently reimbursed under most health insurance policies, it is not clear whether the report will have a meaningful impact on patient care.”
This research was funded by the National Institutes of Health. Dr. Matsushita and Dr. Halperin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
including coronary heart disease (CHD), stroke, and heart failure (HF) in older adults, according to new observational data from the Atherosclerosis Risk in Communities (ARIC) study.
“We found that physical function in older adults predicts future cardiovascular disease (CVD) beyond traditional heart disease risk factors, regardless of whether an individual has a history of cardiovascular disease,” senior author Kunihiro Matsushita, MD, PhD, division of cardiology, Johns Hopkins University, Baltimore, said in a news release.
The study was published online in the Journal of the American Heart Association.
Keeping fit with age
The researchers analyzed health data collected between 2011 and 2013 for 5,570 ARIC participants (mean age, 75 years; 58% women, 22% Black persons). They assessed physical function using the Short Physical Performance Battery (SPPB), which measures walking speed, leg strength, and balance.
On the basis of the results, participants were categorized into three physical function groups: low (score, 0-6; 13% of the cohort), intermediate (score, 7-9; 30%) and high (score, 10-12; 57%).
During a median follow up of 7 years, there were 930 composite CVD events (386 CHD, 251 stroke, and 529 HF).
Adults with lower SPPB scores had a higher cumulative incidence of composite CVD outcomes.
The 5-year cumulative incidence of the composite CVD outcome in the low- and intermediate-SPPB categories was about three times (23.4%) and two times (15.3%) higher than in the high-SPPB category (8.6%), the researchers reported.
In addition, continuous SPPB scores showed significant associations with composite and individual CVD outcomes in all models. A 1-point lower SPPB score was associated with 6%-10% higher risk for CVD events after adjusting for potential confounders.
In the fully adjusted model, the risk for composite CVD outcomes was 47% higher (hazard ratio, 1.47; 95% confidence interval, 1.20-1.79) in those with low physical function and 25% higher in those with intermediate physical function (HR, 1.25; 95% CI, 1.07-1.46) compared with peers with high physical function.
For the individual outcomes, low physical function was associated with higher risk for stroke (HR, 1.81; 95% CI, 1.24-2.64) and HF (HR, 1.33; 95% CI, 1.02-1.73), whereas the association for CHD was not significant.
The associations were largely consistent across subgroups, including those with CVD at baseline.
The addition of SPPB scores significantly improved risk prediction of CVD events beyond traditional CVD risk factors in adults regardless of prior CVD history, suggesting that this tool may be useful for classifying CVD risk in older adults, the researchers said.
Meaningful impact on care?
“Our findings highlight the value of assessing the physical function level of older adults in clinical practice,” lead author Xiao Hu, MHS, with the department of epidemiology at Johns Hopkins, said in the news release. “In addition to heart health, older adults are at higher risk for falls and disability. The assessment of physical function may also inform the risk of these concerning conditions in older adults.”
Weighing in on the study, Jonathan Halperin, MD, cardiologist at Mount Sinai Heart and professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai, both in New York, said that “It’s known that cardiorespiratory fitness is an important predictor of cardiovascular risk, but it is one of the few physiological risk factors that are subjectively queried but not objectively assessed in routine clinical practice.”
In this study, Dr. Halperin noted, the investigators found that a battery of physical performance assessments, including a walk test, chair standing, and balance testing, improved cardiovascular risk prediction.
Dr. Halperin cautioned, however, that “since even the short sequence of tests takes time to perform and interpret, and is not currently reimbursed under most health insurance policies, it is not clear whether the report will have a meaningful impact on patient care.”
This research was funded by the National Institutes of Health. Dr. Matsushita and Dr. Halperin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Blood type linked to higher risk for early onset stroke
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
Conversely, results from a meta-analysis of nearly 17,000 cases of ischemic stroke in adults younger than 60 years showed that having type O blood reduced the risk for EOS by 12%.
In addition, the associations with risk were significantly stronger in EOS than in those with late-onset stroke (LOS), pointing to a stronger role for prothrombotic factors in younger patients, the researchers noted.
“What this is telling us is that maybe what makes you susceptible to stroke as a young adult is the blood type, which is really giving you a much higher risk of clotting and stroke compared to later onset,” coinvestigator Braxton Mitchell, PhD, professor of medicine and epidemiology and public health at the University of Maryland, Baltimore, said in an interview.
The findings were published online in Neurology.
Strong association
The genome-wide association study (GWAS) was done as part of the Genetics of Early Onset Ischemic Stroke Consortium, a collaboration of 48 different studies across North America, Europe, Japan, Pakistan, and Australia. It assessed early onset ischemic stroke in patients aged 18-59 years.
Researchers included data from 16,927 patients with stroke. Of these, 5,825 had a stroke before age 60, defined as early onset. GWAS results were also examined for nearly 600,000 individuals without stroke.
Results showed two genetic variants tied to blood types A and O emerged as highly associated with risk for early stroke.
Researchers found that the protective effects of type O were significantly stronger with EOS vs. LOS (odds ratio [OR], 0.88 vs. 0.96, respectively; P = .001). Likewise, the association between type A and increased EOS risk was significantly stronger than that found in LOS (OR, 1.16 vs. 1.05; P = .005).
Using polygenic risk scores, the investigators also found that the greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared with LOS (P = .008).
Previous studies have shown a link between stroke risk and variants of the ABO gene, which determines blood type. The new analysis suggests that type A and O gene variants represent nearly all of those genetically linked with early stroke, the researchers noted.
While the findings point to blood type as a risk factor for stroke in younger people, Dr. Mitchell cautions that “at the moment, blood group does not have implications for preventive care.”
“The risk of stroke due to blood type is smaller than other risk factors that we know about, like smoking and hypertension,” he said. “I would be much more worried about these other risk factors, especially because those may be modifiable.”
He noted the next step in the study is to assess how blood type interacts with other known risk factors to raise stroke risk.
“There may be a subset of people where, if you have blood type A and you have some of these other risk factors, it’s possible that you may be at particularly high risk,” Dr. Mitchell said.
More research needed on younger patients
In an accompanying editorial, Jennifer Juhl Majersik, MD, associate professor of neurology at the University of Utah, Salt Lake City, and Paul Lacaze, PhD, associate professor and head of the public health genomics program at Monash University, Australia, noted that the study fills a gap in stroke research, which often focuses mostly on older individuals.
“In approximately 40% of people with EOS, the stroke is cryptogenic, and there is scant data from clinical trials to guide the selection of preventative strategies in this population, as people with EOS are often excluded from trials,” Dr. Majersik and Dr. Lacaze wrote.
“This work has deepened our understanding of EOS pathophysiology,” they added.
The editorialists noted that future research can build on the results from this analysis, “with the goal of a more precise understanding of stroke pathophysiology, leading to targeted preventative treatments for EOS and a reduction in disability in patients’ most productive years.”
Dr. Mitchell echoed the call for greater inclusion of young patients with stroke in clinical trials.
“As we’re learning, stroke in older folks isn’t the same as stroke in younger people,” he said. “There are many shared risk factors but there are also some that are different ... so there really is a need to include younger people.”
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Rivaroxaban outmatched by VKAs for AFib in rheumatic heart disease
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
AXIOMATIC-SSP: Cautious optimism on factor XI inhibitor in stroke
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022