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Supermarket diet advice improves DASH adherence: SuperWIN
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
People who received personalized nutrition education in a series of sessions at their regular grocery store significantly improved adherence to a healthy diet, in a new “first-of-its-kind” study in which scientific researchers partnered with a large supermarket company.
In the SuperWIN study, participants were given individualized advice from supermarket-based dietitians using data on their own buying habits recorded on their supermarket loyalty cards. This was associated with an increased adherence to the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes vegetables, fruits and whole grains while limiting foods that are high in saturated fat, sugar, and sodium and has been shown to lower blood pressure and LDL cholesterol.
One group of patients also received additional education about healthy eating and meal planning through online technologies, and this group showed even better adherence to the DASH diet.
The study was presented at the annual scientific sessions of the American College of Cardiology by Dylan Steen, MD, adjunct associate professor of medicine at the University of Cincinnati.
“The SuperWIN study provides evidence for the benefit of delivering healthy-eating interventions at modern supermarkets and retail-based clinics,” Dr. Steen said. “It demonstrates the efficacy of dietary interventions harnessing the physical environment of the supermarket, the retail-based dietitians working within the store, and the purchasing data captured on the store’s loyalty cards.”
The study was conducted in partnership with Kroger, the largest supermarket chain in the United States, which also operates a large chain of pharmacies and health clinics.
Dr. Steen said the study was addressing one of the biggest public health problems – unhealthy eating – with an innovative approach. “We need to think about how we can extend the reach of modern health care systems into communities and better deliver services right where people are; meet them where they live,” he said at an ACC press conference.
Commenting on the study at the press conference, Eileen Handberg, PhD, professor of medicine at University of Florida, Gainesville, and immediate past chair of the ACC Cardiovascular Care Team Council, said: “I am amazingly excited about this. There is so much potential here. We have never really taken advantage of the current explosion in retail-based health care before.”
Dr. Handberg suggested the study had major implications for the primary prevention of cardiovascular disease. “Little kids go shopping with their parents, so you have the ability here to change behavior from children on up if you can change the dynamic of the choices they make in the grocery store.”
In his presentation, Dr. Steen noted that, despite many longstanding guidelines on healthy eating, about 75% of Americans still have a poor-quality diet. This trial was conducted to see if a new approach could improve that situation. “If we change the environment in which we deliver dietary education, we can make a difference.”
The SuperWIN trial was conducted in 13 Kroger stores in Ohio and Kentucky. The study enrolled 267 people with at least one cardiovascular risk factor from a primary care network who regularly shopped at one of the study stores. All participants also had to be willing to follow the DASH diet, which was taught at each educational session in the trial.
All participants received one “enhanced” medical nutrition therapy that was guided by the individual’s own dietary intake analytics.
They were then randomly assigned to one of three arms. The control group received no further education. The strategy 1 group received six additional teaching sessions in the supermarket aisles over a 3-month period. Each session was guided by updated individualized purchasing data provided to the dietitian and the participant.
The strategy 2 group received the same six additional teaching sessions as strategy 1, but they also had some additional teaching on healthy eating and meal planning from a variety of online shopping tools, and nutrition and health care apps.
“The supermarket analytics were automatically collected so the dietitians could tell what each person liked to eat, how much of each product they were buying and how much they were spending,” Dr. Steen explained.
COVID hit halfway through the trial, and 20 participants were withdrawn for their own safety as they could no longer visit the stores, but the trial continued with the rest of the participants with enhanced safety precautions. The overall analysis cohort was 247 participants.
The average age of the participants was mid-50s, around 70% were female, and most did not have a history of cardiovascular disease.
Eating habits were assessed by three 24-hour dietary recalls assessed at the start of the study and at 3 and 6 months. The DASH score, which is a measure of adherence to the DASH diet, was calculated from this information. The score can range from 0 to 90, with an increased score showing increased adherence.
In one analysis, the researchers compared the DASH scores from the two intervention groups together with the control group, and in a second analysis they compared the scores in the strategy 2 group with those in the strategy 1 group.
Before the pandemic there was “near 100%” attendance for the six visits over the 3-month study period, which Dr. Steen said he thought was “remarkable.” During the pandemic, attendance came down to around 80%.
Results showed that the DASH score increased in all three groups at 3 months, with stepwise increases corresponding to the intensity of the intervention. DASH scores increased by 5.8 points in the control group, by 8.6 points in the strategy 1 group, and by 12.4 points in the strategy 2 group.
DASH scores significantly differed between the two intervention groups and the control group (P = .02). “This shows that purchasing data–guided in-store tours do increase the efficacy of dietary education,” Dr. Steen said.
The difference in scores between the strategy 1 and strategy 2 groups was also significant (P = .01). “This shows online enhancements increase adherence to the DASH diet even further,” Dr. Steen commented
By 6 months, the scores had dropped off a little but were still increased from baseline: by 4.4 points in the control group, 6.6 points in the strategy 1 group, and 8.4 points in the strategy 2 group. “There was again a stepwise increase as the intervention intensified, but there was no longer a significant difference between the interventions and control,” Dr. Steen noted.
Secondary endpoints included blood pressure and body mass index. Systolic blood pressure decreased slightly in all three groups: by 2.8 mm Hg in the control group, 6.6 mm Hg in the strategy 1 group, and 5.7 mm Hg in the strategy 2 group. Body mass index was reduced by 0.2, 0.4 and 0.8, respectively, but the between-group differences were not significant.
Dr. Steen said this is the first study of its kind to date in which scientific researchers collaborated with a large supermarket chain. He explained they also involved a primary care network so that health care utilization information will be available.
“We can the integrate retail-based health care information with traditional health care information. And we can start to look at downstream health care utilization and cost outcomes as well, which will be important as we start to think how to evolve the health care system,” he commented. “The hope is that we can get more scientists working with more retailers to really drive the evidence to shape the evolution of our health care system.”
Challenges ahead
Dr. Handberg pointed out there would be challenges in reaching the underserved population who do not shop at the major supermarkets. “We need to figure out how to get partnerships across the whole spectrum of grocery stores.”
She also noted that 3 months (the duration of the study intervention) was not much time to change the eating habits of a family. “Interventions may have to be a bit more intensive to get the change in blood pressure and weight that we would want to see.”
Dr Handberg hoped the major grocery store companies will see the opportunities in this approach. “Changing behavior is very complicated, and the key will be how to make people stick with the changes. But grocery stores are smart. They have got us going to their pharmacies, so getting us to see a dietitian is not that much of a stretch.”
Moderator of the ACC late-breaker session at which the study was presented, Pamela Morris, MD, from the Medical University of South Carolina, Charleston, who is also ACC annual scientific session chair, asked whether the approach could be sustained.
“I am thinking back to the barber shop study of blood pressure treatment and to my knowledge those PharmDs are no longer in those barbershops, taking blood pressures, counseling patients, and prescribing antihypertensives. So is Kroger maintaining a long-term commitment to providing this education, or how can this be financed over the long term?” she asked.
Dr. Steen replied that he believed sustainability to be one of the key strengths of this model. “Retail-based health care is exploding in the U.S. The number of retail outlets offering a comprehensive list of services is going up all the time. These programs exist regardless of whether this trial was conducted or not.”
But Dr. Steen stressed that having an evidence base will be critically important.
“Validation is an enormous part of this evolution in retail-based health care – not only to figure out what works but also to engage payors and others in the process of supporting these interventions. I think the sustainability is there – it is sort of baked into the model – but research will be a huge part of cementing this in and helping us to understand what we should do.”
The study was funded by Kroger. Dr. Steen is a consultant for Sanofi and CEO and cofounder of High Enroll.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
Novel cholesterol drug disappoints: TRANSLATE-TIMI 70
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
An investigational drug targeting a novel cholesterol pathway has shown disappointing results in the TRANSLATE-TIMI 70 phase 2b study.
Vupanorsen is an antisense oligonucleotide targeting hepatic angiopoietin-like protein 3 (ANGPTL3), a protein that inhibits enzymes involved in the metabolism of triglyceride and cholesterol. Inhibition of ANGPTL3 is one of several novel targets for lowering triglycerides and non-HDL cholesterol.
Results of the TRANSLATE-TIMI 70 study were presented at the annual scientific sessions of the American College of Cardiology by Brian Bergmark, MD, a cardiologist at Brigham and Women’s Hospital, Boston. They were also simultaneously published online in Circulation.
“While vupanorsen significantly reduced triglycerides and non-HDL cholesterol, the reduction in non-HDL cholesterol of 22%-27% was not to a degree that was clinically meaningful for cardiovascular risk reduction, and there were also some potentially important safety issues,” Dr. Bergmark said in an interview.
Pfizer has announced that, after reviewing the results of this study, it is discontinuing development of vupanorsen and will return rights to Ionis, from which it licensed the investigational therapy in 2019.
In response to a question at an ACC press conference on whether there could be any future for the drug, Dr. Bergmark said that “the degree of lipid lowering was not as much as what had been suggested was potentially possible by acting on this pathway, and then there are the additional safety concerns. So, for the specific question of what we were looking at – cardiovascular risk reduction by impacting non-HDL cholesterol and apo [apolipoprotein] B – the modest efficacy paired with the safety concerns does not look favorable for future development of this drug.”
But he added: “Whether some other person or company wants to think about triglyceride lowering and try to find a dose that is a bit safer, that is not for me to say.”
In his ACC presentation, Dr. Bergmark explained that ANGPTL3 is a protein secreted by the liver that inhibits lipases, including lipoprotein lipase. Loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids and a monoclonal antibody targeting ANGPTL3, evinacumab (Evkeeza, Regeneron), is approved as an intravenous infusion for the treatment of familial hypercholesterolemia. Vupanorsen is a second-generation antisense oligonucleotide targeting hepatic ANGPTL3 messenger RNA with a potential role for cardiovascular risk reduction.
A previous phase 2a study of vupanorsen in patients with hypertriglyceridemia, hepatic steatosis, and type 2 diabetes mellitus showed significant reductions in triglycerides at all doses studied, as well as reductions in non-HDL cholesterol at the highest doses (80 mg per month given by subcutaneous injection).
Dr. Bergmark noted that, because a potential cardiovascular benefit of vupanorsen would best be reflected by its effects on non-HDL cholesterol, the current TRANSLATE-TIMI 70 trial was designed to assess the effect of escalating doses of vupanorsen on non-HDL cholesterol levels in statin-treated adults with hyperlipidemia.
For the study, 286 adults with non-HDL cholesterol levels of 100 mg/dL or greater (median, 132 mg/dL) and triglyceride levels of 150-500 mg/dL (median, 216 mg/dL) who were receiving statin therapy were randomly assigned to placebo or one of seven vupanorsen dose regimens (80, 120, or 160 mg every 4 weeks or 60, 80, 120, or 160 mg every 2 weeks). All doses were given by subcutaneous injection.
The study population was said to reflect “a typical cohort intended for cardiovascular risk reduction, with type 2 diabetes in approximately one-half of patients and prevalent atherosclerotic cardiovascular disease in a substantial portion,” the researchers wrote in the published report.
The primary endpoint was placebo-adjusted percentage change from baseline in non-HDL cholesterol at 24 weeks. Secondary endpoints included placebo-adjusted percentage changes from baseline in triglycerides, LDL cholesterol, apo B, and ANGPTL3.
Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL cholesterol ranging from 22.0% in the group receiving 60 mg every 2 weeks to 27.7% in the group receiving 80 mg every 2 weeks, but there did not appear to be a dose response.
Regarding additional lipid endpoints, vupanorsen reduced triglyceride levels in a dose-dependent manner, ranging from 41.3% in the group receiving 120 mg every 4 weeks to 56.8% in the group receiving 160 mg every 2 weeks.
The effects of vupanorsen on LDL cholesterol and apo B were more modest and without a clear dose response. Vupanorsen also lowered HDL cholesterol levels at all doses studied, and there was no significant change in high-sensitivity C-reactive protein at any dose.
Liver enzymes and hepatic fat increases of concern
In terms of safety, vupanorsen treatment was linked to liver enzyme elevations; more than three-times elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively). Injection site reactions were also an issue, including recall reactions at sites of previous injections when subsequent injections were given. In addition, there was a dose-related increase (up to 76%) in hepatic fat fraction.
In the Circulation paper, the researchers say it is unclear whether the increases in hepatic fat fraction and liver enzymes reflect a metabolic effect of vupanorsen specifically or an off-target effect resulting from hepatic targeting of ANGPTL3. “Regardless, these are medically meaningful findings with important safety ramifications,” they wrote.
They pointed out that, whereas the reduction in ANGPTL3 levels increased with total monthly dose of vupanorsen, there was no clear dose-response reduction in LDL cholesterol, apo B, or non-HDL cholesterol.
In comparison, evinacumab, a monoclonal antibody against ANGPTL3 that is thought to cause near-total suppression of ANGPTL3 activity, reduces apo B levels by more than 40% in adults with refractory hypercholesterolemia or homozygous familial hypercholesterolemia.
Asked why vupanorsen showed less of an effect on non-HDL cholesterol than evinacumab, Dr. Bergmark suggested that the monoclonal antibody may achieve greater inhibition of ANGPTL3. “It may be that near complete suppression is needed to obtain clinically meaningful reductions in apo B and non-HDL cholesterol. That is a speculative and simplistic explanation,” he commented.
Conversely, reductions in triglycerides with vupanorsen showed a dose-response relationship, mirroring the reduction in ANGPTL3 and consistent with the expected increases in lipoprotein lipase activity, the researchers reported.
They note that the “relatively muted effect on apo B levels” suggests that vupanorsen is primarily decreasing the triglyceride and, to a lesser extent, cholesterol content of very low-density lipoprotein cholesterol particles rather than reducing the number of such particles.
“These observations have important implications for the potential ability of this mechanism to reduce lipid-mediated cardiovascular risk, which largely appears to be a function of the number of ApoB-containing lipoproteins,” they said.
Designated discussant of the study at the ACC late-breaking session, Pradeep Natarajan, MD, director of preventive cardiology at Massachusetts General Hospital in Boston, asked Dr. Bergmark what minimum degree of non-HDL cholesterol reduction would be compelling for a new drug to be considered for wide-scale use.
Dr. Bergmark replied there was no clear to answer to that question, as it would depend on many factors, including the risk of the population and the time horizon involved. But he added: “I think a minimum of at least a 30%-40% reduction in non-HDL cholesterol would be needed for a meaningful reduction in cardiovascular risk across a variety of settings.”
The TRANSLATE-TIMI 70 study was funded by Pfizer. Dr. Bergmark is a member of the TIMI Study Group, which has received institutional grant support through Brigham and Women’s Hospital from numerous pharmaceutical companies. Dr. Bergmark also reported receiving grant support through Brigham and Women’s Hospital from Pfizer, Ionis, AstraZeneca, and Abbott Vascular and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
Low-sodium diet did not cut clinical events in heart failure trial
A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.
The results of the SODIUM-HF trial were presented April 2 at the annual scientific sessions of the American College of Cardiology, conducted virtually and in person in Washington. They were also simultaneously published online in the Lancet.
The study found that a strategy to reduce dietary sodium intake to less than 1,500 mg daily was not more effective than usual care in reducing the primary endpoint of risk for hospitalization or emergency department visits due to cardiovascular causes or all-cause death at 12 months.
“This is the largest and longest trial to look at the question of reducing dietary sodium in heart failure patients,” lead author Justin Ezekowitz, MBBCh, from the Canadian VIGOUR Center at the University of Alberta, Edmonton, Canada, told this news organization.
But he pointed out that there were fewer events than expected in the study, which was stopped early because of a combination of futility and practical difficulties caused by the COVID pandemic, so it could have been underpowered. Dr. Ezekowitz also suggested that a greater reduction in sodium than achieved in this study or a longer follow-up may be required to show an effect on clinical events.
“We hope others will do additional studies of sodium as well as other dietary recommendations as part of a comprehensive diet for heart failure patients,” he commented.
Dr. Ezekowitz said that the study results did not allow blanket recommendations to be made on reducing sodium intake in heart failure.
But he added: “I don’t think we should write off sodium reduction in this population. I think we can tell patients that reducing dietary sodium may potentially improve symptoms and quality of life, and I will continue to recommend reducing sodium as part of an overall healthy diet. We don’t want to throw the baby out with the bathwater.”
Dr. Ezekowitz noted that heart failure is associated with neurohormonal activation and abnormalities in autonomic control that lead to sodium and water retention; thus, dietary restriction of sodium has been historically endorsed as a mechanism to prevent fluid overload and subsequent clinical outcomes; however, clinical trials so far have shown mixed results.
“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.
SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.
In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.
Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.
Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.
“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.
Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.
By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).
All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).
The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.
Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).
There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.
NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).
No safety events related to the study treatment were reported in either group.
Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.
Questions on food recall and blinding
Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.
“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.
But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.
Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.
Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.
To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.
Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.
“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.
This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.
A version of this article first appeared on Medscape.com.
A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.
The results of the SODIUM-HF trial were presented April 2 at the annual scientific sessions of the American College of Cardiology, conducted virtually and in person in Washington. They were also simultaneously published online in the Lancet.
The study found that a strategy to reduce dietary sodium intake to less than 1,500 mg daily was not more effective than usual care in reducing the primary endpoint of risk for hospitalization or emergency department visits due to cardiovascular causes or all-cause death at 12 months.
“This is the largest and longest trial to look at the question of reducing dietary sodium in heart failure patients,” lead author Justin Ezekowitz, MBBCh, from the Canadian VIGOUR Center at the University of Alberta, Edmonton, Canada, told this news organization.
But he pointed out that there were fewer events than expected in the study, which was stopped early because of a combination of futility and practical difficulties caused by the COVID pandemic, so it could have been underpowered. Dr. Ezekowitz also suggested that a greater reduction in sodium than achieved in this study or a longer follow-up may be required to show an effect on clinical events.
“We hope others will do additional studies of sodium as well as other dietary recommendations as part of a comprehensive diet for heart failure patients,” he commented.
Dr. Ezekowitz said that the study results did not allow blanket recommendations to be made on reducing sodium intake in heart failure.
But he added: “I don’t think we should write off sodium reduction in this population. I think we can tell patients that reducing dietary sodium may potentially improve symptoms and quality of life, and I will continue to recommend reducing sodium as part of an overall healthy diet. We don’t want to throw the baby out with the bathwater.”
Dr. Ezekowitz noted that heart failure is associated with neurohormonal activation and abnormalities in autonomic control that lead to sodium and water retention; thus, dietary restriction of sodium has been historically endorsed as a mechanism to prevent fluid overload and subsequent clinical outcomes; however, clinical trials so far have shown mixed results.
“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.
SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.
In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.
Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.
Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.
“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.
Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.
By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).
All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).
The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.
Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).
There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.
NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).
No safety events related to the study treatment were reported in either group.
Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.
Questions on food recall and blinding
Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.
“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.
But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.
Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.
Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.
To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.
Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.
“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.
This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.
A version of this article first appeared on Medscape.com.
A low-sodium diet was not associated with a reduction in future clinical events in a new study in ambulatory patients with heart failure. But there was a moderate benefit on quality of life and New York Heart Association (NYHA) functional class.
The results of the SODIUM-HF trial were presented April 2 at the annual scientific sessions of the American College of Cardiology, conducted virtually and in person in Washington. They were also simultaneously published online in the Lancet.
The study found that a strategy to reduce dietary sodium intake to less than 1,500 mg daily was not more effective than usual care in reducing the primary endpoint of risk for hospitalization or emergency department visits due to cardiovascular causes or all-cause death at 12 months.
“This is the largest and longest trial to look at the question of reducing dietary sodium in heart failure patients,” lead author Justin Ezekowitz, MBBCh, from the Canadian VIGOUR Center at the University of Alberta, Edmonton, Canada, told this news organization.
But he pointed out that there were fewer events than expected in the study, which was stopped early because of a combination of futility and practical difficulties caused by the COVID pandemic, so it could have been underpowered. Dr. Ezekowitz also suggested that a greater reduction in sodium than achieved in this study or a longer follow-up may be required to show an effect on clinical events.
“We hope others will do additional studies of sodium as well as other dietary recommendations as part of a comprehensive diet for heart failure patients,” he commented.
Dr. Ezekowitz said that the study results did not allow blanket recommendations to be made on reducing sodium intake in heart failure.
But he added: “I don’t think we should write off sodium reduction in this population. I think we can tell patients that reducing dietary sodium may potentially improve symptoms and quality of life, and I will continue to recommend reducing sodium as part of an overall healthy diet. We don’t want to throw the baby out with the bathwater.”
Dr. Ezekowitz noted that heart failure is associated with neurohormonal activation and abnormalities in autonomic control that lead to sodium and water retention; thus, dietary restriction of sodium has been historically endorsed as a mechanism to prevent fluid overload and subsequent clinical outcomes; however, clinical trials so far have shown mixed results.
“The guidelines used to strongly recommend a reduction in sodium intake in heart failure patients, but this advice has backed off in recent years because of the lack of data. Most heart failure guidelines now do not make any recommendations on dietary sodium,” he said.
SODIUM-HF was a pragmatic, multinational, open-label, randomized trial conducted in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand), which included 809 patients (median age, 67 years) with chronic heart failure (NYHA functional class II–III) who were receiving optimally tolerated guideline-directed medical treatment. They were randomly assigned to usual care according to local guidelines or a low-sodium diet of less than 100 mmol (<1,500 mg/day). Patients with a baseline sodium intake of less than 1,500 mg/day were excluded.
In the intervention group, patients were asked to follow low-sodium menus developed by dietitians localized to each region. They also received behavioral counseling by trained dietitians or physicians or nurses.
Dietary sodium intake was assessed by using a 3-day food record (including 1 weekend day) at baseline, 6 months, and 12 months in both groups and, for the intervention group, also at 3 and 9 months to monitor and support dietary adherence.
Dr. Ezekowitz explained that although the best method for measuring sodium levels would normally be a 24-hour urine sodium, this would be impractical in a large clinical trial. In addition, he pointed out that urinary sodium is not an accurate measure of actual sodium levels in patients taking diuretics, so it is not a good measure to use in a heart failure population.
“The food record method of assessing sodium levels has been well validated; I think we measured it as accurately as we could have done,” he added.
Results showed that between baseline and 12 months, the median sodium intake decreased from 2,286 mg/day to 1,658 mg/day in the low-sodium group and from 2,119 mg/day to 2,073 mg/day in the usual care group. The median difference between groups was 415 mg/day at 12 months.
By 12 months, events comprising the primary outcome (hospitalization or emergency department visits due to cardiovascular causes or all-cause death) had occurred in 15% of patients in the low-sodium diet group and 17% of those in the usual care group (hazard ratio [HR], 0.89 [95% CI, 0.63 - 1.26]; P = .53).
All-cause death occurred in 6% of patients in the low-sodium diet group and 4% of those in the usual care group (HR, 1.38; P = .32). Cardiovascular-related hospitalization occurred in 10% of the low-sodium group and 12% of the usual care group (HR, 0.82; P = .36), and cardiovascular-related emergency department visits occurred in 4% of both groups (HR, 1.21; P = .60).
The absence of treatment effect for the primary outcome was consistent across most prespecified subgroups, including those with higher vs lower baseline sodium intake. But there was a suggestion of a greater reduction in the primary outcome in individuals younger than age 65 years than in those age 65 years and older.
Quality-of-life measures on the Kansas City Cardiomyopathy Questionnaire (KCCQ) suggested a benefit in the low-sodium group, with mean between-group differences in the change from baseline to 12 months of 3.38 points in the overall summary score, 3.29 points in the clinical summary score, and 3.77 points in the physical limitation score (all differences were statistically significant).
There was no significant difference in 6-minute-walk distance at 12 months between the low-sodium diet group and the usual care group.
NYHA functional class at 12 months differed significantly between groups; the low-sodium diet group had a greater likelihood of improving by one NYHA class than the usual care group (odds ratio, 0.59; P = .0061).
No safety events related to the study treatment were reported in either group.
Dr. Ezekowitz said that to investigate whether longer follow-up may show a difference in events, further analyses are planned at 2 years and 5 years.
Questions on food recall and blinding
Commenting on the findings at the late-breaking clinical trials session at the ACC meeting, Biykem Bozkurt, MD, professor of medicine at Baylor College of Medicine, Houston, congratulated Dr. Ezekowitz on conducting this trial.
“We have been chasing the holy grail of sodium reduction in heart failure for a very long time, so I have to commend you and your team for taking on this challenge, especially during the pandemic,” she said.
But Dr. Bozkurt questioned whether the intervention group actually had a meaningful sodium reduction given that this was measured by food recall and this may have been accounted for by under-reporting of certain food intakes.
Dr. Ezekowitz responded that patients acted as their own controls in that calorie intake, fluid intake, and weight were also assessed and did not change. “So I think we did have a meaningful reduction in sodium,” he said.
Dr. Bozkurt also queried whether the improvements in quality of life and functional status were reliable given that this was an unblinded study.
To this point, Dr. Ezekowitz pointed out that the KCCQ quality-of-life measure was a highly validated instrument and that improvements were seen in these measures at 3, 6, and 12 months. “It is not like these were spurious findings, so I think we have to look at this as a real result,” he argued.
Commenting on the study at an ACC press conference, Mary Norine Walsh, MD, director of the heart failure and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis, said the trial had answered two important questions: that sodium reduction in heart failure may not reduce heart failure hospitalization/death but that patients feel better.
“I think we can safely tell patients that if they slip up a bit they may not end up in hospital,” she added.
This study was funded by the Canadian Institutes of Health Research and the University Hospital Foundation (Edmonton, Alberta, Canada) and the Health Research Council of New Zealand. Dr. Ezekowitz reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, eko.ai, US2.ai, Merck, Novartis, Otsuka, Sanofi, and Servier and consulting fees from American Regent, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Otsuka, Sanofi, and Servier.
A version of this article first appeared on Medscape.com.
FROM ACC 2022
Even light drinking ups CV risk; harm rises along with intake
Even very light alcohol intake is associated with an increased risk for cardiovascular disease, compared with not drinking at all, and the risk increases exponentially as alcohol intake rises, even at moderate levels, a new study shows.
“Our findings suggest that the observed benefit in individuals with light to moderate alcohol intake, which is consistently shown in epidemiological studies, is likely due to other positive lifestyle factors that are common in these individuals who drink lightly,” senior author Krishna Aragam, MD, Massachusetts General Hospital, Boston, told this news organization.
“Our results also showed that while all levels of alcohol were linked to increased risk of cardiovascular disease, the association was not linear. Rather, light alcohol intake was associated with rather modest risk increases, but there were exponential increases in cardiovascular risk with increasing amounts of alcohol consumption,” he said.
As the risk gradient appeared to increase quite sharply even between 1 and 2 drinks per day, Dr. Aragam suggested that what might be regarded as safe levels of drinking may trend downward in the future.
The study was published online March 25 in JAMA Network Open.
The cohort study used data from the UK Biobank, collected between 2006 and 2010 with follow-up until 2016, to assess the relationship between various levels of alcohol consumption and risk for cardiovascular disease.
Data were analyzed from 371,463 participants (mean age, 57 years; 46% men) who consumed an average of 9.2 standard drinks per week. Of these participants, 33% had hypertension and 7.5% had coronary artery disease.
“Use of the UK biobank database gives the advantage of a large, well-phenotyped population with a lot of information on various lifestyle factors that could be potential confounders,” Dr. Aragam noted.
Results showed that well-established J- or U-shaped curves were seen for the association between alcohol consumption and both the prevalence and hazards of hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation.
However, individuals in the light and moderate consumption group had healthier lifestyle behaviors than abstainers, self-reporting better overall health and exhibiting lower rates of smoking, lower body mass index, higher physical activity, and higher vegetable intake.
Adjustment for these lifestyle factors attenuated the cardioprotective associations with modest alcohol intake. For example, in baseline models, moderate intake was associated with significantly lower risk of hypertension and coronary artery disease, but adjustment for just six lifestyle factors rendered these results insignificant.
“Adjustments for yet unmeasured or unknown factors may further attenuate, if not eliminate, the residual, cardioprotective associations observed among light drinkers,” the researchers suggest.
They also conducted genetic analyses to examine the effect of alcohol and cardiovascular disease.
Dr. Aragam explained that previous work has shown good evidence, in individuals who choose to drink, that several relevant genetic variants predict levels of alcohol consumption quite accurately.
“Mendelian randomization using these gene variants allows for stronger inferences about potential causality than do observational studies, as they are less affected by confounding factors,” he noted.
Newer techniques in Mendelian randomization in which data on several gene variants linked to alcohol consumption are combined into a score allow for a greater understanding of the risk linked to different amount of alcohol intake, he added.
In these Mendelian randomization analyses, a 1-standard deviation increase in genetically predicted alcohol consumption was associated with 1.3-fold higher risk of hypertension (P < .001) and 1.4-fold higher risk of coronary artery disease (P = .006).
Further analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease; light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease.
These results were replicated in a second database of 30,716 individuals from the Mass General Brigham Biobank.
“The findings of this study suggest that the observed cardioprotective effects of light to moderate alcohol intake may be largely mediated by confounding lifestyle factors,” the researchers conclude. “Genetic analyses suggest causal associations between alcohol intake and cardiovascular disease but with unequal and exponential increases in risk at greater levels of intake, which should be accounted for in health recommendations around the habitual consumption of alcohol.”
What is an acceptable level?
“Specifically, our results suggest that consuming as many as 7 drinks per week is associated with relatively modest increases in cardiovascular risk,” they write.
But they point out that there are unequal increases in cardiovascular risk when progressing from 0 to 7 versus 7 to 14 drinks per week in both men and women.
“Although risk thresholds are inherently somewhat subjective, these findings again bring into question whether an average consumption of 2 drinks per day (14 drinks per week) should be designated a low-risk behavior,” they say.
“Furthermore, as several-fold increases in risk were observed for those consuming 21 or more drinks per week, our results emphasize the importance of aggressive efforts to reduce alcohol intake among heavy drinkers,” they add.
Dr. Aragam elaborated: “Our data suggest that reducing alcohol intake will reduce cardiovascular risk in all individuals, but the extent of the relative risk reduction is quite different depending on the current levels of consumption. For the same absolute reduction in alcohol intake, the gains in terms of reduction in cardiovascular risk will be more pronounced in those who drink heavily and will be more modest in those who drink at a light level.”
The results also suggest that while all levels of alcohol intake increase cardiovascular risk, there are low levels of alcohol consumption that do not carry major elevations in risk, but these are probably lower than those currently recommended, Dr. Aragam pointed out.
“This doesn’t mean that everyone has to give up drinking alcohol completely, just that you shouldn’t consume with the goal of improving cardiovascular health. In fact, our analyses suggest that in an otherwise healthy person, up to 1 drink per day may not pose outsized risks,” he said. “And, even in a less healthy person who might be smoking, eating poorly, and drinking up to 1 drink per day, it may be a higher priority to focus on smoking cessation and diet than cutting back further on alcohol.”
“Beyond that amount, though, the jury is still out. Our models suggested marked increases in risk even between 1 and 2 drinks per day, and of course even greater risk increases beyond that. So, it’s probably worth revisiting what one might consider a ‘safe’ amount within the moderate drinking categories. The conservative move for now might be to advise a limit of 1 drink per day,” he said.
Dr. Aragam is supported by grants from the National Institutes of Health and the American Heart Association. He reports receiving speaking fees from the Novartis Institute for Biomedical Research.
A version of this article first appeared on Medscape.com.
Even very light alcohol intake is associated with an increased risk for cardiovascular disease, compared with not drinking at all, and the risk increases exponentially as alcohol intake rises, even at moderate levels, a new study shows.
“Our findings suggest that the observed benefit in individuals with light to moderate alcohol intake, which is consistently shown in epidemiological studies, is likely due to other positive lifestyle factors that are common in these individuals who drink lightly,” senior author Krishna Aragam, MD, Massachusetts General Hospital, Boston, told this news organization.
“Our results also showed that while all levels of alcohol were linked to increased risk of cardiovascular disease, the association was not linear. Rather, light alcohol intake was associated with rather modest risk increases, but there were exponential increases in cardiovascular risk with increasing amounts of alcohol consumption,” he said.
As the risk gradient appeared to increase quite sharply even between 1 and 2 drinks per day, Dr. Aragam suggested that what might be regarded as safe levels of drinking may trend downward in the future.
The study was published online March 25 in JAMA Network Open.
The cohort study used data from the UK Biobank, collected between 2006 and 2010 with follow-up until 2016, to assess the relationship between various levels of alcohol consumption and risk for cardiovascular disease.
Data were analyzed from 371,463 participants (mean age, 57 years; 46% men) who consumed an average of 9.2 standard drinks per week. Of these participants, 33% had hypertension and 7.5% had coronary artery disease.
“Use of the UK biobank database gives the advantage of a large, well-phenotyped population with a lot of information on various lifestyle factors that could be potential confounders,” Dr. Aragam noted.
Results showed that well-established J- or U-shaped curves were seen for the association between alcohol consumption and both the prevalence and hazards of hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation.
However, individuals in the light and moderate consumption group had healthier lifestyle behaviors than abstainers, self-reporting better overall health and exhibiting lower rates of smoking, lower body mass index, higher physical activity, and higher vegetable intake.
Adjustment for these lifestyle factors attenuated the cardioprotective associations with modest alcohol intake. For example, in baseline models, moderate intake was associated with significantly lower risk of hypertension and coronary artery disease, but adjustment for just six lifestyle factors rendered these results insignificant.
“Adjustments for yet unmeasured or unknown factors may further attenuate, if not eliminate, the residual, cardioprotective associations observed among light drinkers,” the researchers suggest.
They also conducted genetic analyses to examine the effect of alcohol and cardiovascular disease.
Dr. Aragam explained that previous work has shown good evidence, in individuals who choose to drink, that several relevant genetic variants predict levels of alcohol consumption quite accurately.
“Mendelian randomization using these gene variants allows for stronger inferences about potential causality than do observational studies, as they are less affected by confounding factors,” he noted.
Newer techniques in Mendelian randomization in which data on several gene variants linked to alcohol consumption are combined into a score allow for a greater understanding of the risk linked to different amount of alcohol intake, he added.
In these Mendelian randomization analyses, a 1-standard deviation increase in genetically predicted alcohol consumption was associated with 1.3-fold higher risk of hypertension (P < .001) and 1.4-fold higher risk of coronary artery disease (P = .006).
Further analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease; light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease.
These results were replicated in a second database of 30,716 individuals from the Mass General Brigham Biobank.
“The findings of this study suggest that the observed cardioprotective effects of light to moderate alcohol intake may be largely mediated by confounding lifestyle factors,” the researchers conclude. “Genetic analyses suggest causal associations between alcohol intake and cardiovascular disease but with unequal and exponential increases in risk at greater levels of intake, which should be accounted for in health recommendations around the habitual consumption of alcohol.”
What is an acceptable level?
“Specifically, our results suggest that consuming as many as 7 drinks per week is associated with relatively modest increases in cardiovascular risk,” they write.
But they point out that there are unequal increases in cardiovascular risk when progressing from 0 to 7 versus 7 to 14 drinks per week in both men and women.
“Although risk thresholds are inherently somewhat subjective, these findings again bring into question whether an average consumption of 2 drinks per day (14 drinks per week) should be designated a low-risk behavior,” they say.
“Furthermore, as several-fold increases in risk were observed for those consuming 21 or more drinks per week, our results emphasize the importance of aggressive efforts to reduce alcohol intake among heavy drinkers,” they add.
Dr. Aragam elaborated: “Our data suggest that reducing alcohol intake will reduce cardiovascular risk in all individuals, but the extent of the relative risk reduction is quite different depending on the current levels of consumption. For the same absolute reduction in alcohol intake, the gains in terms of reduction in cardiovascular risk will be more pronounced in those who drink heavily and will be more modest in those who drink at a light level.”
The results also suggest that while all levels of alcohol intake increase cardiovascular risk, there are low levels of alcohol consumption that do not carry major elevations in risk, but these are probably lower than those currently recommended, Dr. Aragam pointed out.
“This doesn’t mean that everyone has to give up drinking alcohol completely, just that you shouldn’t consume with the goal of improving cardiovascular health. In fact, our analyses suggest that in an otherwise healthy person, up to 1 drink per day may not pose outsized risks,” he said. “And, even in a less healthy person who might be smoking, eating poorly, and drinking up to 1 drink per day, it may be a higher priority to focus on smoking cessation and diet than cutting back further on alcohol.”
“Beyond that amount, though, the jury is still out. Our models suggested marked increases in risk even between 1 and 2 drinks per day, and of course even greater risk increases beyond that. So, it’s probably worth revisiting what one might consider a ‘safe’ amount within the moderate drinking categories. The conservative move for now might be to advise a limit of 1 drink per day,” he said.
Dr. Aragam is supported by grants from the National Institutes of Health and the American Heart Association. He reports receiving speaking fees from the Novartis Institute for Biomedical Research.
A version of this article first appeared on Medscape.com.
Even very light alcohol intake is associated with an increased risk for cardiovascular disease, compared with not drinking at all, and the risk increases exponentially as alcohol intake rises, even at moderate levels, a new study shows.
“Our findings suggest that the observed benefit in individuals with light to moderate alcohol intake, which is consistently shown in epidemiological studies, is likely due to other positive lifestyle factors that are common in these individuals who drink lightly,” senior author Krishna Aragam, MD, Massachusetts General Hospital, Boston, told this news organization.
“Our results also showed that while all levels of alcohol were linked to increased risk of cardiovascular disease, the association was not linear. Rather, light alcohol intake was associated with rather modest risk increases, but there were exponential increases in cardiovascular risk with increasing amounts of alcohol consumption,” he said.
As the risk gradient appeared to increase quite sharply even between 1 and 2 drinks per day, Dr. Aragam suggested that what might be regarded as safe levels of drinking may trend downward in the future.
The study was published online March 25 in JAMA Network Open.
The cohort study used data from the UK Biobank, collected between 2006 and 2010 with follow-up until 2016, to assess the relationship between various levels of alcohol consumption and risk for cardiovascular disease.
Data were analyzed from 371,463 participants (mean age, 57 years; 46% men) who consumed an average of 9.2 standard drinks per week. Of these participants, 33% had hypertension and 7.5% had coronary artery disease.
“Use of the UK biobank database gives the advantage of a large, well-phenotyped population with a lot of information on various lifestyle factors that could be potential confounders,” Dr. Aragam noted.
Results showed that well-established J- or U-shaped curves were seen for the association between alcohol consumption and both the prevalence and hazards of hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation.
However, individuals in the light and moderate consumption group had healthier lifestyle behaviors than abstainers, self-reporting better overall health and exhibiting lower rates of smoking, lower body mass index, higher physical activity, and higher vegetable intake.
Adjustment for these lifestyle factors attenuated the cardioprotective associations with modest alcohol intake. For example, in baseline models, moderate intake was associated with significantly lower risk of hypertension and coronary artery disease, but adjustment for just six lifestyle factors rendered these results insignificant.
“Adjustments for yet unmeasured or unknown factors may further attenuate, if not eliminate, the residual, cardioprotective associations observed among light drinkers,” the researchers suggest.
They also conducted genetic analyses to examine the effect of alcohol and cardiovascular disease.
Dr. Aragam explained that previous work has shown good evidence, in individuals who choose to drink, that several relevant genetic variants predict levels of alcohol consumption quite accurately.
“Mendelian randomization using these gene variants allows for stronger inferences about potential causality than do observational studies, as they are less affected by confounding factors,” he noted.
Newer techniques in Mendelian randomization in which data on several gene variants linked to alcohol consumption are combined into a score allow for a greater understanding of the risk linked to different amount of alcohol intake, he added.
In these Mendelian randomization analyses, a 1-standard deviation increase in genetically predicted alcohol consumption was associated with 1.3-fold higher risk of hypertension (P < .001) and 1.4-fold higher risk of coronary artery disease (P = .006).
Further analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease; light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease.
These results were replicated in a second database of 30,716 individuals from the Mass General Brigham Biobank.
“The findings of this study suggest that the observed cardioprotective effects of light to moderate alcohol intake may be largely mediated by confounding lifestyle factors,” the researchers conclude. “Genetic analyses suggest causal associations between alcohol intake and cardiovascular disease but with unequal and exponential increases in risk at greater levels of intake, which should be accounted for in health recommendations around the habitual consumption of alcohol.”
What is an acceptable level?
“Specifically, our results suggest that consuming as many as 7 drinks per week is associated with relatively modest increases in cardiovascular risk,” they write.
But they point out that there are unequal increases in cardiovascular risk when progressing from 0 to 7 versus 7 to 14 drinks per week in both men and women.
“Although risk thresholds are inherently somewhat subjective, these findings again bring into question whether an average consumption of 2 drinks per day (14 drinks per week) should be designated a low-risk behavior,” they say.
“Furthermore, as several-fold increases in risk were observed for those consuming 21 or more drinks per week, our results emphasize the importance of aggressive efforts to reduce alcohol intake among heavy drinkers,” they add.
Dr. Aragam elaborated: “Our data suggest that reducing alcohol intake will reduce cardiovascular risk in all individuals, but the extent of the relative risk reduction is quite different depending on the current levels of consumption. For the same absolute reduction in alcohol intake, the gains in terms of reduction in cardiovascular risk will be more pronounced in those who drink heavily and will be more modest in those who drink at a light level.”
The results also suggest that while all levels of alcohol intake increase cardiovascular risk, there are low levels of alcohol consumption that do not carry major elevations in risk, but these are probably lower than those currently recommended, Dr. Aragam pointed out.
“This doesn’t mean that everyone has to give up drinking alcohol completely, just that you shouldn’t consume with the goal of improving cardiovascular health. In fact, our analyses suggest that in an otherwise healthy person, up to 1 drink per day may not pose outsized risks,” he said. “And, even in a less healthy person who might be smoking, eating poorly, and drinking up to 1 drink per day, it may be a higher priority to focus on smoking cessation and diet than cutting back further on alcohol.”
“Beyond that amount, though, the jury is still out. Our models suggested marked increases in risk even between 1 and 2 drinks per day, and of course even greater risk increases beyond that. So, it’s probably worth revisiting what one might consider a ‘safe’ amount within the moderate drinking categories. The conservative move for now might be to advise a limit of 1 drink per day,” he said.
Dr. Aragam is supported by grants from the National Institutes of Health and the American Heart Association. He reports receiving speaking fees from the Novartis Institute for Biomedical Research.
A version of this article first appeared on Medscape.com.
New test for Lp(a) allows more accurate LDL-cholesterol results
A new study has drawn attention to inaccurate measurement of LDL-cholesterol levels in some patients with current assays, which could lead to incorrect therapeutic approaches.
The patient groups most affected are those with high levels of the lipoprotein Lp(a), in whom LDL-cholesterol levels are being overestimated in current laboratory tests, the authors say.
“Current laboratory assays all have the limitation that they cannot measure or report LDL cholesterol accurately. They are actually measuring the combination of LDL and Lp(a),” senior study author Sotirios Tsimikas, MD, University of California, San Diego, explained to this news organization.
“While this may not matter much in individuals with normal Lp(a) levels, in those with elevated Lp(a), the Lp(a) cholesterol may constitute a substantial proportion of the reported LDL cholesterol, and the actual LDL-cholesterol levels could be much lower that the value the lab is telling us,” he said.
Dr. Tsimikas gave the example of a patient with an LDL-cholesterol lab measurement of 75 mg/dL. “If that patient has an Lp(a) level of zero, then they do actually have an LDL level of 75. But as the Lp(a) increases, then the proportion of the result accounted for by LDL cholesterol decreases. So, if a patient with a measured LDL cholesterol of 75 has an Lp(a)-cholesterol level of 20, then their actual LDL level is 55.”
Dr. Tsimikas said it is important to know levels of both lipoproteins individually, so the correct therapeutic approach is used in situations where the Lp(a) cholesterol might be elevated.
“By understanding the actual values of LDL cholesterol and Lp(a) cholesterol, this will allow us to personalize the use of cholesterol-lowering medications and decide where to focus treatment. In the patient with a high level of Lp(a), their residual risk could be coming from Lp(a) cholesterol and less so from LDL cholesterol,” he added. “As we develop drugs to lower Lp(a), this patient might be better off on one of these rather than increasing efforts to lower LDL cholesterol, which might already be at goal.”
The study was published in the March 22 issue of the Journal of the American College of Cardiology.
Dr. Tsimikas noted that Lp(a) is now accepted as a genetic, independent, causal risk factor for cardiovascular disease, but current LDL-lowering drugs do not have much effect on Lp(a).
“Lp(a) can be lowered a little with niacin and PCSK9 inhibitors, but both have a quite a weak effect, and statins increase Lp(a). However, there are now multiple RNA-based therapeutics specifically targeting Lp(a) in clinical development,” he said.
At present, Lp(a) cholesterol has to be mathematically estimated, most commonly with the Dahlén formula, because of the lack of a validated, quantitative method to measure Lp(a) cholesterol, Dr. Tsimikas says.
For the current study, the researchers used a novel, quantitative, sensitive method to directly measure Lp(a) cholesterol, then applied this method to data from a recent study with the one of the new Lp(a)-lowering drugs in development – pelacarsen – which was conducted in patients with elevated Lp(a) levels.
Results showed that direct Lp(a)-cholesterol assessment, and subtracting this value from the laboratory LDL-cholesterol value, provides a more accurate reflection of the baseline and change in LDL cholesterol, the authors report. In the current study, corrected LDL cholesterol was 13 to 16 mg/dL lower than laboratory-reported LDL cholesterol.
Using the corrected LDL-cholesterol results, the study showed that pelacarsen significantly decreases Lp(a) cholesterol, with neutral to modest effects on LDL.
The study also suggests that the current method of calculating Lp(a) cholesterol, and then deriving a corrected LDL cholesterol – the Dahlén formula – is not accurate.
“The Dahlén formula relies on the assumption that Lp(a) cholesterol is universally a fixed 30% of Lp(a) mass, but this usually isn’t the case. The Dahlén formula needs to be discontinued. It can be highly inaccurate,” Dr. Tsimikas said.
Important implications
In an accompanying editorial, Guillaume Paré, MD, Michael Chong, PhD student, and Pedrum Mohammadi-Shemirani, BSc, all of McMaster University, Hamilton, Ont., say the current findings have three important clinical implications.
“First, they provide further proof that in individuals with elevated Lp(a), the contribution of Lp(a)-cholesterol to LDL-cholesterol is non-negligible using standard assays, with 13-16 mg/dL lower LDL-cholesterol post-correction.”
Secondly, the editorialists point out that these new findings confirm that the effect of Lp(a) inhibitors is likely to be mostly confined to Lp(a), “as would be expected.”
Finally, “and perhaps more importantly, the authors highlight the need to improve clinical reporting of lipid fractions to properly treat LDL-cholesterol and Lp(a) in high-risk patients,” they note.
“The report paves the way for future studies investigating the clinical utility of these additional measurements to initiate and monitor lipid-lowering therapy,” they conclude.
The clinical trial was funded by Ionis Pharmaceuticals, and the direct Lp(a)-cholesterol measurements were funded by Novartis through a research grant to the University of California, San Diego. Dr. Tsimikas is an employee of Ionis Pharmaceuticals and of the University of California, San Diego, and he is a cofounder of Covicept Therapeutics. He is also a coinventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and on biomarkers related to oxidized lipoproteins, as well as a cofounder and has equity interest in Oxitope and Kleanthi Diagnostics.
A version of this article first appeared on Medscape.com.
A new study has drawn attention to inaccurate measurement of LDL-cholesterol levels in some patients with current assays, which could lead to incorrect therapeutic approaches.
The patient groups most affected are those with high levels of the lipoprotein Lp(a), in whom LDL-cholesterol levels are being overestimated in current laboratory tests, the authors say.
“Current laboratory assays all have the limitation that they cannot measure or report LDL cholesterol accurately. They are actually measuring the combination of LDL and Lp(a),” senior study author Sotirios Tsimikas, MD, University of California, San Diego, explained to this news organization.
“While this may not matter much in individuals with normal Lp(a) levels, in those with elevated Lp(a), the Lp(a) cholesterol may constitute a substantial proportion of the reported LDL cholesterol, and the actual LDL-cholesterol levels could be much lower that the value the lab is telling us,” he said.
Dr. Tsimikas gave the example of a patient with an LDL-cholesterol lab measurement of 75 mg/dL. “If that patient has an Lp(a) level of zero, then they do actually have an LDL level of 75. But as the Lp(a) increases, then the proportion of the result accounted for by LDL cholesterol decreases. So, if a patient with a measured LDL cholesterol of 75 has an Lp(a)-cholesterol level of 20, then their actual LDL level is 55.”
Dr. Tsimikas said it is important to know levels of both lipoproteins individually, so the correct therapeutic approach is used in situations where the Lp(a) cholesterol might be elevated.
“By understanding the actual values of LDL cholesterol and Lp(a) cholesterol, this will allow us to personalize the use of cholesterol-lowering medications and decide where to focus treatment. In the patient with a high level of Lp(a), their residual risk could be coming from Lp(a) cholesterol and less so from LDL cholesterol,” he added. “As we develop drugs to lower Lp(a), this patient might be better off on one of these rather than increasing efforts to lower LDL cholesterol, which might already be at goal.”
The study was published in the March 22 issue of the Journal of the American College of Cardiology.
Dr. Tsimikas noted that Lp(a) is now accepted as a genetic, independent, causal risk factor for cardiovascular disease, but current LDL-lowering drugs do not have much effect on Lp(a).
“Lp(a) can be lowered a little with niacin and PCSK9 inhibitors, but both have a quite a weak effect, and statins increase Lp(a). However, there are now multiple RNA-based therapeutics specifically targeting Lp(a) in clinical development,” he said.
At present, Lp(a) cholesterol has to be mathematically estimated, most commonly with the Dahlén formula, because of the lack of a validated, quantitative method to measure Lp(a) cholesterol, Dr. Tsimikas says.
For the current study, the researchers used a novel, quantitative, sensitive method to directly measure Lp(a) cholesterol, then applied this method to data from a recent study with the one of the new Lp(a)-lowering drugs in development – pelacarsen – which was conducted in patients with elevated Lp(a) levels.
Results showed that direct Lp(a)-cholesterol assessment, and subtracting this value from the laboratory LDL-cholesterol value, provides a more accurate reflection of the baseline and change in LDL cholesterol, the authors report. In the current study, corrected LDL cholesterol was 13 to 16 mg/dL lower than laboratory-reported LDL cholesterol.
Using the corrected LDL-cholesterol results, the study showed that pelacarsen significantly decreases Lp(a) cholesterol, with neutral to modest effects on LDL.
The study also suggests that the current method of calculating Lp(a) cholesterol, and then deriving a corrected LDL cholesterol – the Dahlén formula – is not accurate.
“The Dahlén formula relies on the assumption that Lp(a) cholesterol is universally a fixed 30% of Lp(a) mass, but this usually isn’t the case. The Dahlén formula needs to be discontinued. It can be highly inaccurate,” Dr. Tsimikas said.
Important implications
In an accompanying editorial, Guillaume Paré, MD, Michael Chong, PhD student, and Pedrum Mohammadi-Shemirani, BSc, all of McMaster University, Hamilton, Ont., say the current findings have three important clinical implications.
“First, they provide further proof that in individuals with elevated Lp(a), the contribution of Lp(a)-cholesterol to LDL-cholesterol is non-negligible using standard assays, with 13-16 mg/dL lower LDL-cholesterol post-correction.”
Secondly, the editorialists point out that these new findings confirm that the effect of Lp(a) inhibitors is likely to be mostly confined to Lp(a), “as would be expected.”
Finally, “and perhaps more importantly, the authors highlight the need to improve clinical reporting of lipid fractions to properly treat LDL-cholesterol and Lp(a) in high-risk patients,” they note.
“The report paves the way for future studies investigating the clinical utility of these additional measurements to initiate and monitor lipid-lowering therapy,” they conclude.
The clinical trial was funded by Ionis Pharmaceuticals, and the direct Lp(a)-cholesterol measurements were funded by Novartis through a research grant to the University of California, San Diego. Dr. Tsimikas is an employee of Ionis Pharmaceuticals and of the University of California, San Diego, and he is a cofounder of Covicept Therapeutics. He is also a coinventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and on biomarkers related to oxidized lipoproteins, as well as a cofounder and has equity interest in Oxitope and Kleanthi Diagnostics.
A version of this article first appeared on Medscape.com.
A new study has drawn attention to inaccurate measurement of LDL-cholesterol levels in some patients with current assays, which could lead to incorrect therapeutic approaches.
The patient groups most affected are those with high levels of the lipoprotein Lp(a), in whom LDL-cholesterol levels are being overestimated in current laboratory tests, the authors say.
“Current laboratory assays all have the limitation that they cannot measure or report LDL cholesterol accurately. They are actually measuring the combination of LDL and Lp(a),” senior study author Sotirios Tsimikas, MD, University of California, San Diego, explained to this news organization.
“While this may not matter much in individuals with normal Lp(a) levels, in those with elevated Lp(a), the Lp(a) cholesterol may constitute a substantial proportion of the reported LDL cholesterol, and the actual LDL-cholesterol levels could be much lower that the value the lab is telling us,” he said.
Dr. Tsimikas gave the example of a patient with an LDL-cholesterol lab measurement of 75 mg/dL. “If that patient has an Lp(a) level of zero, then they do actually have an LDL level of 75. But as the Lp(a) increases, then the proportion of the result accounted for by LDL cholesterol decreases. So, if a patient with a measured LDL cholesterol of 75 has an Lp(a)-cholesterol level of 20, then their actual LDL level is 55.”
Dr. Tsimikas said it is important to know levels of both lipoproteins individually, so the correct therapeutic approach is used in situations where the Lp(a) cholesterol might be elevated.
“By understanding the actual values of LDL cholesterol and Lp(a) cholesterol, this will allow us to personalize the use of cholesterol-lowering medications and decide where to focus treatment. In the patient with a high level of Lp(a), their residual risk could be coming from Lp(a) cholesterol and less so from LDL cholesterol,” he added. “As we develop drugs to lower Lp(a), this patient might be better off on one of these rather than increasing efforts to lower LDL cholesterol, which might already be at goal.”
The study was published in the March 22 issue of the Journal of the American College of Cardiology.
Dr. Tsimikas noted that Lp(a) is now accepted as a genetic, independent, causal risk factor for cardiovascular disease, but current LDL-lowering drugs do not have much effect on Lp(a).
“Lp(a) can be lowered a little with niacin and PCSK9 inhibitors, but both have a quite a weak effect, and statins increase Lp(a). However, there are now multiple RNA-based therapeutics specifically targeting Lp(a) in clinical development,” he said.
At present, Lp(a) cholesterol has to be mathematically estimated, most commonly with the Dahlén formula, because of the lack of a validated, quantitative method to measure Lp(a) cholesterol, Dr. Tsimikas says.
For the current study, the researchers used a novel, quantitative, sensitive method to directly measure Lp(a) cholesterol, then applied this method to data from a recent study with the one of the new Lp(a)-lowering drugs in development – pelacarsen – which was conducted in patients with elevated Lp(a) levels.
Results showed that direct Lp(a)-cholesterol assessment, and subtracting this value from the laboratory LDL-cholesterol value, provides a more accurate reflection of the baseline and change in LDL cholesterol, the authors report. In the current study, corrected LDL cholesterol was 13 to 16 mg/dL lower than laboratory-reported LDL cholesterol.
Using the corrected LDL-cholesterol results, the study showed that pelacarsen significantly decreases Lp(a) cholesterol, with neutral to modest effects on LDL.
The study also suggests that the current method of calculating Lp(a) cholesterol, and then deriving a corrected LDL cholesterol – the Dahlén formula – is not accurate.
“The Dahlén formula relies on the assumption that Lp(a) cholesterol is universally a fixed 30% of Lp(a) mass, but this usually isn’t the case. The Dahlén formula needs to be discontinued. It can be highly inaccurate,” Dr. Tsimikas said.
Important implications
In an accompanying editorial, Guillaume Paré, MD, Michael Chong, PhD student, and Pedrum Mohammadi-Shemirani, BSc, all of McMaster University, Hamilton, Ont., say the current findings have three important clinical implications.
“First, they provide further proof that in individuals with elevated Lp(a), the contribution of Lp(a)-cholesterol to LDL-cholesterol is non-negligible using standard assays, with 13-16 mg/dL lower LDL-cholesterol post-correction.”
Secondly, the editorialists point out that these new findings confirm that the effect of Lp(a) inhibitors is likely to be mostly confined to Lp(a), “as would be expected.”
Finally, “and perhaps more importantly, the authors highlight the need to improve clinical reporting of lipid fractions to properly treat LDL-cholesterol and Lp(a) in high-risk patients,” they note.
“The report paves the way for future studies investigating the clinical utility of these additional measurements to initiate and monitor lipid-lowering therapy,” they conclude.
The clinical trial was funded by Ionis Pharmaceuticals, and the direct Lp(a)-cholesterol measurements were funded by Novartis through a research grant to the University of California, San Diego. Dr. Tsimikas is an employee of Ionis Pharmaceuticals and of the University of California, San Diego, and he is a cofounder of Covicept Therapeutics. He is also a coinventor and receives royalties from patents owned by UCSD on oxidation-specific antibodies and on biomarkers related to oxidized lipoproteins, as well as a cofounder and has equity interest in Oxitope and Kleanthi Diagnostics.
A version of this article first appeared on Medscape.com.
New ACC guidance on cardiovascular consequences of COVID-19
The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.
The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.
The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.
“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”
The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine.
“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
Myocarditis
The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.
It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.
The document makes the following recommendations in regard to COVID-related myocarditis:
When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.
Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.
Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.
As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.
The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.
But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.
In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
Long COVID
The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.
Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.
Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”
The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:
PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.
PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.
The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.
For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.
Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.
Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.
Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.
Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
Return to play for athletes
The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.
But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.
They make the following recommendations:
- For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
- For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
- Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
- For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
- For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.
Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.
Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.
The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.
“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.
The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.
A version of this article first appeared on Medscape.com.
The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.
The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.
The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.
“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”
The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine.
“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
Myocarditis
The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.
It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.
The document makes the following recommendations in regard to COVID-related myocarditis:
When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.
Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.
Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.
As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.
The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.
But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.
In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
Long COVID
The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.
Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.
Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”
The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:
PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.
PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.
The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.
For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.
Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.
Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.
Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.
Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
Return to play for athletes
The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.
But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.
They make the following recommendations:
- For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
- For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
- Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
- For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
- For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.
Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.
Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.
The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.
“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.
The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.
A version of this article first appeared on Medscape.com.
The American College of Cardiology has issued an expert consensus clinical guidance document for the evaluation and management of adults with key cardiovascular consequences of COVID-19.
The document makes recommendations on how to evaluate and manage COVID-associated myocarditis and long COVID and gives advice on resumption of exercise following COVID-19 infection.
The clinical guidance was published online March 16 in the Journal of the American College of Cardiology.
“The best means to diagnose and treat myocarditis and long COVID following SARS-CoV-2 infection continues to evolve,” said Ty Gluckman, MD, MHA, cochair of the expert consensus decision pathway. “This document attempts to provide key recommendations for how to evaluate and manage adults with these conditions, including guidance for safe return to play for both competitive and noncompetitive athletes.”
The authors of the guidance note that COVID-19 can be associated with various abnormalities in cardiac testing and a wide range of cardiovascular complications. For some patients, cardiac symptoms such as chest pain, shortness of breath, fatigue, and palpitations persist, lasting months after the initial illness, and evidence of myocardial injury has also been observed in both symptomatic and asymptomatic individuals, as well as after receipt of the COVID-19 mRNA vaccine.
“For clinicians treating these individuals, a growing number of questions exist related to evaluation and management of these conditions, as well as safe resumption of physical activity,” they say. This report is intended to provide practical guidance on these issues.
Myocarditis
The report states that myocarditis has been recognized as a rare but serious complication of SARS-CoV-2 infection as well as COVID-19 mRNA vaccination.
It defines myocarditis as: 1.cardiac symptoms such as chest pain, dyspnea, palpitations, or syncope; 2. elevated cardiac troponin; and 3. abnormal electrocardiographic, echocardiographic, cardiac MRI, and/or histopathologic findings on biopsy.
The document makes the following recommendations in regard to COVID-related myocarditis:
When there is increased suspicion for cardiac involvement with COVID-19, initial testing should consist of an ECG, measurement of cardiac troponin, and an echocardiogram. Cardiology consultation is recommended for those with a rising cardiac troponin and/or echocardiographic abnormalities. Cardiac MRI is recommended in hemodynamically stable patients with suspected myocarditis.
Hospitalization is recommended for patients with definite myocarditis, ideally at an advanced heart failure center. Patients with fulminant myocarditis should be managed at centers with an expertise in advanced heart failure, mechanical circulatory support, and other advanced therapies.
Patients with myocarditis and COVID-19 pneumonia (with an ongoing need for supplemental oxygen) should be treated with corticosteroids. For patients with suspected pericardial involvement, treatment with NSAIDs, colchicine, and/or prednisone is reasonable. Intravenous corticosteroids may be considered in those with suspected or confirmed COVID-19 myocarditis with hemodynamic compromise or MIS-A (multisystem inflammatory syndrome in adults). Empiric use of corticosteroids may also be considered in those with biopsy evidence of severe myocardial infiltrates or fulminant myocarditis, balanced against infection risk.
As appropriate, guideline-directed medical therapy for heart failure should be initiated and continued after discharge.
The document notes that myocarditis following COVID-19 mRNA vaccination is rare, with highest rates seen in young males after the second vaccine dose. As of May 22, 2021, the U.S. Vaccine Adverse Event Reporting System noted rates of 40.6 cases per million after the second vaccine dose among male individuals aged 12-29 years and 2.4 cases per million among male individuals aged 30 and older. Corresponding rates in female individuals were 4.2 and 1 cases per million, respectively.
But the report says that COVID-19 vaccination is associated with “a very favorable benefit-to-risk ratio” for all age and sex groups evaluated thus far.
In general, vaccine-associated myocarditis should be diagnosed, categorized, and treated in a manner analogous to myocarditis following SARS-CoV-2 infection, the guidance advises.
Long COVID
The document refers to long COVID as postacute sequelae of SARS-CoV-2 infection (PASC), and reports that this condition is experienced by up to 10%-30% of infected individuals. It is defined by a constellation of new, returning, or persistent health problems experienced by individuals 4 or more weeks after COVID-19 infection.
Although individuals with this condition may experience wide-ranging symptoms, the symptoms that draw increased attention to the cardiovascular system include tachycardia, exercise intolerance, chest pain, and shortness of breath.
Nicole Bhave, MD, cochair of the expert consensus decision pathway, says: “There appears to be a ‘downward spiral’ for long-COVID patients. Fatigue and decreased exercise capacity lead to diminished activity and bed rest, in turn leading to worsening symptoms and decreased quality of life.” She adds that “the writing committee recommends a basic cardiopulmonary evaluation performed up front to determine if further specialty care and formalized medical therapy is needed for these patients.”
The authors propose two terms to better understand potential etiologies for those with cardiovascular symptoms:
PASC-CVD, or PASC-cardiovascular disease, refers to a broad group of cardiovascular conditions (including myocarditis) that manifest at least 4 weeks after COVID-19 infection.
PASC-CVS, or PASC-cardiovascular syndrome, includes a wide range of cardiovascular symptoms without objective evidence of cardiovascular disease following standard diagnostic testing.
The document makes the following recommendations for the management of PASC-CVD and PASC-CVS.
For patients with cardiovascular symptoms and suspected PASC, the authors suggest that a reasonable initial testing approach includes basic laboratory testing, including cardiac troponin, an ECG, an echocardiogram, an ambulatory rhythm monitor, chest imaging, and/or pulmonary function tests.
Cardiology consultation is recommended for patients with PASC who have abnormal cardiac test results, known cardiovascular disease with new or worsening symptoms, documented cardiac complications during SARS-CoV-2 infection, and/or persistent cardiopulmonary symptoms that are not otherwise explained.
Recumbent or semirecumbent exercise (for example, rowing, swimming, or cycling) is recommended initially for PASC-CVS patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning, with transition to upright exercise as orthostatic intolerance improves. Exercise duration should also be short (5-10 minutes/day) initially, with gradual increases as functional capacity improves.
Salt and fluid loading represent nonpharmacologic interventions that may provide symptomatic relief for patients with tachycardia, palpitations, and/or orthostatic hypotension.
Beta-blockers, nondihydropyridine calcium-channel blockers, ivabradine, fludrocortisone, and midodrine may be used empirically as well.
Return to play for athletes
The authors note that concerns about possible cardiac injury after COVID-19 fueled early apprehension regarding the safety of competitive sports for athletes recovering from the infection.
But they say that subsequent data from large registries have demonstrated an overall low prevalence of clinical myocarditis, without a rise in the rate of adverse cardiac events. Based on this, updated guidance is provided with a practical, evidence-based framework to guide resumption of athletics and intense exercise training.
They make the following recommendations:
- For athletes recovering from COVID-19 with ongoing cardiopulmonary symptoms (chest pain, shortness of breath, palpitations, lightheadedness) or those requiring hospitalization with increased suspicion for cardiac involvement, further evaluation with triad testing – an ECG, measurement of cardiac troponin, and an echocardiogram – should be performed.
- For those with abnormal test results, further evaluation with cardiac MRI should be considered. Individuals diagnosed with clinical myocarditis should abstain from exercise for 3-6 months.
- Cardiac testing is not recommended for asymptomatic individuals following COVID-19 infection. Individuals should abstain from training for 3 days to ensure that symptoms do not develop.
- For those with mild or moderate noncardiopulmonary symptoms (fever, lethargy, muscle aches), training may resume after symptom resolution.
- For those with remote infection (≥3 months) without ongoing cardiopulmonary symptoms, a gradual increase in exercise is recommended without the need for cardiac testing.
Based on the low prevalence of myocarditis observed in competitive athletes with COVID-19, the authors note that these recommendations can be reasonably applied to high-school athletes (aged 14 and older) along with adult recreational exercise enthusiasts.
Future study is needed, however, to better understand how long cardiac abnormalities persist following COVID-19 infection and the role of exercise training in long COVID.
The authors conclude that the current guidance is intended to help clinicians understand not only when testing may be warranted, but also when it is not.
“Given that it reflects the current state of knowledge through early 2022, it is anticipated that recommendations will change over time as our understanding evolves,” they say.
The 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19: Myocarditis, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and Return to Play will be discussed in a session at the American College of Cardiology’s annual scientific session meeting in Washington in April.
A version of this article first appeared on Medscape.com.
ESC suspension of Russia, Belarus societies sparks controversy
, provoking a heated discussion on whether medical organizations should become involved in politics.
“In the light of the continued aggression against Ukraine by the leaderships of the Russian Federation and Belarus, the European Society of Cardiology (ESC) has temporarily suspended the memberships of the Russian Society of Cardiology and the Belarussian Society of Cardiologists in the ESC,” the ESC statement reads.
“Individuals based in the Russian Federation or in Belarus are excluded from active participation in any ESC event or activity,” it states.
“The ESC very much regrets the effect this may have on individual Russian and Belarussian cardiologists and scientists, but the message to Russian and Belarussian leadership must be distinct and unequivocal,” it adds.
This action from the ESC has provoked a storm of heated discussions on the issue.
In a Twitter thread on the subject, Italian cardiologist Giuseppe Galati, MD, writes: “An astonishing decision by ESC that’s excluding all the Russian and Belarussian scientists from ESC congresses and activities. Treating doctors and scientists as [if] they are Putin and are responsible for the war.”
Dr. Galati adds: “A strong message that brings us to 70 years ago. ESC is promoting exclusion and not inclusion and diversity.”
Another commentator on the thread says: “It is a very unfortunate decision. Science, medicine should not be involved in politics. We are colleagues gathering together during congresses to exchange information for the sake of our patients. Politics should not overshadow this.”
And another added: “I think most cardiologists from Russia will not be able to participate in the events anyway, since international payments will soon be impossible from Russia. But it is wrong to limit the rights of doctors because of their nationality.”
But others support the ESC’s stance. Polish cardiologist Blazej Michalski, MD, says: “I think it is [a] good decision. Russians if they do not actively support dictatorship of Putin, the silence is also an agreement.” He adds: “I am proud of ESC. They did what they were supposed to do.”
A Twitter poll started by Ali Elzieny, MD, a cardiologist from Boston, titled “Do you agree that ESC suspend membership of Russian Society of Cardiology?” as of March 8 had 1,300 votes, with 61% of respondents disagreeing with the ESC decision and 39% in favor.
Medical societies respond
Several other medical societies have issued communications appearing to disagree with the action by the ESC.
The American College of Cardiology issued a statement saying medicine should be above politics.
“The American College of Cardiology believes that patients come first, and now, more than ever, there is a need to rally around our members across the globe to ensure that they have the support and resources they need to care for their patients,” said ACC President Dipti Itchhaporia, MD.
“Medicine is above politics and ACC will not exclude any of our colleagues who are working toward a shared mission of improving heart health. The College has a long history of working across borders to improve heart health and remains committed to that now and in the future. The ACC continues to express its support and concern for our members in the Ukraine and the patients they are working to treat on the frontlines,” the ACC statement added.
The Tele-Cardiology Working Group of the International Society for Telemedicine & eHealth (ISFTEH) also issued a statement disagreeing with the action from the ESC.
“In light of recent events, the cardiology working group of the ISFTEH will not restrict access to its events to cardiologists with regards to their nationality, religious beliefs or other characteristics that may seem discriminatory. We believe medical information should be widely available for all, especially for those doctors that find themselves in difficulty,” it said.
The European Academy of Neurology (EAN) said: “EAN is looking at ways to give practical support to Ukrainian neurologists and healthcare professionals there. EAN is not considering suspension of any individual member based on country of residence or nationality or any National Society member.”
But one oncology professional group has also cut ties with Russia.
The international cancer specialist network, OncoAlert, issued a statement saying it has severed all cooperation with doctors in Russia as part of the Western sanctions.
“The OncoAlert Network is non-political, but we cannot stand idle and not take a stand against this aggression towards our Ukrainian friends & colleagues,” OncoAlert said, adding that it will be pulling out of all collaborations and congresses in Russia. That statement was also greeted with a barrage of criticism on Twitter, mainly from Russian users.
A version of this article first appeared on Medscape.com.
, provoking a heated discussion on whether medical organizations should become involved in politics.
“In the light of the continued aggression against Ukraine by the leaderships of the Russian Federation and Belarus, the European Society of Cardiology (ESC) has temporarily suspended the memberships of the Russian Society of Cardiology and the Belarussian Society of Cardiologists in the ESC,” the ESC statement reads.
“Individuals based in the Russian Federation or in Belarus are excluded from active participation in any ESC event or activity,” it states.
“The ESC very much regrets the effect this may have on individual Russian and Belarussian cardiologists and scientists, but the message to Russian and Belarussian leadership must be distinct and unequivocal,” it adds.
This action from the ESC has provoked a storm of heated discussions on the issue.
In a Twitter thread on the subject, Italian cardiologist Giuseppe Galati, MD, writes: “An astonishing decision by ESC that’s excluding all the Russian and Belarussian scientists from ESC congresses and activities. Treating doctors and scientists as [if] they are Putin and are responsible for the war.”
Dr. Galati adds: “A strong message that brings us to 70 years ago. ESC is promoting exclusion and not inclusion and diversity.”
Another commentator on the thread says: “It is a very unfortunate decision. Science, medicine should not be involved in politics. We are colleagues gathering together during congresses to exchange information for the sake of our patients. Politics should not overshadow this.”
And another added: “I think most cardiologists from Russia will not be able to participate in the events anyway, since international payments will soon be impossible from Russia. But it is wrong to limit the rights of doctors because of their nationality.”
But others support the ESC’s stance. Polish cardiologist Blazej Michalski, MD, says: “I think it is [a] good decision. Russians if they do not actively support dictatorship of Putin, the silence is also an agreement.” He adds: “I am proud of ESC. They did what they were supposed to do.”
A Twitter poll started by Ali Elzieny, MD, a cardiologist from Boston, titled “Do you agree that ESC suspend membership of Russian Society of Cardiology?” as of March 8 had 1,300 votes, with 61% of respondents disagreeing with the ESC decision and 39% in favor.
Medical societies respond
Several other medical societies have issued communications appearing to disagree with the action by the ESC.
The American College of Cardiology issued a statement saying medicine should be above politics.
“The American College of Cardiology believes that patients come first, and now, more than ever, there is a need to rally around our members across the globe to ensure that they have the support and resources they need to care for their patients,” said ACC President Dipti Itchhaporia, MD.
“Medicine is above politics and ACC will not exclude any of our colleagues who are working toward a shared mission of improving heart health. The College has a long history of working across borders to improve heart health and remains committed to that now and in the future. The ACC continues to express its support and concern for our members in the Ukraine and the patients they are working to treat on the frontlines,” the ACC statement added.
The Tele-Cardiology Working Group of the International Society for Telemedicine & eHealth (ISFTEH) also issued a statement disagreeing with the action from the ESC.
“In light of recent events, the cardiology working group of the ISFTEH will not restrict access to its events to cardiologists with regards to their nationality, religious beliefs or other characteristics that may seem discriminatory. We believe medical information should be widely available for all, especially for those doctors that find themselves in difficulty,” it said.
The European Academy of Neurology (EAN) said: “EAN is looking at ways to give practical support to Ukrainian neurologists and healthcare professionals there. EAN is not considering suspension of any individual member based on country of residence or nationality or any National Society member.”
But one oncology professional group has also cut ties with Russia.
The international cancer specialist network, OncoAlert, issued a statement saying it has severed all cooperation with doctors in Russia as part of the Western sanctions.
“The OncoAlert Network is non-political, but we cannot stand idle and not take a stand against this aggression towards our Ukrainian friends & colleagues,” OncoAlert said, adding that it will be pulling out of all collaborations and congresses in Russia. That statement was also greeted with a barrage of criticism on Twitter, mainly from Russian users.
A version of this article first appeared on Medscape.com.
, provoking a heated discussion on whether medical organizations should become involved in politics.
“In the light of the continued aggression against Ukraine by the leaderships of the Russian Federation and Belarus, the European Society of Cardiology (ESC) has temporarily suspended the memberships of the Russian Society of Cardiology and the Belarussian Society of Cardiologists in the ESC,” the ESC statement reads.
“Individuals based in the Russian Federation or in Belarus are excluded from active participation in any ESC event or activity,” it states.
“The ESC very much regrets the effect this may have on individual Russian and Belarussian cardiologists and scientists, but the message to Russian and Belarussian leadership must be distinct and unequivocal,” it adds.
This action from the ESC has provoked a storm of heated discussions on the issue.
In a Twitter thread on the subject, Italian cardiologist Giuseppe Galati, MD, writes: “An astonishing decision by ESC that’s excluding all the Russian and Belarussian scientists from ESC congresses and activities. Treating doctors and scientists as [if] they are Putin and are responsible for the war.”
Dr. Galati adds: “A strong message that brings us to 70 years ago. ESC is promoting exclusion and not inclusion and diversity.”
Another commentator on the thread says: “It is a very unfortunate decision. Science, medicine should not be involved in politics. We are colleagues gathering together during congresses to exchange information for the sake of our patients. Politics should not overshadow this.”
And another added: “I think most cardiologists from Russia will not be able to participate in the events anyway, since international payments will soon be impossible from Russia. But it is wrong to limit the rights of doctors because of their nationality.”
But others support the ESC’s stance. Polish cardiologist Blazej Michalski, MD, says: “I think it is [a] good decision. Russians if they do not actively support dictatorship of Putin, the silence is also an agreement.” He adds: “I am proud of ESC. They did what they were supposed to do.”
A Twitter poll started by Ali Elzieny, MD, a cardiologist from Boston, titled “Do you agree that ESC suspend membership of Russian Society of Cardiology?” as of March 8 had 1,300 votes, with 61% of respondents disagreeing with the ESC decision and 39% in favor.
Medical societies respond
Several other medical societies have issued communications appearing to disagree with the action by the ESC.
The American College of Cardiology issued a statement saying medicine should be above politics.
“The American College of Cardiology believes that patients come first, and now, more than ever, there is a need to rally around our members across the globe to ensure that they have the support and resources they need to care for their patients,” said ACC President Dipti Itchhaporia, MD.
“Medicine is above politics and ACC will not exclude any of our colleagues who are working toward a shared mission of improving heart health. The College has a long history of working across borders to improve heart health and remains committed to that now and in the future. The ACC continues to express its support and concern for our members in the Ukraine and the patients they are working to treat on the frontlines,” the ACC statement added.
The Tele-Cardiology Working Group of the International Society for Telemedicine & eHealth (ISFTEH) also issued a statement disagreeing with the action from the ESC.
“In light of recent events, the cardiology working group of the ISFTEH will not restrict access to its events to cardiologists with regards to their nationality, religious beliefs or other characteristics that may seem discriminatory. We believe medical information should be widely available for all, especially for those doctors that find themselves in difficulty,” it said.
The European Academy of Neurology (EAN) said: “EAN is looking at ways to give practical support to Ukrainian neurologists and healthcare professionals there. EAN is not considering suspension of any individual member based on country of residence or nationality or any National Society member.”
But one oncology professional group has also cut ties with Russia.
The international cancer specialist network, OncoAlert, issued a statement saying it has severed all cooperation with doctors in Russia as part of the Western sanctions.
“The OncoAlert Network is non-political, but we cannot stand idle and not take a stand against this aggression towards our Ukrainian friends & colleagues,” OncoAlert said, adding that it will be pulling out of all collaborations and congresses in Russia. That statement was also greeted with a barrage of criticism on Twitter, mainly from Russian users.
A version of this article first appeared on Medscape.com.
ARBs and cancer risk: New meta-analysis raises questions again
The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.
The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.
The findings are reported in a study published online in PLOS ONE.
The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.
“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.
“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.
Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.
Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.
Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).
“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.
“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.
From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.
“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.
For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.
“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”
The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.
In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.
Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).
In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).
There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).
In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.
Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).
But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.
Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.
He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”
Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
A ‘clear increase’ in risk
Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.
“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.
Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.
Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.
“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.
Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”
Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”
Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
Analysis ‘should be taken seriously’
Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously.
Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.
He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.
“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.
“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
Limitations of trial-level analysis
Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.
“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.
He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer.
“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.
Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”
He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
Cardiologists skeptical?
Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.
Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”
But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”
He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”
Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”
Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.
George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”
“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”
Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.
“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”
Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.
Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”
Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”
Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.
A version of this article first appeared on Medscape.com.
The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.
The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.
The findings are reported in a study published online in PLOS ONE.
The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.
“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.
“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.
Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.
Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.
Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).
“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.
“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.
From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.
“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.
For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.
“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”
The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.
In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.
Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).
In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).
There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).
In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.
Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).
But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.
Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.
He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”
Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
A ‘clear increase’ in risk
Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.
“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.
Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.
Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.
“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.
Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”
Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”
Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
Analysis ‘should be taken seriously’
Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously.
Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.
He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.
“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.
“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
Limitations of trial-level analysis
Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.
“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.
He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer.
“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.
Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”
He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
Cardiologists skeptical?
Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.
Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”
But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”
He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”
Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”
Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.
George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”
“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”
Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.
“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”
Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.
Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”
Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”
Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.
A version of this article first appeared on Medscape.com.
The debate on whether the popular class of antihypertensive drugs, angiotensin receptor blockers (ARBs), may be associated with an increased risk for cancer has been reopened with the publication of a new meta-analysis.
The analysis found an increasing risk for cancer, and specifically lung cancer, with increasing cumulative exposure to these drugs.
The findings are reported in a study published online in PLOS ONE.
The author of this new meta-analysis is Ilke Sipahi, MD, a cardiologist from Acibadem University Medical School, Istanbul, who previously raised this issue in an initial meta-analysis published in 2010.
“The new meta-analysis is important because it is the first study to investigate whether there is a dose response in the association between ARBs and cancer,” Dr. Sipahi told this news organization.
“I found a clear signal of increased risk of cancer as exposure to ARBs increased, and the association started to become significant when the maximum dose was taken for 3 years,” he added.
Dr. Sipahi explained that in the first meta-analysis published in Lancet Oncology, he and his colleagues reported an increased cancer risk with ARBs based on observations from high-exposure trials – those that included higher doses of ARBs with a long duration of follow-up.
Following this publication, an investigation by the U.S. Food and Drug Administration refuted the risk, and a collaboration of ARB trial investigators also performed an analysis published in the Journal of Hypertension (2011. doi: 10.1097/HJH.0b013e328344a7de), which again did not show an increased risk for cancer with use of ARBs.
Dr. Sipahi claims that those analyses by the FDA and the ARB Trialists Collaboration, which were all trial-level meta-analyses, diluted the “high exposure” data (including higher doses taken for longer periods of time) with a large amount of other data on much lower exposures (lower doses and/or shorter time periods).
“The overall risk would then inevitably become nonsignificant. These analyses also did not look at different exposure levels,” he says.
“For cancer, the degree of exposure is obviously very important. The risk associated with smoking 2 or 3 cigarettes a day for a year is very different from that of smoking 2 packs a day for 40 years. The same principle applies to taking a medication,” Dr. Sipahi asserts.
From these latest data, he estimates that 120 patients needed to be treated with the maximal daily dose of an ARB for 4.7 years for one excess cancer diagnosis, and 464 patients needed to be treated for one excess lung cancer.
“Given that at least 200 million individuals are being treated with an ARB globally, approximately 1.7 million excess cancers (and 430,000 lung cancers) in 4.6 years could be potentially caused by this class of drugs,” he suggests.
For the current analysis, Dr. Sipahi used trial-level data taken from the paper by the ARB Trialists Collaboration and investigated the effect of exposure to ARBs – including both the dose taken and the length of treatment – on risk for cancer. He performed metaregression analyses that he says has not been done before.
“I mathematically quantitated the degree of exposure in each trial. And when the degree of exposure was correlated with risk of cancer, there was a significant association.”
The new meta-analysis includes 15 randomized controlled trials. The two coprimary outcomes were the relationship between cumulative exposure to ARBs and risk for all cancers combined and the relationship between cumulative exposure and risk for lung cancer.
In the trials, 74,021 patients were randomly assigned to an ARB, resulting in a total cumulative exposure of 172,389 person-years of exposure to daily high dose (or equivalent), and 61,197 patients were randomly assigned to control.
Results showed a highly significant correlation between the degree of cumulative exposure to ARBs and risk for all cancers combined (slope = 0.07; 95% confidence interval, 0.03-0.11; P < .001) and also lung cancer (slope = 0.16; 95% CI, 0.05-0.27; P = .003).
In trials where the cumulative exposure was greater than 3 years of exposure to daily high dose, there was a statistically significant increase in risk for all cancers combined (risk ratio, 1.11; 95% CI, 1.03-1.19; P = .006).
There was also a statistically significant increase in risk for lung cancers in trials where the cumulative exposure was greater than 2.5 years (RR, 1.21; 95% CI, 1.02-1.44; P = .03).
In trials with lower cumulative exposure to ARBs, there was no increased risk either for all cancers combined or lung cancer.
Dr. Sipahi reports that the cumulative exposure-risk relationship with ARBs was independent of background angiotensin-converting enzyme (ACE) inhibitor treatment or the type of control (placebo or nonplacebo control).
But he acknowledges that since this is a trial-level analysis, the effects of patient characteristics such as age and smoking status could not be examined because of lack of patient-level data.
Dr. Sipahi says he does not know the mechanism behind these findings, but he draws attention to the recent withdrawal of several thousand lots of ARB formulations because of the presence of potentially carcinogenic impurities that have been suggested to be a byproduct of ARB synthesis.
He also claims that unlike some other classes of antihypertensives, ARBs have not been shown to reduce the risk for MI, leading him to conclude that “other classes of antihypertensives with good safety and efficacy data (such as ACE-inhibitors, calcium-channel blockers or others) should become the preferred first-line agents in the treatment of hypertension.”
Dr. Sipahi wants the FDA to reinvestigate the issue of ARBs and cancer risk using individual patient data. “They already have the patient-level data from the trials. They should look at it more carefully and look at exposure levels and how they relate to cancer risk,” he said. “And the fact that there have been studies linking high ARB exposure levels to increased cancer risk should at least get a warning on the drug labels.”
A ‘clear increase’ in risk
Dr. Sipahi also points out that a link between ARBs and cancer has been found in another meta-analysis performed in 2013 by senior FDA analyst Thomas Marciniak, MD.
“Because he worked at the FDA, [Dr.] Marciniak had access to individual patent data. This is the best type of analysis and generally produces more accurate results than a trial-level meta-analysis,” Dr. Sipahi commented.
Dr. Marciniak’s analysis, which is available on the FDA website as part of another document, was not officially published elsewhere, and no further action has been taken on the issue.
Contacted by this news organization, Dr. Marciniak, who has now retired from the FDA, said he not only conducted a patient-level meta-analysis but also followed up adverse effects reported in the trials that could have been a symptom of cancer to establish further whether the patient was later diagnosed with cancer or not.
“I used every scrap of information sent in, including serious adverse event reports. I saw a clear increase in lung cancer risk with the ARBs,” Dr. Marciniak said. He did not, however, perform a dose-response relationship analysis.
Asked why his analysis and those from Dr. Sipahi reach different conclusions to those from the ARB Trialists Collaboration and the official FDA investigations, Dr. Marciniak said: “It may be that there were too many low-exposure trials that just washed out the difference. But trial data generally do not capture adverse events such as cancer, which takes a long time to develop, very well, and if you’re not really looking for it, you’re probably not going to find it.”
Dr. Marciniak said that Dr. Sipahi’s current findings are in line with his results. “Finding a dose response, to me, is extremely compelling, and I think the signal here is real,” he commented. “I think this new paper from Dr. Sipahi verifies what I found. I think the FDA should now release all individual patient data it has.”
Contacted for comment, an FDA spokesperson said, “Generally the FDA does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
They added: “The FDA has ongoing assessment, surveillance, compliance, and pharmaceutical quality efforts across every product area, and we will continue to work with drug manufacturers to ensure safe, effective, and high-quality drugs for the American public. When we identify new and previously unrecognized risks to safety and quality, we react swiftly to resolve the problem, as we have done in responding to the recent findings of nitrosamines in certain medicines.”
Analysis ‘should be taken seriously’
Commenting on this new study, Steve Nissen, MD, a key figure in analyzing such complex data and who has himself uncovered problems with high-profile drugs in the past, says the current analysis should be taken seriously.
Dr. Nissen, who was Dr. Sipahi’s senior during his post-doc position at the Cleveland Clinic, wrote an editorial accompanying Dr. Sipahi’s first paper and calling for urgent regulatory review of the evidence.
He says the new findings add to previous evidence suggesting a possible risk for cancer with ARBs.
“[Dr.] Sipahi is a capable researcher, and this analysis needs to be taken seriously, but it needs to be verified. It is not possible to draw a strong conclusion on this analysis, as it is not based on individual patient data, but I don’t think it should be ignored,” Dr. Nissen stated.
“I will say again what I said 12 years ago – that the regulatory agencies need to carefully review all their data in a very detailed way. The FDA and EMA have access to the individual patient data and are both very capable of doing the required analyses.”
Limitations of trial-level analysis
Asked to evaluate the statistics in the current paper, Andrew Althouse, PhD, an assistant professor of medicine at the University of Pittsburgh, and a clinical trial statistician, explained that the best way to do a thorough analysis of the relationship between ARB exposure and risk for incident cancer would involve the use of patient-level data.
“As such data were not available to Dr. Sipahi, I believe he is doing as well as he can. But without full access to individual patient-level data from the respective trials, it is difficult to support any firm conclusions,” Dr. Althouse said in an interview.
He suggested that the meta-regression analyses used in the paper were unable to properly estimate the relationship between ARB exposure and risk for incident cancer.
“Taken at face value, the current analysis suggests that [in] trials with longer follow-up duration (and therefore greater cumulative exposure to ARB for the treatment group), the risk of developing cancer for patients in the ARB group versus the non-ARB group was progressively higher. But this study doesn’t take into account the actual amount of follow-up time for individual patients or potential differences in the amount of follow-up time between the two groups in each trial,” he noted.
Dr. Althouse says this raises the possibility of “competing risks” or the idea that if ARBs reduce cardiovascular disease and cardiovascular death, then there would be more patients remaining in that arm who could go on to develop cancer. “So a crude count of the number of cancer cases may look as though patients receiving ARBs are ‘more likely’ to develop cancer, but this is a mirage.”
He added: “When there are some patients dying during the study, the only way to tell whether the intervention actually increased the risk of other health-related complications is to have an analysis that properly accounts for each patient’s time-at-risk of the outcome. Unfortunately, properly analyzing this requires the use of patient-level data.”
Cardiologists skeptical?
Cardiology experts asked for thoughts on the new meta-analysis were also cautious to read too much into the findings.
Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “Perhaps one would simply ignore this rambling, cherrypicking-based condemnation of ARBs if it were not for the powerful negative connotation of the word cancer. Thus, the meta-analysis of Dr. Sipahi purporting that ARBs could be increasing the development of cancers in a cumulative way is of concern to both physicians and patients.”
But, raising a similar point to Dr. Althouse about competing risks, Dr. Messerli said: “We have to consider that as one gets older, the cardiovascular disease state and cancer state will compete with each other for the outcome of death. The better that therapies protect against cardiovascular death, the more they will increase life expectancy and thus the risk of cancer.”
He also added that “in head-to-head comparisons with ACE inhibitors, ARBs showed similar efficacy in terms of death, CV mortality, MI, stroke, and end-stage kidney disease, so can we agree that the attempt of Dr. Sipahi to disparage ARBs as a class is much ado about nothing?”
Dr. Nissen, however, said he views the idea of competing risk as “a bit of a stretch” in this case. “Although ARBs are effective antihypertensive drugs, I would say there is very little evidence that they would prolong survival versus other antihypertensives.”
Dr. Sipahi also claims that this argument is not relevant to the current analysis. “ARBs did not increase survival in any of the high-exposure trials that showed an excess in cancers. Therefore, competing outcomes, or ‘survival bias’ to be more specific, is not a possibility here,” he says.
George Bakris, MD, professor of medicine at the University of Chicago Medicine, noted that while the current study shows a slight increase in cancer incidence, especially lung cancer, among those taking ARBs for more than 3 years, it “totally ignores the overwhelming cardiovascular risk reduction seen in the trials.”
“Moreover,” he adds, “the author notes that the findings were independent of ACE-inhibitors, but he can’t rule out smoking and age as factors, two major risk factors for cancer and lung cancer, specifically. Thus, as typical of these types of analyses, the associations are probably true/true unrelated or, at best, partially related.”
Dr. Bakris referred to the potentially carcinogenic nitrosamine and azido compounds found in several ARB formulations that have resulted in recalls.
“At any stage of drug synthesis throughout each product’s lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions,” he said. “Drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products. The studies noted in the author’s analysis were done well before these guidelines were implemented. Hence, many of the issues raised by the authors using trials from 10-20 years ago are not of significant concern.”
Still, the cardiology experts all agreed on one thing – that patients should continue to take ARBs as prescribed.
Noting that worldwide authorities are now addressing the issue of possible carcinogen contamination, Dr. Bakris stressed that patients “should not panic and should not stop their meds.”
Dr. Nissen added: “What we don’t want is for patents who are taking ARBs to stop taking these medications – hypertension is a deadly disorder, and these drugs have proven cardiovascular benefits.”
Dr. Sipahi received no specific funding for this work. He reports receiving lecture honoraria from Novartis, Boehringer Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier, and ARIS and served on advisory boards for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay. The other commenters do not report any relevant disclosures.
A version of this article first appeared on Medscape.com.
Oil spill cleanup work tied to hypertension risk years later
Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.
Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.
“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.
The study was published online in JAMA Network Open.
For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.
“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”
Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.
“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.
Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.
Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.
Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.
Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.
Similar results were seen for the relationship between cumulative mean THC exposure levels and the development of hypertension.
Despite the limitations of accurately estimating THC exposure, Dr. Kwok believes the results are real. “We looked at many different covariates including smoking, education, gender, race, ethnicity, and body mass index, but even after controlling for all these we still saw an association between the amount of exposure to THC and risk of hypertension.”
But the risk of developing hypertension did appear to be greater in those individuals with other risk factors for hypertension such as high body mass index or smokers. “There seems to be a combined effect,” Dr. Kwok said.
He pointed out that, while previous studies have shown possible health effects related to THC exposure on an acute basis, in this study, the effect on blood pressure was still evident years after the exposure had ended.
Other occupational studies have looked at people in jobs that have had longer exposures to volatile organic compounds such as taxi drivers, but this is one of the first to look at the long-term effect of a more limited period of exposure, he added.
“Our results suggest that the damage caused by THCs is not just an acute effect, but is still there several years later,” Dr. Kwok commented.
He says he hoped this study will raise awareness of the health hazards to workers involved in future oil spills. “Our results suggest that we need better protective equipment and monitoring of workers and the local community with longer-term follow up for health outcomes.”
Another analysis showed no clear differences in hypertension risk between individuals who worked on the oil spill cleanup (workers) and others who had completed required safety training but did not participate in the clean-up operation (nonworkers). Dr. Kwok suggested this may have been a result of the “healthy worker effect,” which is based on the premise that individuals able to work are healthier than those unable to work.
This study was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The authors reported no disclosures.
A version of this article first appeared on Medscape.com.
Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.
Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.
“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.
The study was published online in JAMA Network Open.
For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.
“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”
Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.
“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.
Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.
Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.
Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.
Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.
Similar results were seen for the relationship between cumulative mean THC exposure levels and the development of hypertension.
Despite the limitations of accurately estimating THC exposure, Dr. Kwok believes the results are real. “We looked at many different covariates including smoking, education, gender, race, ethnicity, and body mass index, but even after controlling for all these we still saw an association between the amount of exposure to THC and risk of hypertension.”
But the risk of developing hypertension did appear to be greater in those individuals with other risk factors for hypertension such as high body mass index or smokers. “There seems to be a combined effect,” Dr. Kwok said.
He pointed out that, while previous studies have shown possible health effects related to THC exposure on an acute basis, in this study, the effect on blood pressure was still evident years after the exposure had ended.
Other occupational studies have looked at people in jobs that have had longer exposures to volatile organic compounds such as taxi drivers, but this is one of the first to look at the long-term effect of a more limited period of exposure, he added.
“Our results suggest that the damage caused by THCs is not just an acute effect, but is still there several years later,” Dr. Kwok commented.
He says he hoped this study will raise awareness of the health hazards to workers involved in future oil spills. “Our results suggest that we need better protective equipment and monitoring of workers and the local community with longer-term follow up for health outcomes.”
Another analysis showed no clear differences in hypertension risk between individuals who worked on the oil spill cleanup (workers) and others who had completed required safety training but did not participate in the clean-up operation (nonworkers). Dr. Kwok suggested this may have been a result of the “healthy worker effect,” which is based on the premise that individuals able to work are healthier than those unable to work.
This study was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The authors reported no disclosures.
A version of this article first appeared on Medscape.com.
Workers who had the highest exposure to hydrocarbons during the Deepwater Horizon oil spill disaster had a higher risk of having a hypertension diagnosis in the years following the event, a new study suggests.
Results showed that the highest exposure to total petroleum hydrocarbons during the cleanup operation was associated with a 31% higher risk of new hypertension 1-3 years later.
“What is remarkable is that we still found an increased risk of hypertension a couple of years after the cleanup had been completed. This suggests working in this environment even for a short period could have long-term health consequences,” lead author Richard Kwok, PhD, told this news organization.
The study was published online in JAMA Network Open.
For the study, Dr. Kwok, a scientist at the U.S. National Institute of Environmental Health Sciences, and colleagues estimated the levels of exposure to toxic hydrocarbons in 6,846 adults who had worked on the oil spill cleanup after the Deepwater Horizon disaster in 2010, during which 200 million gallons of oil spilled into the Gulf of Mexico. They then investigated whether there was an association with the development of hypertension 1-3 years later.
“Clean-up efforts started almost immediately and lasted over a year,” Dr. Kwok noted. “In the first few months, oil flowed freely into the Gulf of Mexico which released high levels of volatile organic compounds into the air that the workers could have been exposed to. The exposures change over time because the oil becomes weathered and starts to decompose and harden. This is associated with a lower level of volatile organic compounds but can still cause damage.”
Workers involved in the cleanup may have been there for just a few days or could have spent many months at the site and would have had different exposures depending on what types of jobs they were doing, Dr. Kwok reported.
“The highest levels of exposure to total hydrocarbons would have been to those involved in the early months of the oil spill response and cleanup when the oil was flowing freely, and those who were skimming oil off the water, burning oil, handling dispersants, or involved in the decontamination of the vessels. Others who were involved in the cleanup on land or support functions would have had lower exposures,” he said.
Each worker was interviewed and asked about their activities during the cleanup operation, the location of work, and period of work. Their level of exposure to total petroleum hydrocarbons (THCs) was estimated based on their self-reported activities, and when and where they worked.
Two measures of estimated cumulative THC were calculated: cumulative maximum daily exposure, which summed the maximum daily THC exposure level, and cumulative mean exposure, which summed the mean daily exposure levels. These THC values were categorized into quintiles based on the exposure distribution among workers.
Systolic and diastolic blood pressure measurements were collected for the workers during home exams from 2011 to 2013 using automated oscillometric monitors. Newly detected hypertension was defined as either antihypertensive medication use or elevated blood pressure since the spill.
Results showed a clear dose relationship between the level of THC exposure and the development of hypertension at follow-up.
Similar results were seen for the relationship between cumulative mean THC exposure levels and the development of hypertension.
Despite the limitations of accurately estimating THC exposure, Dr. Kwok believes the results are real. “We looked at many different covariates including smoking, education, gender, race, ethnicity, and body mass index, but even after controlling for all these we still saw an association between the amount of exposure to THC and risk of hypertension.”
But the risk of developing hypertension did appear to be greater in those individuals with other risk factors for hypertension such as high body mass index or smokers. “There seems to be a combined effect,” Dr. Kwok said.
He pointed out that, while previous studies have shown possible health effects related to THC exposure on an acute basis, in this study, the effect on blood pressure was still evident years after the exposure had ended.
Other occupational studies have looked at people in jobs that have had longer exposures to volatile organic compounds such as taxi drivers, but this is one of the first to look at the long-term effect of a more limited period of exposure, he added.
“Our results suggest that the damage caused by THCs is not just an acute effect, but is still there several years later,” Dr. Kwok commented.
He says he hoped this study will raise awareness of the health hazards to workers involved in future oil spills. “Our results suggest that we need better protective equipment and monitoring of workers and the local community with longer-term follow up for health outcomes.”
Another analysis showed no clear differences in hypertension risk between individuals who worked on the oil spill cleanup (workers) and others who had completed required safety training but did not participate in the clean-up operation (nonworkers). Dr. Kwok suggested this may have been a result of the “healthy worker effect,” which is based on the premise that individuals able to work are healthier than those unable to work.
This study was funded by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The authors reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Robotic transcranial Doppler improves PFO detection after stroke
in a new study.
Being far easier to perform than regular transcranial Doppler ultrasound, it’s hoped that use of the robotic device will enable many more patients to undergo the more sensitive transcranial screening modality and increase the number of shunts identified.
“I believe robot-assisted transcranial Doppler ultrasound can fill the gap between the gold standard transcranial Doppler and transthoracic echocardiography, which is the current standard of care,” said lead author Mark Rubin, MD.
Dr. Rubin, who is assistant professor of neurology at University of Tennessee Health Science Center, Memphis, presented results of the BUBL study at the International Stroke Conference (ISC) 2022, where they were greeted with applause from the floor.
An improvement in the current standard of care
Dr. Rubin explained that patients with suspected embolic stroke are routinely screened for shunts in the heart, such as patent foramen ovale (PFO), that allow blood to flow from the right chamber to the left chamber and can lead to clots from the venous system, accessing the arterial system, then traveling to the brain and causing a stroke.
The current standard of care in screening for such shunts is the use of transthoracic echocardiography (TTE), a widely available and easy to perform, non-invasive procedure. “But we have known for decades that TTE does not pick up these shunts very well. With a sensitivity of only around 45%, it identifies less than half of the patients affected,” Dr. Rubin noted.
The more sensitive transesophageal echocardiography (TEE) gives much better results, but it is an invasive and unpleasant procedure with the ultrasound probe being passed down the throat, and the patient needing to be sedated, so it’s not appropriate for everyone, he noted.
“Transcranial Doppler ultrasound (TCD) also gives excellent results, with a sensitivity of about 96% for detecting PFO, but this procedure is difficult to perform and requires a great deal of skill in placing the probes in the right position and interpreting the signal,” Dr. Rubin said. “TCD has been around for decades, but it hasn’t caught on, as it is too difficult to do. It takes a lot of time to learn the technique.”
“With the robotic-assisted transcranial Doppler device, we can achieve the sensitivity of TCD without needing expert operators. This should vastly improve accessibility to this technology,” he said. “With such technology we can make significant strides into more accurate diagnoses on the cause of stroke, which should lead to better preventive treatments in those found to have right-to-left shunts.”
Robotic detection of shunts
For the BUBL study, the robotic TCD technique was compared with the standard TTE in 129 patients who had a diagnosis of presumed embolic stroke or transient ischemic attack (TIA), with all patients undergoing both procedures.
The robotic TCD device resembles a giant pair of headphones containing the ultrasound probes, which are attached to a frame. In the study, it was operated by a health care professional without TCD skills. Each ultrasound probe independently scans the temporal area autonomously – with angling and positive pressure against the scalp akin to a sonographer – to find and optimize bilateral middle cerebral artery signals, Dr. Rubin explained.
The primary endpoint was the detection of a right-to-left shunt. This occurred in 82 of the 129 patients (63.6%) with the robotic TCD device but in only 27 patients (20.9%) when TTE was used. This gives an absolute difference of 42.6% (95% confidence interval, 28.6%-56.7%; P < .001), which Dr. Rubin described as “astounding.”
However, he said he was not surprised by these results.
“In my experience with transcranial Doppler, I find shunts in patients every day that have not been seen with transthoracic echo,” he commented.
He noted that a previous meta-analysis has suggested a similar difference between TCD and transthoracic echo, but the current study provides prospectively collected data produced in a clinical trial setting and is therefore more reliable.
“What I hope comes from this is that more patients will be able to undergo transcranial Doppler, which is a far superior screening technique for identifying right-to-left shunts. There is so much evidence to support the use of transcranial Doppler, but with this new artificial-intelligence robotic device, we don’t need an expert to use it,” Dr. Rubin said.
He explained that finding a right-to-left shunt in stroke patients is particularly important, as it can direct treatment strategies to reduce future risk of recurrent strokes.
“If a patient has a large shunt, then they have a high risk of having another stroke, and the PFO should be closed.”
In this study, the robotic-assisted TCD detected three times as many large shunts that were considered “intervenable,” compared with transthoracic echo, identifying these shunts in 35 patients (27%) compared to just 13 (10%) with TTE.
“Of the 35 patients with intervenable shunts detected with robotic transcranial Doppler, TTE was completely negative in 18 of them and only suggested a small shunt in the others. So, the standard of care (TTE) missed half the patients with intervenable PFOs,” Dr. Rubin reported.
Study should ‘dramatically change’ practice
Commenting on the study, Patrick Lyden, MD, professor of physiology and neuroscience and of neurology, University of Southern California, Los Angeles, said: “Most clinicians hesitate to use transcranial Doppler given the need for specialized technical expertise to obtain a reliable result. This study showed that a robotic transcranial Doppler device – which can be applied by any cardiac non-invasive lab technician – provides reliable and rigorous data.”
He added: “This result will dramatically change the typical evaluation of patients with suspected PFO: In place of an invasive transesophageal echo that requires anesthesia and a cardiologist, most patients can have a non-invasive, robotic-guided transcranial Doppler and get the same diagnostic benefit.”
Dr. Lyden also pointed out that the cost of TCD is typically one-tenth that of TEE, although he said the cost of the robotic guided TCD “is not clear.”
A representative of the company that makes the robotic assisted device, NovaSignal, says the cost of the equipment is approximately $250,000, but “understanding the importance of the technology, we work with each hospital to meet their unique needs.”
The company adds that it currently has “over 45 commercial solutions deployed across 25 centers with 3-4 times growth expected year over year.”
The study was supported by NovaSignal, the company which makes the robotic device. Dr. Rubin reports acting as a consultant for the NovaSignal.
A version of this article first appeared on Medscape.com.
in a new study.
Being far easier to perform than regular transcranial Doppler ultrasound, it’s hoped that use of the robotic device will enable many more patients to undergo the more sensitive transcranial screening modality and increase the number of shunts identified.
“I believe robot-assisted transcranial Doppler ultrasound can fill the gap between the gold standard transcranial Doppler and transthoracic echocardiography, which is the current standard of care,” said lead author Mark Rubin, MD.
Dr. Rubin, who is assistant professor of neurology at University of Tennessee Health Science Center, Memphis, presented results of the BUBL study at the International Stroke Conference (ISC) 2022, where they were greeted with applause from the floor.
An improvement in the current standard of care
Dr. Rubin explained that patients with suspected embolic stroke are routinely screened for shunts in the heart, such as patent foramen ovale (PFO), that allow blood to flow from the right chamber to the left chamber and can lead to clots from the venous system, accessing the arterial system, then traveling to the brain and causing a stroke.
The current standard of care in screening for such shunts is the use of transthoracic echocardiography (TTE), a widely available and easy to perform, non-invasive procedure. “But we have known for decades that TTE does not pick up these shunts very well. With a sensitivity of only around 45%, it identifies less than half of the patients affected,” Dr. Rubin noted.
The more sensitive transesophageal echocardiography (TEE) gives much better results, but it is an invasive and unpleasant procedure with the ultrasound probe being passed down the throat, and the patient needing to be sedated, so it’s not appropriate for everyone, he noted.
“Transcranial Doppler ultrasound (TCD) also gives excellent results, with a sensitivity of about 96% for detecting PFO, but this procedure is difficult to perform and requires a great deal of skill in placing the probes in the right position and interpreting the signal,” Dr. Rubin said. “TCD has been around for decades, but it hasn’t caught on, as it is too difficult to do. It takes a lot of time to learn the technique.”
“With the robotic-assisted transcranial Doppler device, we can achieve the sensitivity of TCD without needing expert operators. This should vastly improve accessibility to this technology,” he said. “With such technology we can make significant strides into more accurate diagnoses on the cause of stroke, which should lead to better preventive treatments in those found to have right-to-left shunts.”
Robotic detection of shunts
For the BUBL study, the robotic TCD technique was compared with the standard TTE in 129 patients who had a diagnosis of presumed embolic stroke or transient ischemic attack (TIA), with all patients undergoing both procedures.
The robotic TCD device resembles a giant pair of headphones containing the ultrasound probes, which are attached to a frame. In the study, it was operated by a health care professional without TCD skills. Each ultrasound probe independently scans the temporal area autonomously – with angling and positive pressure against the scalp akin to a sonographer – to find and optimize bilateral middle cerebral artery signals, Dr. Rubin explained.
The primary endpoint was the detection of a right-to-left shunt. This occurred in 82 of the 129 patients (63.6%) with the robotic TCD device but in only 27 patients (20.9%) when TTE was used. This gives an absolute difference of 42.6% (95% confidence interval, 28.6%-56.7%; P < .001), which Dr. Rubin described as “astounding.”
However, he said he was not surprised by these results.
“In my experience with transcranial Doppler, I find shunts in patients every day that have not been seen with transthoracic echo,” he commented.
He noted that a previous meta-analysis has suggested a similar difference between TCD and transthoracic echo, but the current study provides prospectively collected data produced in a clinical trial setting and is therefore more reliable.
“What I hope comes from this is that more patients will be able to undergo transcranial Doppler, which is a far superior screening technique for identifying right-to-left shunts. There is so much evidence to support the use of transcranial Doppler, but with this new artificial-intelligence robotic device, we don’t need an expert to use it,” Dr. Rubin said.
He explained that finding a right-to-left shunt in stroke patients is particularly important, as it can direct treatment strategies to reduce future risk of recurrent strokes.
“If a patient has a large shunt, then they have a high risk of having another stroke, and the PFO should be closed.”
In this study, the robotic-assisted TCD detected three times as many large shunts that were considered “intervenable,” compared with transthoracic echo, identifying these shunts in 35 patients (27%) compared to just 13 (10%) with TTE.
“Of the 35 patients with intervenable shunts detected with robotic transcranial Doppler, TTE was completely negative in 18 of them and only suggested a small shunt in the others. So, the standard of care (TTE) missed half the patients with intervenable PFOs,” Dr. Rubin reported.
Study should ‘dramatically change’ practice
Commenting on the study, Patrick Lyden, MD, professor of physiology and neuroscience and of neurology, University of Southern California, Los Angeles, said: “Most clinicians hesitate to use transcranial Doppler given the need for specialized technical expertise to obtain a reliable result. This study showed that a robotic transcranial Doppler device – which can be applied by any cardiac non-invasive lab technician – provides reliable and rigorous data.”
He added: “This result will dramatically change the typical evaluation of patients with suspected PFO: In place of an invasive transesophageal echo that requires anesthesia and a cardiologist, most patients can have a non-invasive, robotic-guided transcranial Doppler and get the same diagnostic benefit.”
Dr. Lyden also pointed out that the cost of TCD is typically one-tenth that of TEE, although he said the cost of the robotic guided TCD “is not clear.”
A representative of the company that makes the robotic assisted device, NovaSignal, says the cost of the equipment is approximately $250,000, but “understanding the importance of the technology, we work with each hospital to meet their unique needs.”
The company adds that it currently has “over 45 commercial solutions deployed across 25 centers with 3-4 times growth expected year over year.”
The study was supported by NovaSignal, the company which makes the robotic device. Dr. Rubin reports acting as a consultant for the NovaSignal.
A version of this article first appeared on Medscape.com.
in a new study.
Being far easier to perform than regular transcranial Doppler ultrasound, it’s hoped that use of the robotic device will enable many more patients to undergo the more sensitive transcranial screening modality and increase the number of shunts identified.
“I believe robot-assisted transcranial Doppler ultrasound can fill the gap between the gold standard transcranial Doppler and transthoracic echocardiography, which is the current standard of care,” said lead author Mark Rubin, MD.
Dr. Rubin, who is assistant professor of neurology at University of Tennessee Health Science Center, Memphis, presented results of the BUBL study at the International Stroke Conference (ISC) 2022, where they were greeted with applause from the floor.
An improvement in the current standard of care
Dr. Rubin explained that patients with suspected embolic stroke are routinely screened for shunts in the heart, such as patent foramen ovale (PFO), that allow blood to flow from the right chamber to the left chamber and can lead to clots from the venous system, accessing the arterial system, then traveling to the brain and causing a stroke.
The current standard of care in screening for such shunts is the use of transthoracic echocardiography (TTE), a widely available and easy to perform, non-invasive procedure. “But we have known for decades that TTE does not pick up these shunts very well. With a sensitivity of only around 45%, it identifies less than half of the patients affected,” Dr. Rubin noted.
The more sensitive transesophageal echocardiography (TEE) gives much better results, but it is an invasive and unpleasant procedure with the ultrasound probe being passed down the throat, and the patient needing to be sedated, so it’s not appropriate for everyone, he noted.
“Transcranial Doppler ultrasound (TCD) also gives excellent results, with a sensitivity of about 96% for detecting PFO, but this procedure is difficult to perform and requires a great deal of skill in placing the probes in the right position and interpreting the signal,” Dr. Rubin said. “TCD has been around for decades, but it hasn’t caught on, as it is too difficult to do. It takes a lot of time to learn the technique.”
“With the robotic-assisted transcranial Doppler device, we can achieve the sensitivity of TCD without needing expert operators. This should vastly improve accessibility to this technology,” he said. “With such technology we can make significant strides into more accurate diagnoses on the cause of stroke, which should lead to better preventive treatments in those found to have right-to-left shunts.”
Robotic detection of shunts
For the BUBL study, the robotic TCD technique was compared with the standard TTE in 129 patients who had a diagnosis of presumed embolic stroke or transient ischemic attack (TIA), with all patients undergoing both procedures.
The robotic TCD device resembles a giant pair of headphones containing the ultrasound probes, which are attached to a frame. In the study, it was operated by a health care professional without TCD skills. Each ultrasound probe independently scans the temporal area autonomously – with angling and positive pressure against the scalp akin to a sonographer – to find and optimize bilateral middle cerebral artery signals, Dr. Rubin explained.
The primary endpoint was the detection of a right-to-left shunt. This occurred in 82 of the 129 patients (63.6%) with the robotic TCD device but in only 27 patients (20.9%) when TTE was used. This gives an absolute difference of 42.6% (95% confidence interval, 28.6%-56.7%; P < .001), which Dr. Rubin described as “astounding.”
However, he said he was not surprised by these results.
“In my experience with transcranial Doppler, I find shunts in patients every day that have not been seen with transthoracic echo,” he commented.
He noted that a previous meta-analysis has suggested a similar difference between TCD and transthoracic echo, but the current study provides prospectively collected data produced in a clinical trial setting and is therefore more reliable.
“What I hope comes from this is that more patients will be able to undergo transcranial Doppler, which is a far superior screening technique for identifying right-to-left shunts. There is so much evidence to support the use of transcranial Doppler, but with this new artificial-intelligence robotic device, we don’t need an expert to use it,” Dr. Rubin said.
He explained that finding a right-to-left shunt in stroke patients is particularly important, as it can direct treatment strategies to reduce future risk of recurrent strokes.
“If a patient has a large shunt, then they have a high risk of having another stroke, and the PFO should be closed.”
In this study, the robotic-assisted TCD detected three times as many large shunts that were considered “intervenable,” compared with transthoracic echo, identifying these shunts in 35 patients (27%) compared to just 13 (10%) with TTE.
“Of the 35 patients with intervenable shunts detected with robotic transcranial Doppler, TTE was completely negative in 18 of them and only suggested a small shunt in the others. So, the standard of care (TTE) missed half the patients with intervenable PFOs,” Dr. Rubin reported.
Study should ‘dramatically change’ practice
Commenting on the study, Patrick Lyden, MD, professor of physiology and neuroscience and of neurology, University of Southern California, Los Angeles, said: “Most clinicians hesitate to use transcranial Doppler given the need for specialized technical expertise to obtain a reliable result. This study showed that a robotic transcranial Doppler device – which can be applied by any cardiac non-invasive lab technician – provides reliable and rigorous data.”
He added: “This result will dramatically change the typical evaluation of patients with suspected PFO: In place of an invasive transesophageal echo that requires anesthesia and a cardiologist, most patients can have a non-invasive, robotic-guided transcranial Doppler and get the same diagnostic benefit.”
Dr. Lyden also pointed out that the cost of TCD is typically one-tenth that of TEE, although he said the cost of the robotic guided TCD “is not clear.”
A representative of the company that makes the robotic assisted device, NovaSignal, says the cost of the equipment is approximately $250,000, but “understanding the importance of the technology, we work with each hospital to meet their unique needs.”
The company adds that it currently has “over 45 commercial solutions deployed across 25 centers with 3-4 times growth expected year over year.”
The study was supported by NovaSignal, the company which makes the robotic device. Dr. Rubin reports acting as a consultant for the NovaSignal.
A version of this article first appeared on Medscape.com.
FROM ISC 2022