User login
Proteins in Plasma Linked to MI, Especially for Women
Forty-five circulating proteins in plasma are linked to the risk for myocardial infarction (MI), showed a new study that confirms some known associations and identifies new ones. Several proteins are associated with MI in women but not men, and some proteins linked with MI in both men and women are more strongly associated with MI in women.
“We hope that our study will shed light on pathways in MI,” said principal author Olga Titova, PhD, an epidemiologist at Uppsala University in Uppsala, Sweden. The work was published in the European Heart Journal.
Martha Gulati, MD, a cardiologist and associate director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles and coauthor of an accompanying editorial, said the novel discovery of different patterns between men and women makes this an exciting study. The findings “highlight that sex differences in disease phenotype begin at the molecular level,” she said.
Titova and her team analyzed thousands of patients in two databases — one in Sweden (11,751 patients), the other in the United Kingdom (51,613 patients) — to discover proteins in the patients who went on to have an MI. Using one database to discover biomarkers and a second to replicate the findings is a common approach, said Titova.
Casting a Wide Net to Catch Proteins
The two databases “make findings more generalizable, allow us to confirm robust associations, and help minimize the risk of false positives.” The two databases mean researchers are more confident that the findings can be applied across populations, Titova added.
A total of 44 proteins were associated with later MI in both databases, adjusted for common MI risk factors as well as such factors as education, diet, physical activity, and alcohol intake, Titova explained. An additional protein was included from the first database that was unavailable in the second. Some of the proteins have been found in other studies, and this study confirms the link. Others were new, and a few appear to protect patients from MI.
“Most of the proteins are related to or involved in inflammation and atherosclerosis,” said Titova.
This is the first study to cast such a wide net, Titova pointed out. While several proteins have previously been linked to MI, most earlier studies have focused on specific proteins in populations that already have coronary artery disease or have involved cohorts of men only.
But she stresses that this study poses more questions than it answers. More research is needed to determine how proteins are involved in pathways leading to MI. The study found that some proteins may be mediators of general cardiovascular disease risk, whereas others are involved in mechanisms specifically linked to MI. Many proteins are involved in atherosclerosis, thrombosis, inflammation, immune system–related pathways, injury and tissue repair, coagulation, bone homeostasis, and iron metabolism.
“At this point, some [proteins] appear to be causal, some seem to be an association,” said Titova. It remains to be determined “which are on the causal path, which are potential biomarkers, which are going to shed light on the mechanisms” of MI.
The study took a step toward determining which proteins might be involved in causing MI through an analysis of some protein levels determined by genetics. This found three proteins linked to a higher risk for MI and three linked to a lower risk.
It’s Different for Women
Thirteen of the proteins were linked with later MI in women, either exclusively or more strongly than in men. Many of these associations were replicated in the second database, showing an alignment across populations.
Titova said the reason for the sex difference remains a mystery. “We have to go to the molecular level. It could be a consequence of risk factors affecting the sexes differently or different biology” between men and women.
Gulati, who specializes in women’s heart health, explained, “We know inflammation is much more prevalent in women and is the pathway to cardiovascular disease.” She points out that noncardiac inflammatory diseases are also more prevalent in women. Other biomarkers for inflammation, such as C-reactive protein, are higher in women than in men. She thinks the underlying mechanisms could involve “how we [women] make our proteins and how we respond to hormones.”
By identifying proteins linked to MI in women, the study helps to fill an important gap in our knowledge. “I can’t tell you how many papers don’t even look at sex differences. If we don’t look, we won’t know there are differences,” Gulati said. “In much of our cardiac research, women are underrepresented.”
The findings of this trial and others like it may lead to new approaches to prevention and treatment, Titova and Gulati agreed. Several proteins found in this study that may have a causal link with MI are already targets of drug development, they added.
Titova said other proteins may be useful in the future as biomarkers that indicate a need for preventive action.
Gulati asked, “If we can show some of the proteins are involved in the inflammatory response — if they are causal and we can prevent them upfront — can we reduce the chance of MI?” She and Titova said the many questions remaining should prove a rewarding avenue for research.
A version of this article appeared on Medscape.com.
Forty-five circulating proteins in plasma are linked to the risk for myocardial infarction (MI), showed a new study that confirms some known associations and identifies new ones. Several proteins are associated with MI in women but not men, and some proteins linked with MI in both men and women are more strongly associated with MI in women.
“We hope that our study will shed light on pathways in MI,” said principal author Olga Titova, PhD, an epidemiologist at Uppsala University in Uppsala, Sweden. The work was published in the European Heart Journal.
Martha Gulati, MD, a cardiologist and associate director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles and coauthor of an accompanying editorial, said the novel discovery of different patterns between men and women makes this an exciting study. The findings “highlight that sex differences in disease phenotype begin at the molecular level,” she said.
Titova and her team analyzed thousands of patients in two databases — one in Sweden (11,751 patients), the other in the United Kingdom (51,613 patients) — to discover proteins in the patients who went on to have an MI. Using one database to discover biomarkers and a second to replicate the findings is a common approach, said Titova.
Casting a Wide Net to Catch Proteins
The two databases “make findings more generalizable, allow us to confirm robust associations, and help minimize the risk of false positives.” The two databases mean researchers are more confident that the findings can be applied across populations, Titova added.
A total of 44 proteins were associated with later MI in both databases, adjusted for common MI risk factors as well as such factors as education, diet, physical activity, and alcohol intake, Titova explained. An additional protein was included from the first database that was unavailable in the second. Some of the proteins have been found in other studies, and this study confirms the link. Others were new, and a few appear to protect patients from MI.
“Most of the proteins are related to or involved in inflammation and atherosclerosis,” said Titova.
This is the first study to cast such a wide net, Titova pointed out. While several proteins have previously been linked to MI, most earlier studies have focused on specific proteins in populations that already have coronary artery disease or have involved cohorts of men only.
But she stresses that this study poses more questions than it answers. More research is needed to determine how proteins are involved in pathways leading to MI. The study found that some proteins may be mediators of general cardiovascular disease risk, whereas others are involved in mechanisms specifically linked to MI. Many proteins are involved in atherosclerosis, thrombosis, inflammation, immune system–related pathways, injury and tissue repair, coagulation, bone homeostasis, and iron metabolism.
“At this point, some [proteins] appear to be causal, some seem to be an association,” said Titova. It remains to be determined “which are on the causal path, which are potential biomarkers, which are going to shed light on the mechanisms” of MI.
The study took a step toward determining which proteins might be involved in causing MI through an analysis of some protein levels determined by genetics. This found three proteins linked to a higher risk for MI and three linked to a lower risk.
It’s Different for Women
Thirteen of the proteins were linked with later MI in women, either exclusively or more strongly than in men. Many of these associations were replicated in the second database, showing an alignment across populations.
Titova said the reason for the sex difference remains a mystery. “We have to go to the molecular level. It could be a consequence of risk factors affecting the sexes differently or different biology” between men and women.
Gulati, who specializes in women’s heart health, explained, “We know inflammation is much more prevalent in women and is the pathway to cardiovascular disease.” She points out that noncardiac inflammatory diseases are also more prevalent in women. Other biomarkers for inflammation, such as C-reactive protein, are higher in women than in men. She thinks the underlying mechanisms could involve “how we [women] make our proteins and how we respond to hormones.”
By identifying proteins linked to MI in women, the study helps to fill an important gap in our knowledge. “I can’t tell you how many papers don’t even look at sex differences. If we don’t look, we won’t know there are differences,” Gulati said. “In much of our cardiac research, women are underrepresented.”
The findings of this trial and others like it may lead to new approaches to prevention and treatment, Titova and Gulati agreed. Several proteins found in this study that may have a causal link with MI are already targets of drug development, they added.
Titova said other proteins may be useful in the future as biomarkers that indicate a need for preventive action.
Gulati asked, “If we can show some of the proteins are involved in the inflammatory response — if they are causal and we can prevent them upfront — can we reduce the chance of MI?” She and Titova said the many questions remaining should prove a rewarding avenue for research.
A version of this article appeared on Medscape.com.
Forty-five circulating proteins in plasma are linked to the risk for myocardial infarction (MI), showed a new study that confirms some known associations and identifies new ones. Several proteins are associated with MI in women but not men, and some proteins linked with MI in both men and women are more strongly associated with MI in women.
“We hope that our study will shed light on pathways in MI,” said principal author Olga Titova, PhD, an epidemiologist at Uppsala University in Uppsala, Sweden. The work was published in the European Heart Journal.
Martha Gulati, MD, a cardiologist and associate director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles and coauthor of an accompanying editorial, said the novel discovery of different patterns between men and women makes this an exciting study. The findings “highlight that sex differences in disease phenotype begin at the molecular level,” she said.
Titova and her team analyzed thousands of patients in two databases — one in Sweden (11,751 patients), the other in the United Kingdom (51,613 patients) — to discover proteins in the patients who went on to have an MI. Using one database to discover biomarkers and a second to replicate the findings is a common approach, said Titova.
Casting a Wide Net to Catch Proteins
The two databases “make findings more generalizable, allow us to confirm robust associations, and help minimize the risk of false positives.” The two databases mean researchers are more confident that the findings can be applied across populations, Titova added.
A total of 44 proteins were associated with later MI in both databases, adjusted for common MI risk factors as well as such factors as education, diet, physical activity, and alcohol intake, Titova explained. An additional protein was included from the first database that was unavailable in the second. Some of the proteins have been found in other studies, and this study confirms the link. Others were new, and a few appear to protect patients from MI.
“Most of the proteins are related to or involved in inflammation and atherosclerosis,” said Titova.
This is the first study to cast such a wide net, Titova pointed out. While several proteins have previously been linked to MI, most earlier studies have focused on specific proteins in populations that already have coronary artery disease or have involved cohorts of men only.
But she stresses that this study poses more questions than it answers. More research is needed to determine how proteins are involved in pathways leading to MI. The study found that some proteins may be mediators of general cardiovascular disease risk, whereas others are involved in mechanisms specifically linked to MI. Many proteins are involved in atherosclerosis, thrombosis, inflammation, immune system–related pathways, injury and tissue repair, coagulation, bone homeostasis, and iron metabolism.
“At this point, some [proteins] appear to be causal, some seem to be an association,” said Titova. It remains to be determined “which are on the causal path, which are potential biomarkers, which are going to shed light on the mechanisms” of MI.
The study took a step toward determining which proteins might be involved in causing MI through an analysis of some protein levels determined by genetics. This found three proteins linked to a higher risk for MI and three linked to a lower risk.
It’s Different for Women
Thirteen of the proteins were linked with later MI in women, either exclusively or more strongly than in men. Many of these associations were replicated in the second database, showing an alignment across populations.
Titova said the reason for the sex difference remains a mystery. “We have to go to the molecular level. It could be a consequence of risk factors affecting the sexes differently or different biology” between men and women.
Gulati, who specializes in women’s heart health, explained, “We know inflammation is much more prevalent in women and is the pathway to cardiovascular disease.” She points out that noncardiac inflammatory diseases are also more prevalent in women. Other biomarkers for inflammation, such as C-reactive protein, are higher in women than in men. She thinks the underlying mechanisms could involve “how we [women] make our proteins and how we respond to hormones.”
By identifying proteins linked to MI in women, the study helps to fill an important gap in our knowledge. “I can’t tell you how many papers don’t even look at sex differences. If we don’t look, we won’t know there are differences,” Gulati said. “In much of our cardiac research, women are underrepresented.”
The findings of this trial and others like it may lead to new approaches to prevention and treatment, Titova and Gulati agreed. Several proteins found in this study that may have a causal link with MI are already targets of drug development, they added.
Titova said other proteins may be useful in the future as biomarkers that indicate a need for preventive action.
Gulati asked, “If we can show some of the proteins are involved in the inflammatory response — if they are causal and we can prevent them upfront — can we reduce the chance of MI?” She and Titova said the many questions remaining should prove a rewarding avenue for research.
A version of this article appeared on Medscape.com.
Monitoring Heart Health Crucial in Patients With Anorexia
TOPLINE:
Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.
METHODOLOGY:
- Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
- They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
- The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
- The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.
TAKEAWAY:
- Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
- Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
- The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.
IN PRACTICE:
“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.
“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
SOURCE:
The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.
LIMITATIONS:
The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.
DISCLOSURES:
This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.
METHODOLOGY:
- Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
- They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
- The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
- The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.
TAKEAWAY:
- Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
- Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
- The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.
IN PRACTICE:
“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.
“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
SOURCE:
The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.
LIMITATIONS:
The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.
DISCLOSURES:
This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Patients with anorexia nervosa are at significantly increased risk for cardiovascular conditions such as heart failure and cardiac arrest, compared with people without an eating disorder, researchers found. The risk for many of these conditions declines after 5 years of follow-up, whereas the risk for ischemic heart disease rises only after that period.
METHODOLOGY:
- Researchers conducted a longitudinal cohort study by analyzing the data from Taiwan’s National Health Insurance database to investigate the incidences and risk for cardiovascular conditions in patients with anorexia.
- They included 22,891 participants (mean age, 24.9 years; 91.3% women), of whom 2081 were diagnosed with anorexia between January 2010 and December 2021 and 20,810 were matched control participants without any eating disorder.
- The mean follow-up duration of this study was 5 years; investigators also assessed the risk for individual cardiovascular conditions during three periods after the diagnosis of anorexia: 0-24 months, between 24 and 60 months, and greater than 60 months.
- The primary outcomes were the occurrence of major adverse cardiovascular events (MACE) and any cardiovascular condition, including heart failure, stroke, ischemic heart diseases, conduction disorder, inflammatory heart disease, valve disease, cardiomyopathy, atherosclerosis, and cardiac arrest.
TAKEAWAY:
- Similarly, the incidence of any cardiovascular condition was higher in patients with anorexia than in those without (6.19% vs 2.27%), which translated to a nearly twofold increased risk (aHR, 1.93; 95% CI, 1.54-2.41).
- Patients with anorexia showed elevated risks for individual cardiovascular conditions such as cardiac arrest, structural heart disease, conduction disorder, and heart failure, but not stroke, atherosclerosis, ischemic heart disease, or inflammatory heart disease.
- The risks for congestive heart failure, structural heart disease, and conduction disorder increased in the first 24 months after the diagnosis of anorexia and disappeared after 5 years of follow-up, whereas the risk for ischemic heart disease increased only after 5 years of follow-up.
IN PRACTICE:
“Clinicians should monitor comorbid cardiovascular conditions among patients with [anorexia] at initial presentation, during treatment, and at follow-up,” the authors of the study wrote.
“In this study, most cardiovascular conditions were in remission after 5 years except ischemic heart disease,” the researchers noted. “This finding is corroborated by the recovery rate of 50%-70% in patients with [anorexia] after 4 years of follow-up in a recent meta-analysis, and in previous studies, most of the cardiac complications improved with weight restoration. Similarly, genome-wide association studies did not support elevated cardiovascular risk in patients with [anorexia] due to shared genetic mechanisms between [anorexia] and cardiovascular diseases, but they suggested that cardiovascular diseases were a downstream consequence” of the eating disorder.
SOURCE:
The study was led by Mei-Chih Meg Tseng, MD, PhD, of the Department of Psychiatry at Taipei Medical University in Taipei, Taiwan. It was published online on December 19, 2024, in JAMA Network Open.
LIMITATIONS:
The cardiovascular outcomes relied on the clinical diagnoses, and the validity of anorexia or its subtype was not confirmed. The study population was limited to patients seeking medical treatment, which may have led to the inclusion of patients with more severe symptoms. Key potential confounders such as body weight, nutritional status, lifestyle, drug use, and family history were unavailable in the claims dataset and could not be adjusted. The generalizability of the study may be limited as it involved only participants from a single ethnic group.
DISCLOSURES:
This study was supported by grants from the National Science and Technology Council, Taiwan, and Taipei Medical University. The authors reported no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Health Impacts of Micro- and Nanoplastics
In preparation for a future international treaty aimed at reducing plastic pollution, the French Parliamentary Office for the Evaluation of Scientific and Technological Choices presented the conclusions of a public hearing on the impact of plastics on various aspects of human health.
Increased Global Plastic Production
Philippe Bolo, a member of the French Democratic Party and the rapporteur for the public mission on the health impacts of plastics, spoke about the latest round of treaty negotiations, held from November 25 to December 1 in South Korea, attended by leading French and global experts about the impact of plastics on human health.
The hearing highlighted a sharp increase in plastic production. “It has doubled in the last 20 years and is expected to exceed 500 million tons in 2024,” Bolo said. This is about 60 kg per person. According to projections from the Organization for Economic Co-operation and Development, on its current trajectory, plastic production will reach 750 million tons by 2040 and surpass 1 billion tons before 2050, he said.
Minimal Plastic Waste Recycling
Around one third (32%) of plastics are used for packaging. “Therefore, most plastic production is still intended for single-use purposes,” he said. Plastic waste follows a similar growth trajectory, with volumes expected to rise from 360 million tons in 2020 to 617 million tons by 2040 unless action is taken. Very little of this waste is recycled, even in the most countries that are most advanced in terms of collection, sorting, and processing.
In France, for example, in 2018, only 0.6 million tons of the 3.6 million tons of plastic waste produced was truly recycled. This is less than one fifth (17%). Globally, less than 10% of plastic waste is recycled. In 2020, plastic waste that ended up in the environment represented 81 million tons, or 22% of the total. “Beyond waste, this leads to pollution by microplastics and nanoplastics, resulting from their fragmentation. All environments are affected: Seas, rivers, soils, air, and even living organisms,” Bolo said.
Methodological Challenges
However, measuring the impact of plastics on health faces methodological difficulties due to the wide variety of composition, size, and shape of plastics. Nevertheless, the French Standardization Association (Association Française de Normalisation) has conducted work to establish a characterization standard for microplastics in water, which serves as an international reference.
“It is also very difficult to know what we are ingesting,” Bolo said. “A study conducted in 2019 estimated that the average human absorbs 5 grams of plastics per week, the equivalent of a credit card.» Since then, other studies have revised this estimate downward, but no consensus has been reached.
A recent study across 109 countries, both industrialized and developing, found significant exposure, estimated at 500 mg/d, particularly in Southeast Asian countries, where it was due mainly to seafood consumption.
A study concluded that plastic water bottles contain 240,000 particles per liter, 90% of which are nanoplastics. These nanoparticles can pass through the intestinal barrier to enter the bloodstream and reach several organs including the heart, brain, and placenta, as well as the fetus.
Changes to the Microbiome
Microplastics also accumulate in organs. Thus, the amount of plastic in the lungs increases with age, suggesting that particles may persist in the body without being eliminated. The health consequences of this are still poorly understood, but exposure to plastics appears to cause changes in the composition of the intestinal microbiota. Pathobionts (commensal bacteria with harmful potential) have been found in both adults and children, which could contribute to dysbiosis of the gut microbiome. Furthermore, a decrease in butyrate, a short-chain fatty acid beneficial to health, has been observed in children’s intestines.
Inhaled nanoplastics may disrupt the mucociliary clearance mechanisms of the respiratory system. The toxicity of inhaled plastic particles was demonstrated as early as the 1970s among workers in the flocking industry. Some developed lung function impairments, shortness of breath, inflammation, fibrosis, and even lung cancer. Similar symptoms have been observed in workers in the textile and polyvinyl chloride industries.
A study published recently in The New England Journal of Medicine measured the amount of microplastics collected from carotid plaque of more than 300 patients who had undergone carotid endarterectomy for asymptomatic carotid artery disease. It found a 4.53 times higher risk for the primary endpoint, a composite of myocardial infarction, stroke, and all-cause mortality, among individuals with microplastics and nanoplastics in plaque compared with those without.
Health Affects High
The danger of plastics is also directly linked to the chemical substances they contain. A general scientific review looked at the health impacts of three chemicals used almost exclusively in plastics: Polybromodiphenyl ethers (PBDEs), used as flame retardants in textiles or electronics; bisphenol A (BPA), used in the lining of cans and bottles; and phthalates, particularly diethylhexyl phthalate (DEHP), used to make plastics more flexible.
The review highlighted strong epidemiological evidence linking fetal exposure to PBDEs during pregnancy to low birth weight and later exposure to delayed or impaired cognitive development in children and even a loss of IQ. Statistically significant evidence of disruption of thyroid function in adults was also found.
BPA is linked to genital malformations in female newborns exposed to BPA in utero, type 2 diabetes in adults, insulin resistance, and polycystic ovary syndrome in women. BPA exposure also increases the risk for obesity and hypertension in both children and adults, as well as the risk for cardiovascular disease in adults.
Finally, the review established links between exposure to DEHP and miscarriages, genital malformations in male newborns, delayed or impaired cognitive development in children, loss of IQ, delayed psychomotor development, early puberty in young girls, and endometriosis in young women. DEHP exposure also has multiple effects on cardiometabolic health, including insulin resistance, obesity, and elevated blood pressure.
The economic costs associated with the health impacts of these three substances have been estimated at $675 billion in the United States.
Bolo said that the solution to this plastic pollution is necessarily international. “We need an ambitious and legally binding treaty to reduce plastic production,” he said. “The damage is already done; we need to act to protect human health,” he concluded. The parliamentary office has made nine recommendations to the treaty negotiators.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
In preparation for a future international treaty aimed at reducing plastic pollution, the French Parliamentary Office for the Evaluation of Scientific and Technological Choices presented the conclusions of a public hearing on the impact of plastics on various aspects of human health.
Increased Global Plastic Production
Philippe Bolo, a member of the French Democratic Party and the rapporteur for the public mission on the health impacts of plastics, spoke about the latest round of treaty negotiations, held from November 25 to December 1 in South Korea, attended by leading French and global experts about the impact of plastics on human health.
The hearing highlighted a sharp increase in plastic production. “It has doubled in the last 20 years and is expected to exceed 500 million tons in 2024,” Bolo said. This is about 60 kg per person. According to projections from the Organization for Economic Co-operation and Development, on its current trajectory, plastic production will reach 750 million tons by 2040 and surpass 1 billion tons before 2050, he said.
Minimal Plastic Waste Recycling
Around one third (32%) of plastics are used for packaging. “Therefore, most plastic production is still intended for single-use purposes,” he said. Plastic waste follows a similar growth trajectory, with volumes expected to rise from 360 million tons in 2020 to 617 million tons by 2040 unless action is taken. Very little of this waste is recycled, even in the most countries that are most advanced in terms of collection, sorting, and processing.
In France, for example, in 2018, only 0.6 million tons of the 3.6 million tons of plastic waste produced was truly recycled. This is less than one fifth (17%). Globally, less than 10% of plastic waste is recycled. In 2020, plastic waste that ended up in the environment represented 81 million tons, or 22% of the total. “Beyond waste, this leads to pollution by microplastics and nanoplastics, resulting from their fragmentation. All environments are affected: Seas, rivers, soils, air, and even living organisms,” Bolo said.
Methodological Challenges
However, measuring the impact of plastics on health faces methodological difficulties due to the wide variety of composition, size, and shape of plastics. Nevertheless, the French Standardization Association (Association Française de Normalisation) has conducted work to establish a characterization standard for microplastics in water, which serves as an international reference.
“It is also very difficult to know what we are ingesting,” Bolo said. “A study conducted in 2019 estimated that the average human absorbs 5 grams of plastics per week, the equivalent of a credit card.» Since then, other studies have revised this estimate downward, but no consensus has been reached.
A recent study across 109 countries, both industrialized and developing, found significant exposure, estimated at 500 mg/d, particularly in Southeast Asian countries, where it was due mainly to seafood consumption.
A study concluded that plastic water bottles contain 240,000 particles per liter, 90% of which are nanoplastics. These nanoparticles can pass through the intestinal barrier to enter the bloodstream and reach several organs including the heart, brain, and placenta, as well as the fetus.
Changes to the Microbiome
Microplastics also accumulate in organs. Thus, the amount of plastic in the lungs increases with age, suggesting that particles may persist in the body without being eliminated. The health consequences of this are still poorly understood, but exposure to plastics appears to cause changes in the composition of the intestinal microbiota. Pathobionts (commensal bacteria with harmful potential) have been found in both adults and children, which could contribute to dysbiosis of the gut microbiome. Furthermore, a decrease in butyrate, a short-chain fatty acid beneficial to health, has been observed in children’s intestines.
Inhaled nanoplastics may disrupt the mucociliary clearance mechanisms of the respiratory system. The toxicity of inhaled plastic particles was demonstrated as early as the 1970s among workers in the flocking industry. Some developed lung function impairments, shortness of breath, inflammation, fibrosis, and even lung cancer. Similar symptoms have been observed in workers in the textile and polyvinyl chloride industries.
A study published recently in The New England Journal of Medicine measured the amount of microplastics collected from carotid plaque of more than 300 patients who had undergone carotid endarterectomy for asymptomatic carotid artery disease. It found a 4.53 times higher risk for the primary endpoint, a composite of myocardial infarction, stroke, and all-cause mortality, among individuals with microplastics and nanoplastics in plaque compared with those without.
Health Affects High
The danger of plastics is also directly linked to the chemical substances they contain. A general scientific review looked at the health impacts of three chemicals used almost exclusively in plastics: Polybromodiphenyl ethers (PBDEs), used as flame retardants in textiles or electronics; bisphenol A (BPA), used in the lining of cans and bottles; and phthalates, particularly diethylhexyl phthalate (DEHP), used to make plastics more flexible.
The review highlighted strong epidemiological evidence linking fetal exposure to PBDEs during pregnancy to low birth weight and later exposure to delayed or impaired cognitive development in children and even a loss of IQ. Statistically significant evidence of disruption of thyroid function in adults was also found.
BPA is linked to genital malformations in female newborns exposed to BPA in utero, type 2 diabetes in adults, insulin resistance, and polycystic ovary syndrome in women. BPA exposure also increases the risk for obesity and hypertension in both children and adults, as well as the risk for cardiovascular disease in adults.
Finally, the review established links between exposure to DEHP and miscarriages, genital malformations in male newborns, delayed or impaired cognitive development in children, loss of IQ, delayed psychomotor development, early puberty in young girls, and endometriosis in young women. DEHP exposure also has multiple effects on cardiometabolic health, including insulin resistance, obesity, and elevated blood pressure.
The economic costs associated with the health impacts of these three substances have been estimated at $675 billion in the United States.
Bolo said that the solution to this plastic pollution is necessarily international. “We need an ambitious and legally binding treaty to reduce plastic production,” he said. “The damage is already done; we need to act to protect human health,” he concluded. The parliamentary office has made nine recommendations to the treaty negotiators.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
In preparation for a future international treaty aimed at reducing plastic pollution, the French Parliamentary Office for the Evaluation of Scientific and Technological Choices presented the conclusions of a public hearing on the impact of plastics on various aspects of human health.
Increased Global Plastic Production
Philippe Bolo, a member of the French Democratic Party and the rapporteur for the public mission on the health impacts of plastics, spoke about the latest round of treaty negotiations, held from November 25 to December 1 in South Korea, attended by leading French and global experts about the impact of plastics on human health.
The hearing highlighted a sharp increase in plastic production. “It has doubled in the last 20 years and is expected to exceed 500 million tons in 2024,” Bolo said. This is about 60 kg per person. According to projections from the Organization for Economic Co-operation and Development, on its current trajectory, plastic production will reach 750 million tons by 2040 and surpass 1 billion tons before 2050, he said.
Minimal Plastic Waste Recycling
Around one third (32%) of plastics are used for packaging. “Therefore, most plastic production is still intended for single-use purposes,” he said. Plastic waste follows a similar growth trajectory, with volumes expected to rise from 360 million tons in 2020 to 617 million tons by 2040 unless action is taken. Very little of this waste is recycled, even in the most countries that are most advanced in terms of collection, sorting, and processing.
In France, for example, in 2018, only 0.6 million tons of the 3.6 million tons of plastic waste produced was truly recycled. This is less than one fifth (17%). Globally, less than 10% of plastic waste is recycled. In 2020, plastic waste that ended up in the environment represented 81 million tons, or 22% of the total. “Beyond waste, this leads to pollution by microplastics and nanoplastics, resulting from their fragmentation. All environments are affected: Seas, rivers, soils, air, and even living organisms,” Bolo said.
Methodological Challenges
However, measuring the impact of plastics on health faces methodological difficulties due to the wide variety of composition, size, and shape of plastics. Nevertheless, the French Standardization Association (Association Française de Normalisation) has conducted work to establish a characterization standard for microplastics in water, which serves as an international reference.
“It is also very difficult to know what we are ingesting,” Bolo said. “A study conducted in 2019 estimated that the average human absorbs 5 grams of plastics per week, the equivalent of a credit card.» Since then, other studies have revised this estimate downward, but no consensus has been reached.
A recent study across 109 countries, both industrialized and developing, found significant exposure, estimated at 500 mg/d, particularly in Southeast Asian countries, where it was due mainly to seafood consumption.
A study concluded that plastic water bottles contain 240,000 particles per liter, 90% of which are nanoplastics. These nanoparticles can pass through the intestinal barrier to enter the bloodstream and reach several organs including the heart, brain, and placenta, as well as the fetus.
Changes to the Microbiome
Microplastics also accumulate in organs. Thus, the amount of plastic in the lungs increases with age, suggesting that particles may persist in the body without being eliminated. The health consequences of this are still poorly understood, but exposure to plastics appears to cause changes in the composition of the intestinal microbiota. Pathobionts (commensal bacteria with harmful potential) have been found in both adults and children, which could contribute to dysbiosis of the gut microbiome. Furthermore, a decrease in butyrate, a short-chain fatty acid beneficial to health, has been observed in children’s intestines.
Inhaled nanoplastics may disrupt the mucociliary clearance mechanisms of the respiratory system. The toxicity of inhaled plastic particles was demonstrated as early as the 1970s among workers in the flocking industry. Some developed lung function impairments, shortness of breath, inflammation, fibrosis, and even lung cancer. Similar symptoms have been observed in workers in the textile and polyvinyl chloride industries.
A study published recently in The New England Journal of Medicine measured the amount of microplastics collected from carotid plaque of more than 300 patients who had undergone carotid endarterectomy for asymptomatic carotid artery disease. It found a 4.53 times higher risk for the primary endpoint, a composite of myocardial infarction, stroke, and all-cause mortality, among individuals with microplastics and nanoplastics in plaque compared with those without.
Health Affects High
The danger of plastics is also directly linked to the chemical substances they contain. A general scientific review looked at the health impacts of three chemicals used almost exclusively in plastics: Polybromodiphenyl ethers (PBDEs), used as flame retardants in textiles or electronics; bisphenol A (BPA), used in the lining of cans and bottles; and phthalates, particularly diethylhexyl phthalate (DEHP), used to make plastics more flexible.
The review highlighted strong epidemiological evidence linking fetal exposure to PBDEs during pregnancy to low birth weight and later exposure to delayed or impaired cognitive development in children and even a loss of IQ. Statistically significant evidence of disruption of thyroid function in adults was also found.
BPA is linked to genital malformations in female newborns exposed to BPA in utero, type 2 diabetes in adults, insulin resistance, and polycystic ovary syndrome in women. BPA exposure also increases the risk for obesity and hypertension in both children and adults, as well as the risk for cardiovascular disease in adults.
Finally, the review established links between exposure to DEHP and miscarriages, genital malformations in male newborns, delayed or impaired cognitive development in children, loss of IQ, delayed psychomotor development, early puberty in young girls, and endometriosis in young women. DEHP exposure also has multiple effects on cardiometabolic health, including insulin resistance, obesity, and elevated blood pressure.
The economic costs associated with the health impacts of these three substances have been estimated at $675 billion in the United States.
Bolo said that the solution to this plastic pollution is necessarily international. “We need an ambitious and legally binding treaty to reduce plastic production,” he said. “The damage is already done; we need to act to protect human health,” he concluded. The parliamentary office has made nine recommendations to the treaty negotiators.
This story was translated from Medscape’s French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Flu Shot Reminders Improve Use in Heart Attack Survivors
, showed the NUDGE FLU series of clinical trials.
Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.
“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.
In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).
The NUDGE FLU Trials
Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.
Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.
People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.
“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.
The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.
“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.
About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.
Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.
The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.
Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.
A version of this article first appeared on Medscape.com.
, showed the NUDGE FLU series of clinical trials.
Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.
“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.
In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).
The NUDGE FLU Trials
Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.
Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.
People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.
“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.
The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.
“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.
About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.
Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.
The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.
Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.
A version of this article first appeared on Medscape.com.
, showed the NUDGE FLU series of clinical trials.
Influenza has the potential to be a dangerous infection on its own, but it increases the risk for cardiovascular events among people with a history of heart attack, said the study’s lead author, Ankeet Bhatt, MD, a cardiologist at Kaiser Permanente San Francisco Medical Center, San Francisco.
“Yearly influenza vaccines help prevent influenza infection and, in patients with a heart attack, are potentially cardioprotective,” he said during his presentation at the American Heart Association (AHA) Scientific Sessions 2024 in Chicago. The NUDGE FLU results were simultaneously published online in JAMA Cardiology.
In Denmark, where the trials were conducted, about 80% of older adults get flu shots, but only about 40% of younger adults with chronic diseases do, Bhatt reported. In the United States, about 45% of adults and 55% of children received at least one dose of the flu vaccine in the 2023/24 flu season, according to the US Centers for Disease Control and Prevention (CDC).
The NUDGE FLU Trials
Bhatt and his colleagues conducted three related clinical trials during the 2022/23 and 2023/24 flu seasons: NUDGE-FLU and NUDGE-FLU-2 targeted older adults, whereas NUDGE-FLU-CHRONIC targeted younger adults with chronic diseases. Nearly 2 million people were involved in the three trials.
Participants were randomized to receive one of a series of different behavioral-science-informed letters, delivered through a government-run electronic communication system, or no reminder.
People who received any of the nudges had higher rates of vaccination; among heart attack survivors, there was a 1.8% improvement and among adults without a history of heart attack, there was a 1.3% improvement. But a nudge that explained the potential cardiovascular benefits of flu shots was even more effective, leading to a 3.9% increase among people with a history of heart attack and a 2% increase among those with no heart attack history.
“A simple sentence resulted in a durable improvement in the vaccination rate,” said Bhatt.
The effect was even greater among those who had not been vaccinated in the previous flu season. Among heart attack survivors, nearly 14% more people got the vaccine compared with just 1.5% more survivors who were previously vaccinated. And it was most effective among younger adults who had experienced a recent heart attack, resulting in a 26% increase.
“The impact was larger in patients with a history of acute myocardial infarction, in those who were vaccine-hesitant, and in younger people” — all groups with the most to gain from vaccination in terms of cardiovascular protection — Bhatt reported.
About 25% of people in the United States are unsure about whether to get a flu shot, said Orly Vardeny, PharmD, professor of medicine at the University of Minnesota Medical School in Minneapolis, who was not involved in the study. The fact that previously unvaccinated people were convinced by the nudges is reassuring. “That’s the group where this intervention is most likely to move the needle,” she said.
Around half of all people hospitalized for flu in the United States have cardiovascular disease, CDC data showed, so “even a small increase in the number of patients who get vaccinated has substantial public health benefits,” Vardeny said.
The NUDGE FLU series showed that nudges like this should be employed as a simple tool to improve vaccination rates, but the system would be much more difficult to implement in the United States, Bhatt said.
Denmark has a national health service and a preexisting government electronic communication system, whereas the US system is privately run and more fractured. It would be possible to make it work, he pointed out, but would take some effort.
A version of this article first appeared on Medscape.com.
FROM AHA 2024
New Investigation Casts Doubt on Landmark Ticagrelor Trial
New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.
Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.
The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.
PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).
Failed First Bid for FDA Approval
AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.
Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.
Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.
“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”
Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”
US Department of Justice Investigation
The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.
Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.
The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”
Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.
AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.
Will the Guidelines Be Changed Now?
“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.
“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”
Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.
“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”
A version of this article first appeared on Medscape.com.
New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.
Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.
The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.
PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).
Failed First Bid for FDA Approval
AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.
Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.
Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.
“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”
Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”
US Department of Justice Investigation
The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.
Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.
The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”
Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.
AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.
Will the Guidelines Be Changed Now?
“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.
“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”
Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.
“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”
A version of this article first appeared on Medscape.com.
New questions about the landmark trial that launched the antiplatelet drug ticagrelor worldwide are being raised after an investigation uncovered more information about how the PLATO study was conducted.
Peter Doshi, PhD, senior editor at The BMJ, obtained primary records for the trial and unpublished data through a Freedom of Information Act request, and has detailed inconsistencies and omissions in data reporting from the 2009 trial originally published in The New England Journal of Medicine (NEJM). The new investigation into the Platelet Inhibition and Patient Outcomes (PLATO) trial is published in The BMJ.
The findings come as generic versions of ticagrelor (Brilinta) are expected to become available soon in the United States. Ticagrelor is the only P2Y12 inhibitor still under patent, and in 2022, the United States spent more than $750 million on it, according to the report.
PLATO, sponsored by ticagrelor manufacturer AstraZeneca, included more than 18,000 patients in 43 countries. Investigators reported that ticagrelor reduced deaths from vascular causes, heart attack, or stroke compared with clopidogrel (Plavix). However, in a subgroup analysis, among US patients, there were more deaths in the ticagrelor group, and AstraZeneca failed its first bid for approval from the US Food and Drug Administration (FDA).
Failed First Bid for FDA Approval
AstraZeneca resubmitted its application, which was met with objections by some FDA staff members, including medical officer Thomas Marciniak, who called the resubmission “the worst in my experience regarding completeness of the submissions and the sponsor responding completely and accurately to requests,” Doshi reports.
Despite the objections, the FDA in 2011 approved ticagrelor for acute coronary syndrome, kicking off intense controversy over the trial, as several other studies have failed to replicate PLATO’s positive results.
Doubts have grown about its apparent advantage over cheaper, off-patent P2Y12 inhibitors such as clopidogrel and prasugrel.
“Critics said it was noteworthy that ticagrelor failed in the US,” Doshi writes, “the only high enrolling country where sites were not monitored by the sponsor itself.” Doshi’s report points out that critics of the trial “highlight that AstraZeneca itself carried out the data monitoring for PLATO except for sites that were monitored by third party contract research organizations. In the four countries exclusively monitored by non-sponsor personnel—Georgia, Israel, Russia, and the US—ticagrelor fared worse.”
Victor Serebruany, MD, from Johns Hopkins University, said he was initially impressed by the trial results but became skeptical after noticing inconsistencies and anomalies in the data. He filed a complaint with the US District Court in the District of Columbia, suggesting that the cardiovascular events in the study “may have been manipulated.”
US Department of Justice Investigation
The US Department of Justice (DOJ) opened an investigation in 2013 and closed it in 2014 with no further action. Serebruany continues to publish critiques of the trial 15 years later but told The BMJ he has little hope that the questions will be resolved unless the DOJ re-engages with an investigation.
Doshi also points out discrepancies in the data reported. In the 2009 paper, published as an intent-to-treat analysis, investigators said there were 905 total deaths from any cause among all randomized patients. “An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths ‘discovered after withdrawal of consent,’” he reports.
The NEJM responded to Doshi that while it didn’t dispute the error in the number of deaths, it was uncertain about publishing a correction, citing new — not yet published — guidelines from the International Committee of Medical Journal Editors. NEJM Editor-in-Chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice.”
Doshi’s investigation includes an interview with Eric Bates, MD, professor of internal medicine at the University of Michigan in Ann Arbor, and a co-author of the US guidelines that recommend ticagrelor, who said he was “increasingly disturbed by how trial after trial came out as being not dramatically positive in any way.” Bates is now calling for a review of ticagrelor’s recommendation in guidelines, according to the report.
AstraZeneca declined to be interviewed for the BMJ investigation, according to Doshi, and a spokesperson from the company told the journal by email that they have “nothing to add,” directing editors to its 2014 public statement after the DOJ’s investigation into PLATO. The BMJ said PLATO trial co-chairs Robert A. Harrington, MD, and Lars Wallentin, MD, did not respond to The BMJ’s requests for comment.
Will the Guidelines Be Changed Now?
“I know and have worked with Drs Wallentin and Harrington,” Bates told Medscape Medical News, “and find them to be honest, intelligent clinical scientists with the highest ethical standards who manage conflicts of interest as well as can be done in the clinical research arena, where industry support is required to develop new knowledge,” he said.
“If there is a concern that AstraZeneca was manipulating the dataset and FDA submission, that is an important issue,” Bates said. “The US paradox and the failure of any other antiplatelet trial to find a comparative mortality advantage are two unexplained issues with PLATO that provide good fodder for conspiracy theories. I agree with the NEJM that this trial is 15 years old and may not be worth readjudicating in the current treatment era.”
Other calls for revisiting guidelines have come after disappointing postlicensure studies have repeatedly demonstrated that ticagrelor has “similar efficacy to clopidogrel but with increased bleeding and [dyspnea],” Doshi reports.
“My concern is the marketing spin by AstraZeneca and the promotion of ticagrelor by six to eight ‘thought leaders’ consistently funded by AstraZeneca over the past 10 years,” said Bates. “They have flooded the literature with supportive subset and post hoc analyses, review articles, and ‘meta-analyses’ flawed by selection and intellectual bias, and public interviews that consistently discount the findings of the many subsequent randomized controlled trials that have not supported the superiority of ticagrelor over clopidogrel or prasugrel.”
A version of this article first appeared on Medscape.com.
FROM THE BMJ
Lung CT Can Detect Coronary Artery Disease, Predict Death
“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.
“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.
“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”
The study was published online in The Canadian Medical Association Journal.
Potential Risk Reduction
In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.
The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.
At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.
A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.
On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).
Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).
“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.
“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”
Managing Other Findings
Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”
However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.
Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”
Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”
Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”
Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.
“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”
Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.
No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.
A version of this article first appeared on Medscape.com.
“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.
“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.
“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”
The study was published online in The Canadian Medical Association Journal.
Potential Risk Reduction
In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.
The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.
At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.
A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.
On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).
Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).
“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.
“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”
Managing Other Findings
Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”
However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.
Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”
Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”
Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”
Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.
“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”
Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.
No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.
A version of this article first appeared on Medscape.com.
“The high prevalence of asymptomatic coronary artery disease (83%) was surprising, as was the prevalence of extensive CAC (30%),” principal investigator Gary Small, MBChB, PhD, a cardiologist at the University of Ottawa Heart Institute in Ontario, Canada, said in an interview.
“The size of effect was also surprising, as was the persistence of the effect even in the presence of elevated mortality risk from other causes,” he said. “Extensive coronary disease was associated with a twofold increase in risk for death or cardiovascular events over 4 years of follow-up,” even after adjustment for risk for death from cancer and other comorbidities such as chronic obstructive pulmonary disease.
“CAC as reported on chest CT exams is often ignored and not factored into clinical practice,” he noted. “The presence of CAC, however, provides a very real and very personal perspective on an individual’s cardiovascular risk. It is a true example of personalized medicine.”
The study was published online in The Canadian Medical Association Journal.
Potential Risk Reduction
In March 2017, Ontario Health launched a pilot low-dose CT lung cancer screening program for high-risk individuals between the ages of 55 and 74 years, Small explained. As CAC, a marker of coronary artery disease, is seen easily during such a scan, the researchers analyzed the lung CTs to determine the prevalence of coronary artery disease and whether CAC was associated with increased risk.
The team quantified CAC using an estimated Agatston score and identified the composite primary outcome of all-cause death and cardiovascular events using linked electronic medical record data from Ottawa Hospital up to December 2023. Among the 1486 people who underwent screening (mean age, 66 years; 52% men; 68% current smokers), CAC was detected in 1232 (82.9%). CAC was mild to moderate in 793 participants (53.4%) and extensive in 439 (29.5%). No CAC was detected in 254 (17.1%) participants.
At follow-up, 78 participants (5.2%) experienced the primary composite outcome, including 39 (8.9%) with extensive CAC, 32 (4.0%) with mild to moderate CAC, and 7 (2.8%) with no CAC.
A total of 49 deaths occurred, including 16 cardiovascular deaths and 19 cancer deaths, of which 10 were from lung cancer. Cardiovascular events included sudden cardiac death (eight participants), fatal stroke (six participants), and one each from heart failure and peripheral vascular disease.
On multivariable analysis, extensive CAC was associated with the composite primary outcome (adjusted hazard ratio [aHR], 2.13), all-cause mortality (aHR, 2.39), and cardiovascular events (aHR, 2.06).
Extensive CAC remained predictive of cardiovascular events even after adjustment for noncardiovascular death as a competing risk (HR, 2.05).
“Our data highlight to lung cancer screening professionals the prevalence of this silent risk factor and re-emphasize the importance of this finding [ie, CAC] as an opportunity for risk reduction,” Small said.
“In terms of next steps, the journey toward cardiovascular risk reduction begins with a clear report of CAC on the lung cancer screening record,” he noted. “Following this step, professionals involved in the lung cancer screening program might consider a local management pathway to ensure that this opportunity for health improvement is not lost or ignored. Preventive medicine of this type would typically involve primary care.”
Managing Other Findings
Commenting on the study, Anna Bader, MD, assistant professor of radiology and biomedical imaging at the Yale School of Medicine in New Haven, Connecticut, said that “low-dose CT for lung cancer screening offers valuable insights beyond nodule detection, with CAC being among the most significant incidental findings.”
However, she added, a “robust mechanism” to effectively manage other findings — such as thoracic aortic disease, low bone density, and abnormalities in the thyroid or upper abdominal organs — without overdiagnosis, is needed. A mechanism also is needed to notify cardiologists or primary care providers about severe CAC findings.
Challenges that need to be overcome before such mechanisms can be put in place, she said, “include ensuring standardized CAC reporting, avoiding overburdening healthcare providers, mitigating the risk of excessive downstream testing, and ensuring equitable access to follow-up care for underserved and rural communities.”
Providers involved in lung cancer screening “must be trained to recognize the importance of CAC findings and act upon them,” she added. “Awareness campaigns or continuing medical education modules could address this.”
Multidisciplinary lung cancer screening programs can help with patient education, she noted. “Clear communication about potential findings, including the significance of incidental CAC, should be prioritized and addressed proactively, ideally before the exam, to enhance patient understanding and engagement.”
Matthew Tomey, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, said that, “as a practicing cardiologist, I find it very helpful to look at my patients’ recent or past CT scans to look for vascular calcification. Whether or not a scan is specifically protocoled as a cardiac study, we can often appreciate vascular calcification when it is present. I would encourage every physician involved in helping their patients to prevent heart disease to take advantage of looking at any prior CT scans for evidence of vascular calcification.
“Systems of care to facilitate recognition of patients with incidentally discovered vascular calcification would be welcome and, on a large scale, could help prevent cardiovascular events,” he noted. “Such a system might involve facilitating referral to a prevention specialist. It could involve evidence-based guidance for referring physicians who ordered scans.”
Like Bader, he noted the importance of patient education, adding that it could be quite powerful. “We should be doing more to empower our patients to understand the findings of their imaging and to give them actionable, evidence-based guidance on how they can promote their own cardiovascular health,” he concluded.
No funding for the study was reported. Small reported receiving a research grant for amyloid research from Pfizer and honoraria from Pfizer and Alnylam (all paid to the institution, outside the submitted work). Bader and Tomey declared no relevant conflicts.
A version of this article first appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
New Approaches to Research Beyond Massive Clinical Trials
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
Deprescribe Low-Value Meds to Reduce Polypharmacy Harms
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER, BRITISH COLUMBIA — While polypharmacy is inevitable for patients with multiple chronic diseases, not all medications improve patient-oriented outcomes, members of the Patients, Experience, Evidence, Research (PEER) team, a group of Canadian primary care professionals who develop evidence-based guidelines, told attendees at the Family Medicine Forum (FMF) 2024.
In a thought-provoking presentation called “Axe the Rx: Deprescribing Chronic Medications with PEER,” the panelists gave examples of medications that may be safely stopped or tapered, particularly for older adults “whose pill bag is heavier than their lunch bag.”
Curbing Cardiovascular Drugs
The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults call for reaching an LDL-C < 1.8 mmol/L in secondary cardiovascular prevention by potentially adding on medical therapies such as proprotein convertase subtilisin/kexin type 9 inhibitors or ezetimibe or both if that target is not reached with the maximal dosage of a statin.
But family physicians do not need to follow this guidance for their patients who have had a myocardial infarction, said Ontario family physician Jennifer Young, MD, a physician advisor in the Canadian College of Family Physicians’ Knowledge Experts and Tools Program.
Treating to below 1.8 mmol/L “means lab testing for the patients,” Young told this news organization. “It means increasing doses [of a statin] to try and get to that level.” If the patient is already on the highest dose of a statin, it means adding other medications that lower cholesterol.
“If that was translating into better outcomes like [preventing] death and another heart attack, then all of that extra effort would be worth it,” said Young. “But we don’t have evidence that it actually does have a benefit for outcomes like death and repeated heart attacks,” compared with putting them on a high dose of a potent statin.
Tapering Opioids
Before placing patients on an opioid taper, clinicians should first assess them for opioid use disorder (OUD), said Jessica Kirkwood, MD, assistant professor of family medicine at the University of Alberta in Edmonton, Canada. She suggested using the Prescription Opioid Misuse Index questionnaire to do so.
Clinicians should be much more careful in initiating a taper with patients with OUD, said Kirkwood. They must ensure that these patients are motivated to discontinue their opioids. “We’re losing 21 Canadians a day to the opioid crisis. We all know that cutting someone off their opioids and potentially having them seek opioids elsewhere through illicit means can be fatal.”
In addition, clinicians should spend more time counseling patients with OUD than those without, Kirkwood continued. They must explain to these patients how they are being tapered (eg, the intervals and doses) and highlight the benefits of a taper, such as reduced constipation. Opioid agonist therapy (such as methadone or buprenorphine) can be considered in these patients.
Some research has pointed to the importance of patient motivation as a factor in the success of opioid tapers, noted Kirkwood.
Deprescribing Benzodiazepines
Benzodiazepine receptor agonists, too, often can be deprescribed. These drugs should not be prescribed to promote sleep on a long-term basis. Yet clinicians commonly encounter patients who have been taking them for more than a year, said pharmacist Betsy Thomas, assistant adjunct professor of family medicine at the University of Alberta.
The medications “are usually fairly effective for the first couple of weeks to about a month, and then the benefits start to decrease, and we start to see more harms,” she said.
Some of the harms that have been associated with continued use of benzodiazepine receptor agonists include delayed reaction time and impaired cognition, which can affect the ability to drive, the risk for falls, and the risk for hip fractures, she noted. Some research suggests that these drugs are not an option for treating insomnia in patients aged 65 years or older.
Clinicians should encourage tapering the use of benzodiazepine receptor agonists to minimize dependence and transition patients to nonpharmacologic approaches such as cognitive behavioral therapy to manage insomnia, she said. A recent study demonstrated the efficacy of the intervention, and Thomas suggested that family physicians visit the mysleepwell.ca website for more information.
Young, Kirkwood, and Thomas reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FMF 2024
As Populations Age, Occam’s Razor Loses Its Diagnostic Edge
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.
“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.
But are these two axioms truly in conflict, or is this a false dichotomy?
Occam’s Razor and Simple Diagnoses
Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.
For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.
Beyond Hickam’s Dictum and Occam’s Razor
A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.
Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:
1. Incidentaloma: An asymptomatic condition discovered accidentally.
2. Preexisting diagnosis: A known condition in the patient’s medical history.
3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.
4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.
Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.
Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.
Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.
Practical Insights
The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.
Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Aliens, Ian McShane, and Heart Disease Risk
This transcript has been edited for clarity.
I was really struggling to think of a good analogy to explain the glaring problem of polygenic risk scores (PRS) this week. But I think I have it now. Go with me on this.
An alien spaceship parks itself, Independence Day style, above a local office building.
But unlike the aliens that gave such a hard time to Will Smith and Brent Spiner, these are benevolent, technologically superior guys. They shine a mysterious green light down on the building and then announce, maybe via telepathy, that 6% of the people in that building will have a heart attack in the next year.
They move on to the next building. “Five percent will have a heart attack in the next year.” And the next, 7%. And the next, 2%.
Let’s assume the aliens are entirely accurate. What do you do with this information?
Most of us would suggest that you find out who was in the buildings with the higher percentages. You check their cholesterol levels, get them to exercise more, do some stress tests, and so on.
But that said, you’d still be spending a lot of money on a bunch of people who were not going to have heart attacks. So, a crack team of spies — in my mind, this is definitely led by a grizzled Ian McShane — infiltrate the alien ship, steal this predictive ray gun, and start pointing it, not at buildings but at people.
In this scenario, one person could have a 10% chance of having a heart attack in the next year. Another person has a 50% chance. The aliens, seeing this, leave us one final message before flying into the great beyond: “No, you guys are doing it wrong.”
This week: The people and companies using an advanced predictive technology, PRS , wrong — and a study that shows just how problematic this is.
We all know that genes play a significant role in our health outcomes. Some diseases (Huntington disease, cystic fibrosis, sickle cell disease, hemochromatosis, and Duchenne muscular dystrophy, for example) are entirely driven by genetic mutations.
The vast majority of chronic diseases we face are not driven by genetics, but they may be enhanced by genetics. Coronary heart disease (CHD) is a prime example. There are clearly environmental risk factors, like smoking, that dramatically increase risk. But there are also genetic underpinnings; about half the risk for CHD comes from genetic variation, according to one study.
But in the case of those common diseases, it’s not one gene that leads to increased risk; it’s the aggregate effect of multiple risk genes, each contributing a small amount of risk to the final total.
The promise of PRS was based on this fact. Take the genome of an individual, identify all the risk genes, and integrate them into some final number that represents your genetic risk of developing CHD.
The way you derive a PRS is take a big group of people and sequence their genomes. Then, you see who develops the disease of interest — in this case, CHD. If the people who develop CHD are more likely to have a particular mutation, that mutation goes in the risk score. Risk scores can integrate tens, hundreds, even thousands of individual mutations to create that final score.
There are literally dozens of PRS for CHD. And there are companies that will calculate yours right now for a reasonable fee.
The accuracy of these scores is assessed at the population level. It’s the alien ray gun thing. Researchers apply the PRS to a big group of people and say 20% of them should develop CHD. If indeed 20% develop CHD, they say the score is accurate. And that’s true.
But what happens next is the problem. Companies and even doctors have been marketing PRS to individuals. And honestly, it sounds amazing. “We’ll use sophisticated techniques to analyze your genetic code and integrate the information to give you your personal risk for CHD.” Or dementia. Or other diseases. A lot of people would want to know this information.
It turns out, though, that this is where the system breaks down. And it is nicely illustrated by this study, appearing November 16 in JAMA.
The authors wanted to see how PRS, which are developed to predict disease in a group of people, work when applied to an individual.
They identified 48 previously published PRS for CHD. They applied those scores to more than 170,000 individuals across multiple genetic databases. And, by and large, the scores worked as advertised, at least across the entire group. The weighted accuracy of all 48 scores was around 78%. They aren’t perfect, of course. We wouldn’t expect them to be, since CHD is not entirely driven by genetics. But 78% accurate isn’t too bad.
But that accuracy is at the population level. At the level of the office building. At the individual level, it was a vastly different story.
This is best illustrated by this plot, which shows the score from 48 different PRS for CHD within the same person. A note here: It is arranged by the publication date of the risk score, but these were all assessed on a single blood sample at a single point in time in this study participant.
The individual scores are all over the map. Using one risk score gives an individual a risk that is near the 99th percentile — a ticking time bomb of CHD. Another score indicates a level of risk at the very bottom of the spectrum — highly reassuring. A bunch of scores fall somewhere in between. In other words, as a doctor, the risk I will discuss with this patient is more strongly determined by which PRS I happen to choose than by his actual genetic risk, whatever that is.
This may seem counterintuitive. All these risk scores were similarly accurate within a population; how can they all give different results to an individual? The answer is simpler than you may think. As long as a given score makes one extra good prediction for each extra bad prediction, its accuracy is not changed.
Let’s imagine we have a population of 40 people.
Risk score model 1 correctly classified 30 of them for 75% accuracy. Great.
Risk score model 2 also correctly classified 30 of our 40 individuals, for 75% accuracy. It’s just a different 30.
Risk score model 3 also correctly classified 30 of 40, but another different 30.
I’ve colored this to show you all the different overlaps. What you can see is that although each score has similar accuracy, the individual people have a bunch of different colors, indicating that some scores worked for them and some didn’t. That’s a real problem.
This has not stopped companies from advertising PRS for all sorts of diseases. Companies are even using PRS to decide which fetuses to implant during IVF therapy, which is a particularly egregiously wrong use of this technology that I have written about before.
How do you fix this? Our aliens tried to warn us. This is not how you are supposed to use this ray gun. You are supposed to use it to identify groups of people at higher risk to direct more resources to that group. That’s really all you can do.
It’s also possible that we need to match the risk score to the individual in a better way. This is likely driven by the fact that risk scores tend to work best in the populations in which they were developed, and many of them were developed in people of largely European ancestry.
It is worth noting that if a PRS had perfect accuracy at the population level, it would also necessarily have perfect accuracy at the individual level. But there aren’t any scores like that. It’s possible that combining various scores may increase the individual accuracy, but that hasn’t been demonstrated yet either.
Look, genetics is and will continue to play a major role in healthcare. At the same time, sequencing entire genomes is a technology that is ripe for hype and thus misuse. Or even abuse. Fundamentally, this JAMA study reminds us that accuracy in a population and accuracy in an individual are not the same. But more deeply, it reminds us that just because a technology is new or cool or expensive doesn’t mean it will work in the clinic.
Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I was really struggling to think of a good analogy to explain the glaring problem of polygenic risk scores (PRS) this week. But I think I have it now. Go with me on this.
An alien spaceship parks itself, Independence Day style, above a local office building.
But unlike the aliens that gave such a hard time to Will Smith and Brent Spiner, these are benevolent, technologically superior guys. They shine a mysterious green light down on the building and then announce, maybe via telepathy, that 6% of the people in that building will have a heart attack in the next year.
They move on to the next building. “Five percent will have a heart attack in the next year.” And the next, 7%. And the next, 2%.
Let’s assume the aliens are entirely accurate. What do you do with this information?
Most of us would suggest that you find out who was in the buildings with the higher percentages. You check their cholesterol levels, get them to exercise more, do some stress tests, and so on.
But that said, you’d still be spending a lot of money on a bunch of people who were not going to have heart attacks. So, a crack team of spies — in my mind, this is definitely led by a grizzled Ian McShane — infiltrate the alien ship, steal this predictive ray gun, and start pointing it, not at buildings but at people.
In this scenario, one person could have a 10% chance of having a heart attack in the next year. Another person has a 50% chance. The aliens, seeing this, leave us one final message before flying into the great beyond: “No, you guys are doing it wrong.”
This week: The people and companies using an advanced predictive technology, PRS , wrong — and a study that shows just how problematic this is.
We all know that genes play a significant role in our health outcomes. Some diseases (Huntington disease, cystic fibrosis, sickle cell disease, hemochromatosis, and Duchenne muscular dystrophy, for example) are entirely driven by genetic mutations.
The vast majority of chronic diseases we face are not driven by genetics, but they may be enhanced by genetics. Coronary heart disease (CHD) is a prime example. There are clearly environmental risk factors, like smoking, that dramatically increase risk. But there are also genetic underpinnings; about half the risk for CHD comes from genetic variation, according to one study.
But in the case of those common diseases, it’s not one gene that leads to increased risk; it’s the aggregate effect of multiple risk genes, each contributing a small amount of risk to the final total.
The promise of PRS was based on this fact. Take the genome of an individual, identify all the risk genes, and integrate them into some final number that represents your genetic risk of developing CHD.
The way you derive a PRS is take a big group of people and sequence their genomes. Then, you see who develops the disease of interest — in this case, CHD. If the people who develop CHD are more likely to have a particular mutation, that mutation goes in the risk score. Risk scores can integrate tens, hundreds, even thousands of individual mutations to create that final score.
There are literally dozens of PRS for CHD. And there are companies that will calculate yours right now for a reasonable fee.
The accuracy of these scores is assessed at the population level. It’s the alien ray gun thing. Researchers apply the PRS to a big group of people and say 20% of them should develop CHD. If indeed 20% develop CHD, they say the score is accurate. And that’s true.
But what happens next is the problem. Companies and even doctors have been marketing PRS to individuals. And honestly, it sounds amazing. “We’ll use sophisticated techniques to analyze your genetic code and integrate the information to give you your personal risk for CHD.” Or dementia. Or other diseases. A lot of people would want to know this information.
It turns out, though, that this is where the system breaks down. And it is nicely illustrated by this study, appearing November 16 in JAMA.
The authors wanted to see how PRS, which are developed to predict disease in a group of people, work when applied to an individual.
They identified 48 previously published PRS for CHD. They applied those scores to more than 170,000 individuals across multiple genetic databases. And, by and large, the scores worked as advertised, at least across the entire group. The weighted accuracy of all 48 scores was around 78%. They aren’t perfect, of course. We wouldn’t expect them to be, since CHD is not entirely driven by genetics. But 78% accurate isn’t too bad.
But that accuracy is at the population level. At the level of the office building. At the individual level, it was a vastly different story.
This is best illustrated by this plot, which shows the score from 48 different PRS for CHD within the same person. A note here: It is arranged by the publication date of the risk score, but these were all assessed on a single blood sample at a single point in time in this study participant.
The individual scores are all over the map. Using one risk score gives an individual a risk that is near the 99th percentile — a ticking time bomb of CHD. Another score indicates a level of risk at the very bottom of the spectrum — highly reassuring. A bunch of scores fall somewhere in between. In other words, as a doctor, the risk I will discuss with this patient is more strongly determined by which PRS I happen to choose than by his actual genetic risk, whatever that is.
This may seem counterintuitive. All these risk scores were similarly accurate within a population; how can they all give different results to an individual? The answer is simpler than you may think. As long as a given score makes one extra good prediction for each extra bad prediction, its accuracy is not changed.
Let’s imagine we have a population of 40 people.
Risk score model 1 correctly classified 30 of them for 75% accuracy. Great.
Risk score model 2 also correctly classified 30 of our 40 individuals, for 75% accuracy. It’s just a different 30.
Risk score model 3 also correctly classified 30 of 40, but another different 30.
I’ve colored this to show you all the different overlaps. What you can see is that although each score has similar accuracy, the individual people have a bunch of different colors, indicating that some scores worked for them and some didn’t. That’s a real problem.
This has not stopped companies from advertising PRS for all sorts of diseases. Companies are even using PRS to decide which fetuses to implant during IVF therapy, which is a particularly egregiously wrong use of this technology that I have written about before.
How do you fix this? Our aliens tried to warn us. This is not how you are supposed to use this ray gun. You are supposed to use it to identify groups of people at higher risk to direct more resources to that group. That’s really all you can do.
It’s also possible that we need to match the risk score to the individual in a better way. This is likely driven by the fact that risk scores tend to work best in the populations in which they were developed, and many of them were developed in people of largely European ancestry.
It is worth noting that if a PRS had perfect accuracy at the population level, it would also necessarily have perfect accuracy at the individual level. But there aren’t any scores like that. It’s possible that combining various scores may increase the individual accuracy, but that hasn’t been demonstrated yet either.
Look, genetics is and will continue to play a major role in healthcare. At the same time, sequencing entire genomes is a technology that is ripe for hype and thus misuse. Or even abuse. Fundamentally, this JAMA study reminds us that accuracy in a population and accuracy in an individual are not the same. But more deeply, it reminds us that just because a technology is new or cool or expensive doesn’t mean it will work in the clinic.
Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I was really struggling to think of a good analogy to explain the glaring problem of polygenic risk scores (PRS) this week. But I think I have it now. Go with me on this.
An alien spaceship parks itself, Independence Day style, above a local office building.
But unlike the aliens that gave such a hard time to Will Smith and Brent Spiner, these are benevolent, technologically superior guys. They shine a mysterious green light down on the building and then announce, maybe via telepathy, that 6% of the people in that building will have a heart attack in the next year.
They move on to the next building. “Five percent will have a heart attack in the next year.” And the next, 7%. And the next, 2%.
Let’s assume the aliens are entirely accurate. What do you do with this information?
Most of us would suggest that you find out who was in the buildings with the higher percentages. You check their cholesterol levels, get them to exercise more, do some stress tests, and so on.
But that said, you’d still be spending a lot of money on a bunch of people who were not going to have heart attacks. So, a crack team of spies — in my mind, this is definitely led by a grizzled Ian McShane — infiltrate the alien ship, steal this predictive ray gun, and start pointing it, not at buildings but at people.
In this scenario, one person could have a 10% chance of having a heart attack in the next year. Another person has a 50% chance. The aliens, seeing this, leave us one final message before flying into the great beyond: “No, you guys are doing it wrong.”
This week: The people and companies using an advanced predictive technology, PRS , wrong — and a study that shows just how problematic this is.
We all know that genes play a significant role in our health outcomes. Some diseases (Huntington disease, cystic fibrosis, sickle cell disease, hemochromatosis, and Duchenne muscular dystrophy, for example) are entirely driven by genetic mutations.
The vast majority of chronic diseases we face are not driven by genetics, but they may be enhanced by genetics. Coronary heart disease (CHD) is a prime example. There are clearly environmental risk factors, like smoking, that dramatically increase risk. But there are also genetic underpinnings; about half the risk for CHD comes from genetic variation, according to one study.
But in the case of those common diseases, it’s not one gene that leads to increased risk; it’s the aggregate effect of multiple risk genes, each contributing a small amount of risk to the final total.
The promise of PRS was based on this fact. Take the genome of an individual, identify all the risk genes, and integrate them into some final number that represents your genetic risk of developing CHD.
The way you derive a PRS is take a big group of people and sequence their genomes. Then, you see who develops the disease of interest — in this case, CHD. If the people who develop CHD are more likely to have a particular mutation, that mutation goes in the risk score. Risk scores can integrate tens, hundreds, even thousands of individual mutations to create that final score.
There are literally dozens of PRS for CHD. And there are companies that will calculate yours right now for a reasonable fee.
The accuracy of these scores is assessed at the population level. It’s the alien ray gun thing. Researchers apply the PRS to a big group of people and say 20% of them should develop CHD. If indeed 20% develop CHD, they say the score is accurate. And that’s true.
But what happens next is the problem. Companies and even doctors have been marketing PRS to individuals. And honestly, it sounds amazing. “We’ll use sophisticated techniques to analyze your genetic code and integrate the information to give you your personal risk for CHD.” Or dementia. Or other diseases. A lot of people would want to know this information.
It turns out, though, that this is where the system breaks down. And it is nicely illustrated by this study, appearing November 16 in JAMA.
The authors wanted to see how PRS, which are developed to predict disease in a group of people, work when applied to an individual.
They identified 48 previously published PRS for CHD. They applied those scores to more than 170,000 individuals across multiple genetic databases. And, by and large, the scores worked as advertised, at least across the entire group. The weighted accuracy of all 48 scores was around 78%. They aren’t perfect, of course. We wouldn’t expect them to be, since CHD is not entirely driven by genetics. But 78% accurate isn’t too bad.
But that accuracy is at the population level. At the level of the office building. At the individual level, it was a vastly different story.
This is best illustrated by this plot, which shows the score from 48 different PRS for CHD within the same person. A note here: It is arranged by the publication date of the risk score, but these were all assessed on a single blood sample at a single point in time in this study participant.
The individual scores are all over the map. Using one risk score gives an individual a risk that is near the 99th percentile — a ticking time bomb of CHD. Another score indicates a level of risk at the very bottom of the spectrum — highly reassuring. A bunch of scores fall somewhere in between. In other words, as a doctor, the risk I will discuss with this patient is more strongly determined by which PRS I happen to choose than by his actual genetic risk, whatever that is.
This may seem counterintuitive. All these risk scores were similarly accurate within a population; how can they all give different results to an individual? The answer is simpler than you may think. As long as a given score makes one extra good prediction for each extra bad prediction, its accuracy is not changed.
Let’s imagine we have a population of 40 people.
Risk score model 1 correctly classified 30 of them for 75% accuracy. Great.
Risk score model 2 also correctly classified 30 of our 40 individuals, for 75% accuracy. It’s just a different 30.
Risk score model 3 also correctly classified 30 of 40, but another different 30.
I’ve colored this to show you all the different overlaps. What you can see is that although each score has similar accuracy, the individual people have a bunch of different colors, indicating that some scores worked for them and some didn’t. That’s a real problem.
This has not stopped companies from advertising PRS for all sorts of diseases. Companies are even using PRS to decide which fetuses to implant during IVF therapy, which is a particularly egregiously wrong use of this technology that I have written about before.
How do you fix this? Our aliens tried to warn us. This is not how you are supposed to use this ray gun. You are supposed to use it to identify groups of people at higher risk to direct more resources to that group. That’s really all you can do.
It’s also possible that we need to match the risk score to the individual in a better way. This is likely driven by the fact that risk scores tend to work best in the populations in which they were developed, and many of them were developed in people of largely European ancestry.
It is worth noting that if a PRS had perfect accuracy at the population level, it would also necessarily have perfect accuracy at the individual level. But there aren’t any scores like that. It’s possible that combining various scores may increase the individual accuracy, but that hasn’t been demonstrated yet either.
Look, genetics is and will continue to play a major role in healthcare. At the same time, sequencing entire genomes is a technology that is ripe for hype and thus misuse. Or even abuse. Fundamentally, this JAMA study reminds us that accuracy in a population and accuracy in an individual are not the same. But more deeply, it reminds us that just because a technology is new or cool or expensive doesn’t mean it will work in the clinic.
Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Connecticut. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.