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Similar brain atrophy in obesity and Alzheimer’s disease
Comparisons of MRI scans for more than 1,000 participants indicate correlations between the two conditions, especially in areas of gray matter thinning, suggesting that managing excess weight might slow cognitive decline and lower the risk for AD, according to the researchers.
However, brain maps of obesity did not correlate with maps of amyloid or tau protein accumulation.
“The fact that obesity-related brain atrophy did not correlate with the distribution of amyloid and tau proteins in AD was not what we expected,” study author Filip Morys, PhD, a postdoctoral researcher at McGill University, Montreal, said in an interview. “But it might just show that the specific mechanisms underpinning obesity- and Alzheimer’s disease–related neurodegeneration are different. This remains to be confirmed.”
The study was published in the Journal of Alzheimer’s Disease.
Cortical Thinning
The current study was prompted by the team’s earlier study, which showed that obesity-related neurodegeneration patterns were visually similar to those of AD, said Dr. Morys. “It was known previously that obesity is a risk factor for AD, but we wanted to directly compare brain atrophy patterns in both, which is what we did in this new study.”
The researchers analyzed data from a pooled sample of more than 1,300 participants. From the ADNI database, the researchers selected participants with AD and age- and sex-matched cognitively healthy controls. From the UK Biobank, the researchers drew a sample of lean, overweight, and obese participants without neurologic disease.
To determine how the weight status of patients with AD affects the correspondence between AD and obesity maps, they categorized participants with AD and healthy controls from the ADNI database into lean, overweight, and obese subgroups.
Then, to investigate mechanisms that might drive the similarities between obesity-related brain atrophy and AD-related amyloid-beta accumulation, they looked for overlapping areas in PET brain maps between patients with these outcomes.
The investigations showed that obesity maps were highly correlated with AD maps, but not with amyloid-beta or tau protein maps. The researchers also found significant correlations between obesity and the lean individuals with AD.
Brain regions with the highest similarities between obesity and AD were located mainly in the left temporal and bilateral prefrontal cortices.
“Our research confirms that obesity-related gray matter atrophy resembles that of AD,” the authors concluded. “Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.”
Upcoming research “will focus on investigating how weight loss can affect the risk for AD, other dementias, and cognitive decline in general,” said Dr. Morys. “At this point, our study suggests that obesity prevention, weight loss, but also decreasing other metabolic risk factors related to obesity, such as type-2 diabetes or hypertension, might reduce the risk for AD and have beneficial effects on cognition.”
Lifestyle habits
Commenting on the findings, Claire Sexton, DPhil, vice president of scientific programs and outreach at the Alzheimer’s Association, cautioned that a single cross-sectional study isn’t conclusive. “Previous studies have illustrated that the relationship between obesity and dementia is complex. Growing evidence indicates that people can reduce their risk of cognitive decline by adopting key lifestyle habits, like regular exercise, a heart-healthy diet and staying socially and cognitively engaged.”
The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to study how targeting these risk factors in combination may reduce risk for cognitive decline in older adults.
The work was supported by a Foundation Scheme award from the Canadian Institutes of Health Research. Dr. Morys received a postdoctoral fellowship from Fonds de Recherche du Quebec – Santé. Data collection and sharing were funded by the Alzheimer’s Disease Neuroimaging Initiative, the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and multiple pharmaceutical companies and other private sector organizations. Dr. Morys and Dr. Sexton reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Comparisons of MRI scans for more than 1,000 participants indicate correlations between the two conditions, especially in areas of gray matter thinning, suggesting that managing excess weight might slow cognitive decline and lower the risk for AD, according to the researchers.
However, brain maps of obesity did not correlate with maps of amyloid or tau protein accumulation.
“The fact that obesity-related brain atrophy did not correlate with the distribution of amyloid and tau proteins in AD was not what we expected,” study author Filip Morys, PhD, a postdoctoral researcher at McGill University, Montreal, said in an interview. “But it might just show that the specific mechanisms underpinning obesity- and Alzheimer’s disease–related neurodegeneration are different. This remains to be confirmed.”
The study was published in the Journal of Alzheimer’s Disease.
Cortical Thinning
The current study was prompted by the team’s earlier study, which showed that obesity-related neurodegeneration patterns were visually similar to those of AD, said Dr. Morys. “It was known previously that obesity is a risk factor for AD, but we wanted to directly compare brain atrophy patterns in both, which is what we did in this new study.”
The researchers analyzed data from a pooled sample of more than 1,300 participants. From the ADNI database, the researchers selected participants with AD and age- and sex-matched cognitively healthy controls. From the UK Biobank, the researchers drew a sample of lean, overweight, and obese participants without neurologic disease.
To determine how the weight status of patients with AD affects the correspondence between AD and obesity maps, they categorized participants with AD and healthy controls from the ADNI database into lean, overweight, and obese subgroups.
Then, to investigate mechanisms that might drive the similarities between obesity-related brain atrophy and AD-related amyloid-beta accumulation, they looked for overlapping areas in PET brain maps between patients with these outcomes.
The investigations showed that obesity maps were highly correlated with AD maps, but not with amyloid-beta or tau protein maps. The researchers also found significant correlations between obesity and the lean individuals with AD.
Brain regions with the highest similarities between obesity and AD were located mainly in the left temporal and bilateral prefrontal cortices.
“Our research confirms that obesity-related gray matter atrophy resembles that of AD,” the authors concluded. “Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.”
Upcoming research “will focus on investigating how weight loss can affect the risk for AD, other dementias, and cognitive decline in general,” said Dr. Morys. “At this point, our study suggests that obesity prevention, weight loss, but also decreasing other metabolic risk factors related to obesity, such as type-2 diabetes or hypertension, might reduce the risk for AD and have beneficial effects on cognition.”
Lifestyle habits
Commenting on the findings, Claire Sexton, DPhil, vice president of scientific programs and outreach at the Alzheimer’s Association, cautioned that a single cross-sectional study isn’t conclusive. “Previous studies have illustrated that the relationship between obesity and dementia is complex. Growing evidence indicates that people can reduce their risk of cognitive decline by adopting key lifestyle habits, like regular exercise, a heart-healthy diet and staying socially and cognitively engaged.”
The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to study how targeting these risk factors in combination may reduce risk for cognitive decline in older adults.
The work was supported by a Foundation Scheme award from the Canadian Institutes of Health Research. Dr. Morys received a postdoctoral fellowship from Fonds de Recherche du Quebec – Santé. Data collection and sharing were funded by the Alzheimer’s Disease Neuroimaging Initiative, the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and multiple pharmaceutical companies and other private sector organizations. Dr. Morys and Dr. Sexton reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Comparisons of MRI scans for more than 1,000 participants indicate correlations between the two conditions, especially in areas of gray matter thinning, suggesting that managing excess weight might slow cognitive decline and lower the risk for AD, according to the researchers.
However, brain maps of obesity did not correlate with maps of amyloid or tau protein accumulation.
“The fact that obesity-related brain atrophy did not correlate with the distribution of amyloid and tau proteins in AD was not what we expected,” study author Filip Morys, PhD, a postdoctoral researcher at McGill University, Montreal, said in an interview. “But it might just show that the specific mechanisms underpinning obesity- and Alzheimer’s disease–related neurodegeneration are different. This remains to be confirmed.”
The study was published in the Journal of Alzheimer’s Disease.
Cortical Thinning
The current study was prompted by the team’s earlier study, which showed that obesity-related neurodegeneration patterns were visually similar to those of AD, said Dr. Morys. “It was known previously that obesity is a risk factor for AD, but we wanted to directly compare brain atrophy patterns in both, which is what we did in this new study.”
The researchers analyzed data from a pooled sample of more than 1,300 participants. From the ADNI database, the researchers selected participants with AD and age- and sex-matched cognitively healthy controls. From the UK Biobank, the researchers drew a sample of lean, overweight, and obese participants without neurologic disease.
To determine how the weight status of patients with AD affects the correspondence between AD and obesity maps, they categorized participants with AD and healthy controls from the ADNI database into lean, overweight, and obese subgroups.
Then, to investigate mechanisms that might drive the similarities between obesity-related brain atrophy and AD-related amyloid-beta accumulation, they looked for overlapping areas in PET brain maps between patients with these outcomes.
The investigations showed that obesity maps were highly correlated with AD maps, but not with amyloid-beta or tau protein maps. The researchers also found significant correlations between obesity and the lean individuals with AD.
Brain regions with the highest similarities between obesity and AD were located mainly in the left temporal and bilateral prefrontal cortices.
“Our research confirms that obesity-related gray matter atrophy resembles that of AD,” the authors concluded. “Excess weight management could lead to improved health outcomes, slow down cognitive decline in aging, and lower the risk for AD.”
Upcoming research “will focus on investigating how weight loss can affect the risk for AD, other dementias, and cognitive decline in general,” said Dr. Morys. “At this point, our study suggests that obesity prevention, weight loss, but also decreasing other metabolic risk factors related to obesity, such as type-2 diabetes or hypertension, might reduce the risk for AD and have beneficial effects on cognition.”
Lifestyle habits
Commenting on the findings, Claire Sexton, DPhil, vice president of scientific programs and outreach at the Alzheimer’s Association, cautioned that a single cross-sectional study isn’t conclusive. “Previous studies have illustrated that the relationship between obesity and dementia is complex. Growing evidence indicates that people can reduce their risk of cognitive decline by adopting key lifestyle habits, like regular exercise, a heart-healthy diet and staying socially and cognitively engaged.”
The Alzheimer’s Association is leading a 2-year clinical trial, U.S. Pointer, to study how targeting these risk factors in combination may reduce risk for cognitive decline in older adults.
The work was supported by a Foundation Scheme award from the Canadian Institutes of Health Research. Dr. Morys received a postdoctoral fellowship from Fonds de Recherche du Quebec – Santé. Data collection and sharing were funded by the Alzheimer’s Disease Neuroimaging Initiative, the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and multiple pharmaceutical companies and other private sector organizations. Dr. Morys and Dr. Sexton reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S DISEASE
Long QT syndrome overdiagnosis persists
Five factors underlie the ongoing overdiagnosis and misdiagnosis of long QT syndrome (LQTS), including temporary QT prolongation following vasovagal syncope, a “pseudo”-positive genetic test result, family history of sudden cardiac death, transient QT prolongation, and misinterpretation of the QTc interval, a new study suggests.
Awareness of these characteristics, which led to a diagnostic reversal in 290 of 1,841 (16%) patients, could reduce the burden of overdiagnosis on the health care system and on patients and families, senior author Michael J. Ackerman, MD, PhD, of Mayo Clinic, Rochester, Minn., and colleagues conclude.
“The findings are a disturbing and disappointing sequel to the paper we published about LQTS overdiagnosis back in 2007, which showed that 2 out of every 5 patients who came to Mayo Clinic for a second opinion left without the diagnosis,” Dr. Ackerman told this news organization.
To date, Dr. Ackerman has reversed the diagnosis for 350 patients, he said.
The consequences of an LQTS diagnosis are “profound,” he noted, including years of unnecessary drug therapy, implantation of a cardioverter defibrillator, disqualification from competitive sports, and emotional stress to the individual and family.
By pointing out the five biggest mistakes his team has seen, he said, “we hope to equip the diagnostician with the means to challenge and assess the veracity of a LQTS diagnosis.”
The study was published online in the Journal of the American College of Cardiology.
Time to do better
Dr. Ackerman and colleagues analyzed electronic medical records on 290 of 1,841 (16%) patients who presented with an outside diagnosis of LQTS but subsequently were dismissed as having normal findings. The mean age of these patients at their first Mayo Clinic evaluation was 22, 60% were female, and the mean QTc interval was 427 ±25 milliseconds.
Overall, 38% of misdiagnoses were the result of misinterpretation of clinical factors; 29%, to diagnostic test misinterpretations; 17%, to an apparently positive genetic test in the context of a weak or absent phenotype; and 16%, to a family history of false LQTS or of sudden cardiac or sudden unexplained death.
More specifically, the most common cause of an LQTS misdiagnosis was QT prolongation following vasovagal syncope, which was misinterpreted as LQTS-attributed syncope.
The second most common cause was an apparently positive genetic test for an LQTS gene that turned out to be a benign or likely benign variant.
The third most common cause was an LQTS diagnosis based solely on a family history of sudden unexplained death (26 patients), QT prolongation (11 patients), or sudden cardiac arrest (9 patients).
The fourth most common cause was an isolated event of QT prolongation (44 patients). The transient QT prolongation was observed under myriad conditions unrelated to LQTS. Yet, 31 patients received a diagnosis based solely on the event.
The fifth most common cause was inclusion of the U-wave in the calculation of the QTc interval (40 patients), leading to an inaccurate interpretation of the electrocardiogram.
Dr. Ackerman noted that these LQTS diagnoses were given by heart-rhythm specialists, and most patients self-referred for a second opinion because a family member questioned the diagnosis after doing their own research.
“It’s time that we step up to the plate and do better,” Dr. Ackerman said. The team’s evaluation of the impact of the misdiagnosis on the patients’ lifestyle and quality of life showed that 45% had been restricted from competitive sports (and subsequently resumed sports activity with no adverse events); 80% had been started on beta-blockers (the drugs were discontinued in 84% as a result of the Mayo Clinic evaluation, whereas 16% opted to continue); and 10 of 22 patients (45%) who received an implanted cardioverter device underwent an extraction of the device without complications.
The authors conclude: “Although missing a patient who truly has LQTS can lead to a tragic outcome, the implications of overdiagnosed LQTS are not trivial and are potentially tragic as well.”
‘Tricky diagnosis’
LQTS specialist Peter Aziz, MD, director of pediatric electrophysiology at the Cleveland Clinic, agreed with these findings.
“Most of us ‘channelopathists’ who see LQTS for a living have a good grasp of the disease, but it can be elusive for others,” he said in an interview. “This is a tricky diagnosis. There are ends of the spectrum where people for sure don’t have it and people for sure do. Most clinicians are able to identify that.”
However, he added, “A lot of patients fall into that gray area where it may not be clear at first, even to an expert. But the expert knows how to do a comprehensive evaluation, examining episodes and symptoms and understanding whether they are relevant to LQTS or completely red herrings, and feeling confident about how they calculate the acute interval on an electrocardiogram.”
“All of these may seem mundane, but without the experience, clinicians are vulnerable to miscalculations,” he said. “That’s why our bias, as channelopathists, is that every patient who has a suspected diagnosis or is being treated for LQTS really should see an expert.”
Similarly, Arthur A.M. Wilde, MD, PhD, of the University of Amsterdam, and Peter J. Schwartz, MD, of IRCCS Istituto Auxologico Italiano, Milan, write in a related editorial that it “has to be kept in mind that both diagnostic scores and risk scores are dynamic and can be modified by time and by appropriate therapy.
“Therefore, to make hasty diagnosis of a disease that requires life-long treatment is inappropriate, especially when this is done without the support of adequate, specific experience.”
No commercial funding or relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
Five factors underlie the ongoing overdiagnosis and misdiagnosis of long QT syndrome (LQTS), including temporary QT prolongation following vasovagal syncope, a “pseudo”-positive genetic test result, family history of sudden cardiac death, transient QT prolongation, and misinterpretation of the QTc interval, a new study suggests.
Awareness of these characteristics, which led to a diagnostic reversal in 290 of 1,841 (16%) patients, could reduce the burden of overdiagnosis on the health care system and on patients and families, senior author Michael J. Ackerman, MD, PhD, of Mayo Clinic, Rochester, Minn., and colleagues conclude.
“The findings are a disturbing and disappointing sequel to the paper we published about LQTS overdiagnosis back in 2007, which showed that 2 out of every 5 patients who came to Mayo Clinic for a second opinion left without the diagnosis,” Dr. Ackerman told this news organization.
To date, Dr. Ackerman has reversed the diagnosis for 350 patients, he said.
The consequences of an LQTS diagnosis are “profound,” he noted, including years of unnecessary drug therapy, implantation of a cardioverter defibrillator, disqualification from competitive sports, and emotional stress to the individual and family.
By pointing out the five biggest mistakes his team has seen, he said, “we hope to equip the diagnostician with the means to challenge and assess the veracity of a LQTS diagnosis.”
The study was published online in the Journal of the American College of Cardiology.
Time to do better
Dr. Ackerman and colleagues analyzed electronic medical records on 290 of 1,841 (16%) patients who presented with an outside diagnosis of LQTS but subsequently were dismissed as having normal findings. The mean age of these patients at their first Mayo Clinic evaluation was 22, 60% were female, and the mean QTc interval was 427 ±25 milliseconds.
Overall, 38% of misdiagnoses were the result of misinterpretation of clinical factors; 29%, to diagnostic test misinterpretations; 17%, to an apparently positive genetic test in the context of a weak or absent phenotype; and 16%, to a family history of false LQTS or of sudden cardiac or sudden unexplained death.
More specifically, the most common cause of an LQTS misdiagnosis was QT prolongation following vasovagal syncope, which was misinterpreted as LQTS-attributed syncope.
The second most common cause was an apparently positive genetic test for an LQTS gene that turned out to be a benign or likely benign variant.
The third most common cause was an LQTS diagnosis based solely on a family history of sudden unexplained death (26 patients), QT prolongation (11 patients), or sudden cardiac arrest (9 patients).
The fourth most common cause was an isolated event of QT prolongation (44 patients). The transient QT prolongation was observed under myriad conditions unrelated to LQTS. Yet, 31 patients received a diagnosis based solely on the event.
The fifth most common cause was inclusion of the U-wave in the calculation of the QTc interval (40 patients), leading to an inaccurate interpretation of the electrocardiogram.
Dr. Ackerman noted that these LQTS diagnoses were given by heart-rhythm specialists, and most patients self-referred for a second opinion because a family member questioned the diagnosis after doing their own research.
“It’s time that we step up to the plate and do better,” Dr. Ackerman said. The team’s evaluation of the impact of the misdiagnosis on the patients’ lifestyle and quality of life showed that 45% had been restricted from competitive sports (and subsequently resumed sports activity with no adverse events); 80% had been started on beta-blockers (the drugs were discontinued in 84% as a result of the Mayo Clinic evaluation, whereas 16% opted to continue); and 10 of 22 patients (45%) who received an implanted cardioverter device underwent an extraction of the device without complications.
The authors conclude: “Although missing a patient who truly has LQTS can lead to a tragic outcome, the implications of overdiagnosed LQTS are not trivial and are potentially tragic as well.”
‘Tricky diagnosis’
LQTS specialist Peter Aziz, MD, director of pediatric electrophysiology at the Cleveland Clinic, agreed with these findings.
“Most of us ‘channelopathists’ who see LQTS for a living have a good grasp of the disease, but it can be elusive for others,” he said in an interview. “This is a tricky diagnosis. There are ends of the spectrum where people for sure don’t have it and people for sure do. Most clinicians are able to identify that.”
However, he added, “A lot of patients fall into that gray area where it may not be clear at first, even to an expert. But the expert knows how to do a comprehensive evaluation, examining episodes and symptoms and understanding whether they are relevant to LQTS or completely red herrings, and feeling confident about how they calculate the acute interval on an electrocardiogram.”
“All of these may seem mundane, but without the experience, clinicians are vulnerable to miscalculations,” he said. “That’s why our bias, as channelopathists, is that every patient who has a suspected diagnosis or is being treated for LQTS really should see an expert.”
Similarly, Arthur A.M. Wilde, MD, PhD, of the University of Amsterdam, and Peter J. Schwartz, MD, of IRCCS Istituto Auxologico Italiano, Milan, write in a related editorial that it “has to be kept in mind that both diagnostic scores and risk scores are dynamic and can be modified by time and by appropriate therapy.
“Therefore, to make hasty diagnosis of a disease that requires life-long treatment is inappropriate, especially when this is done without the support of adequate, specific experience.”
No commercial funding or relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
Five factors underlie the ongoing overdiagnosis and misdiagnosis of long QT syndrome (LQTS), including temporary QT prolongation following vasovagal syncope, a “pseudo”-positive genetic test result, family history of sudden cardiac death, transient QT prolongation, and misinterpretation of the QTc interval, a new study suggests.
Awareness of these characteristics, which led to a diagnostic reversal in 290 of 1,841 (16%) patients, could reduce the burden of overdiagnosis on the health care system and on patients and families, senior author Michael J. Ackerman, MD, PhD, of Mayo Clinic, Rochester, Minn., and colleagues conclude.
“The findings are a disturbing and disappointing sequel to the paper we published about LQTS overdiagnosis back in 2007, which showed that 2 out of every 5 patients who came to Mayo Clinic for a second opinion left without the diagnosis,” Dr. Ackerman told this news organization.
To date, Dr. Ackerman has reversed the diagnosis for 350 patients, he said.
The consequences of an LQTS diagnosis are “profound,” he noted, including years of unnecessary drug therapy, implantation of a cardioverter defibrillator, disqualification from competitive sports, and emotional stress to the individual and family.
By pointing out the five biggest mistakes his team has seen, he said, “we hope to equip the diagnostician with the means to challenge and assess the veracity of a LQTS diagnosis.”
The study was published online in the Journal of the American College of Cardiology.
Time to do better
Dr. Ackerman and colleagues analyzed electronic medical records on 290 of 1,841 (16%) patients who presented with an outside diagnosis of LQTS but subsequently were dismissed as having normal findings. The mean age of these patients at their first Mayo Clinic evaluation was 22, 60% were female, and the mean QTc interval was 427 ±25 milliseconds.
Overall, 38% of misdiagnoses were the result of misinterpretation of clinical factors; 29%, to diagnostic test misinterpretations; 17%, to an apparently positive genetic test in the context of a weak or absent phenotype; and 16%, to a family history of false LQTS or of sudden cardiac or sudden unexplained death.
More specifically, the most common cause of an LQTS misdiagnosis was QT prolongation following vasovagal syncope, which was misinterpreted as LQTS-attributed syncope.
The second most common cause was an apparently positive genetic test for an LQTS gene that turned out to be a benign or likely benign variant.
The third most common cause was an LQTS diagnosis based solely on a family history of sudden unexplained death (26 patients), QT prolongation (11 patients), or sudden cardiac arrest (9 patients).
The fourth most common cause was an isolated event of QT prolongation (44 patients). The transient QT prolongation was observed under myriad conditions unrelated to LQTS. Yet, 31 patients received a diagnosis based solely on the event.
The fifth most common cause was inclusion of the U-wave in the calculation of the QTc interval (40 patients), leading to an inaccurate interpretation of the electrocardiogram.
Dr. Ackerman noted that these LQTS diagnoses were given by heart-rhythm specialists, and most patients self-referred for a second opinion because a family member questioned the diagnosis after doing their own research.
“It’s time that we step up to the plate and do better,” Dr. Ackerman said. The team’s evaluation of the impact of the misdiagnosis on the patients’ lifestyle and quality of life showed that 45% had been restricted from competitive sports (and subsequently resumed sports activity with no adverse events); 80% had been started on beta-blockers (the drugs were discontinued in 84% as a result of the Mayo Clinic evaluation, whereas 16% opted to continue); and 10 of 22 patients (45%) who received an implanted cardioverter device underwent an extraction of the device without complications.
The authors conclude: “Although missing a patient who truly has LQTS can lead to a tragic outcome, the implications of overdiagnosed LQTS are not trivial and are potentially tragic as well.”
‘Tricky diagnosis’
LQTS specialist Peter Aziz, MD, director of pediatric electrophysiology at the Cleveland Clinic, agreed with these findings.
“Most of us ‘channelopathists’ who see LQTS for a living have a good grasp of the disease, but it can be elusive for others,” he said in an interview. “This is a tricky diagnosis. There are ends of the spectrum where people for sure don’t have it and people for sure do. Most clinicians are able to identify that.”
However, he added, “A lot of patients fall into that gray area where it may not be clear at first, even to an expert. But the expert knows how to do a comprehensive evaluation, examining episodes and symptoms and understanding whether they are relevant to LQTS or completely red herrings, and feeling confident about how they calculate the acute interval on an electrocardiogram.”
“All of these may seem mundane, but without the experience, clinicians are vulnerable to miscalculations,” he said. “That’s why our bias, as channelopathists, is that every patient who has a suspected diagnosis or is being treated for LQTS really should see an expert.”
Similarly, Arthur A.M. Wilde, MD, PhD, of the University of Amsterdam, and Peter J. Schwartz, MD, of IRCCS Istituto Auxologico Italiano, Milan, write in a related editorial that it “has to be kept in mind that both diagnostic scores and risk scores are dynamic and can be modified by time and by appropriate therapy.
“Therefore, to make hasty diagnosis of a disease that requires life-long treatment is inappropriate, especially when this is done without the support of adequate, specific experience.”
No commercial funding or relevant financial relationships were reported.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
High HDL-C levels linked to increased fracture risk
High levels of high-density lipoprotein cholesterol (HDL-C) in older adults are associated with a higher risk of sustaining a fracture than lower HDL-C levels, a new study suggests.
“Two animal studies showing that HDL-C reduces bone mineral density by reducing osteoblast number and function provide a plausible explanation for why high HDL-C may increase the risk of fractures,” Monira Hussain, MBBS, MPH, PhD, of Monash University in Melbourne, told this news organization. “So, it was not surprising when our analyses provided evidence that amongst those in the highest quintile of HDL-C (> 74 mg/dL), there was a [33%] increased risk of fractures.”
After adjustment, one standard deviation increment in HDL-C level was associated with a 14% higher risk of fracture during a 4-year follow-up.
Based on this and other studies, Dr. Hussain said, “I believe that the finding of a very high HDL-C [should] alert clinicians to a higher risk of mortality, fractures, and possibly other threats to their patient’s health.”
The study was published online in JAMA Cardiology.
Independent risk factor
For this report, the researchers conducted a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy.
ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin. Participants were 16,703 community-dwelling Australians and 2,411 individuals from the United States with a mean age of 75 and without evident cardiovascular disease, dementia, physical disability, or life-limiting chronic illness.
The ASPREE-Fracture substudy collected data on fractures reported post randomization from the Australian participants. Fractures were confirmed by imaging and adjudicated by an expert panel and included both traumatic and minimal trauma fractures.
Of the 16,262 participants who had a plasma HDL-C measurement at baseline (55% women), 1,659 (10.2%) experienced at least one fracture over a median of 4 years. This included 711 minimal trauma fractures (for example, falls from standing height) and 948 other trauma fractures, mainly falls on stairs, ladders, or stools.
Higher rates of fractures occurred in the highest quintile of HDL-C level where the mean level was 89 mg/dL. At baseline, participants in that quintile had a lower BMI, a high prevalence of current/former smoking and current alcohol use, 12 years or longer of school, more physical activity, and higher use of antiosteoporosis medication. They also had less chronic kidney disease, diabetes, prefrailty/frailty, or treatment with lipid-lowering drugs.
In a fully adjusted model, each standard deviation increment in HDL-C level was associated with a 14% higher risk of fractures (hazard ratio, 1.14). When analyzed in quintiles, compared with participants in Q1, those in Q5 had a 33% higher risk for fracture (HR, 1.33).
Prevalence rates were similar between the sexes. The increase in fracture risk appeared to be independent of traditional risk factors for fractures, including age, sex, physical activity, alcohol use, frailty, BMI, smoking status, diabetes, chronic kidney disease, use of lipid-lowering or antiosteoporosis drugs, and education, the authors note.
The results persisted in sensitivity analyses in restricted subgroups of interest and in stratified analyses – including, for example, only minimal fractures; participants not taking antiosteoporosis drugs or statins; never smokers; nondrinkers; and those engaging in minimal physical activity (walking less than 30 minutes per day).
No association was observed between non–HDL-C levels and fractures.
The authors conclude that the study “provides robust evidence that higher levels of HDL-C are associated with incident fractures in both male and female individuals, independent of conventional risk factors.”
Clinically useful?
Commenting on the study for this news organization, Marilyn Tan, MD, clinic chief of the Endocrine Clinic and clinical associate professor of medicine at Stanford (Calif.) University, said, “I certainly would not recommend anyone do anything to actively lower their HDL levels. HDL levels are largely determined by genetics, diet, and lifestyle, with some effects from certain medications/supplements. Studies have demonstrated that moderately higher HDL levels may be protective for atherosclerosis.”
In the current study, she said, “Causation has not been proven, and importantly there is no evidence that reducing HDL levels reduces fracture risk. Also, this association between raised HDL levels and fracture risk has not been demonstrated consistently in other studies.”
Furthermore, she noted, the preclinical trials on which the authors based their hypothesis – that is, an association between HDL and a reduction in the number and function of osteoblasts – “has not been demonstrated widely in human subjects.”
“We have a large armamentarium of FDA-approved treatments for osteoporosis that have been clinically proven to reduce fracture risk very significantly, and these are the tools [in addition to lifestyle changes] we should use to reduce fracture risk,” Dr. Tan concluded.
John Wilkins, MD, of Northwestern University, Chicago, and Anand Rohatgi, MD, MSCS, of UT Southwestern Medical Center, Dallas, also point out some limitations of the study in a related editorial.
They note the inclusion of predominantly healthy adults with a mean age of 75, a population that could yield different findings from middle-aged cohorts with chronic illnesses, as well as a lack of clarity regarding the possible role of alcohol intake among the study participants.
Furthermore, the editorialists write, although significant associations were shown in this study, “models were not adjusted for detailed measures of exercise/activity, triglycerides, or any other lipids, including other HDL compositional measures such as HDL-P or ApoA-I levels. There was no assessment of whether HDL-C improved discrimination, reclassification, or any other validated measures of risk prediction performance.
“Taken together,” they conclude, “this study alone leaves several unanswered questions as to whether high HDL-C could be a useful biomarker to detect fracture risk.”
No commercial funding was disclosed. The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
High levels of high-density lipoprotein cholesterol (HDL-C) in older adults are associated with a higher risk of sustaining a fracture than lower HDL-C levels, a new study suggests.
“Two animal studies showing that HDL-C reduces bone mineral density by reducing osteoblast number and function provide a plausible explanation for why high HDL-C may increase the risk of fractures,” Monira Hussain, MBBS, MPH, PhD, of Monash University in Melbourne, told this news organization. “So, it was not surprising when our analyses provided evidence that amongst those in the highest quintile of HDL-C (> 74 mg/dL), there was a [33%] increased risk of fractures.”
After adjustment, one standard deviation increment in HDL-C level was associated with a 14% higher risk of fracture during a 4-year follow-up.
Based on this and other studies, Dr. Hussain said, “I believe that the finding of a very high HDL-C [should] alert clinicians to a higher risk of mortality, fractures, and possibly other threats to their patient’s health.”
The study was published online in JAMA Cardiology.
Independent risk factor
For this report, the researchers conducted a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy.
ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin. Participants were 16,703 community-dwelling Australians and 2,411 individuals from the United States with a mean age of 75 and without evident cardiovascular disease, dementia, physical disability, or life-limiting chronic illness.
The ASPREE-Fracture substudy collected data on fractures reported post randomization from the Australian participants. Fractures were confirmed by imaging and adjudicated by an expert panel and included both traumatic and minimal trauma fractures.
Of the 16,262 participants who had a plasma HDL-C measurement at baseline (55% women), 1,659 (10.2%) experienced at least one fracture over a median of 4 years. This included 711 minimal trauma fractures (for example, falls from standing height) and 948 other trauma fractures, mainly falls on stairs, ladders, or stools.
Higher rates of fractures occurred in the highest quintile of HDL-C level where the mean level was 89 mg/dL. At baseline, participants in that quintile had a lower BMI, a high prevalence of current/former smoking and current alcohol use, 12 years or longer of school, more physical activity, and higher use of antiosteoporosis medication. They also had less chronic kidney disease, diabetes, prefrailty/frailty, or treatment with lipid-lowering drugs.
In a fully adjusted model, each standard deviation increment in HDL-C level was associated with a 14% higher risk of fractures (hazard ratio, 1.14). When analyzed in quintiles, compared with participants in Q1, those in Q5 had a 33% higher risk for fracture (HR, 1.33).
Prevalence rates were similar between the sexes. The increase in fracture risk appeared to be independent of traditional risk factors for fractures, including age, sex, physical activity, alcohol use, frailty, BMI, smoking status, diabetes, chronic kidney disease, use of lipid-lowering or antiosteoporosis drugs, and education, the authors note.
The results persisted in sensitivity analyses in restricted subgroups of interest and in stratified analyses – including, for example, only minimal fractures; participants not taking antiosteoporosis drugs or statins; never smokers; nondrinkers; and those engaging in minimal physical activity (walking less than 30 minutes per day).
No association was observed between non–HDL-C levels and fractures.
The authors conclude that the study “provides robust evidence that higher levels of HDL-C are associated with incident fractures in both male and female individuals, independent of conventional risk factors.”
Clinically useful?
Commenting on the study for this news organization, Marilyn Tan, MD, clinic chief of the Endocrine Clinic and clinical associate professor of medicine at Stanford (Calif.) University, said, “I certainly would not recommend anyone do anything to actively lower their HDL levels. HDL levels are largely determined by genetics, diet, and lifestyle, with some effects from certain medications/supplements. Studies have demonstrated that moderately higher HDL levels may be protective for atherosclerosis.”
In the current study, she said, “Causation has not been proven, and importantly there is no evidence that reducing HDL levels reduces fracture risk. Also, this association between raised HDL levels and fracture risk has not been demonstrated consistently in other studies.”
Furthermore, she noted, the preclinical trials on which the authors based their hypothesis – that is, an association between HDL and a reduction in the number and function of osteoblasts – “has not been demonstrated widely in human subjects.”
“We have a large armamentarium of FDA-approved treatments for osteoporosis that have been clinically proven to reduce fracture risk very significantly, and these are the tools [in addition to lifestyle changes] we should use to reduce fracture risk,” Dr. Tan concluded.
John Wilkins, MD, of Northwestern University, Chicago, and Anand Rohatgi, MD, MSCS, of UT Southwestern Medical Center, Dallas, also point out some limitations of the study in a related editorial.
They note the inclusion of predominantly healthy adults with a mean age of 75, a population that could yield different findings from middle-aged cohorts with chronic illnesses, as well as a lack of clarity regarding the possible role of alcohol intake among the study participants.
Furthermore, the editorialists write, although significant associations were shown in this study, “models were not adjusted for detailed measures of exercise/activity, triglycerides, or any other lipids, including other HDL compositional measures such as HDL-P or ApoA-I levels. There was no assessment of whether HDL-C improved discrimination, reclassification, or any other validated measures of risk prediction performance.
“Taken together,” they conclude, “this study alone leaves several unanswered questions as to whether high HDL-C could be a useful biomarker to detect fracture risk.”
No commercial funding was disclosed. The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
High levels of high-density lipoprotein cholesterol (HDL-C) in older adults are associated with a higher risk of sustaining a fracture than lower HDL-C levels, a new study suggests.
“Two animal studies showing that HDL-C reduces bone mineral density by reducing osteoblast number and function provide a plausible explanation for why high HDL-C may increase the risk of fractures,” Monira Hussain, MBBS, MPH, PhD, of Monash University in Melbourne, told this news organization. “So, it was not surprising when our analyses provided evidence that amongst those in the highest quintile of HDL-C (> 74 mg/dL), there was a [33%] increased risk of fractures.”
After adjustment, one standard deviation increment in HDL-C level was associated with a 14% higher risk of fracture during a 4-year follow-up.
Based on this and other studies, Dr. Hussain said, “I believe that the finding of a very high HDL-C [should] alert clinicians to a higher risk of mortality, fractures, and possibly other threats to their patient’s health.”
The study was published online in JAMA Cardiology.
Independent risk factor
For this report, the researchers conducted a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy.
ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin. Participants were 16,703 community-dwelling Australians and 2,411 individuals from the United States with a mean age of 75 and without evident cardiovascular disease, dementia, physical disability, or life-limiting chronic illness.
The ASPREE-Fracture substudy collected data on fractures reported post randomization from the Australian participants. Fractures were confirmed by imaging and adjudicated by an expert panel and included both traumatic and minimal trauma fractures.
Of the 16,262 participants who had a plasma HDL-C measurement at baseline (55% women), 1,659 (10.2%) experienced at least one fracture over a median of 4 years. This included 711 minimal trauma fractures (for example, falls from standing height) and 948 other trauma fractures, mainly falls on stairs, ladders, or stools.
Higher rates of fractures occurred in the highest quintile of HDL-C level where the mean level was 89 mg/dL. At baseline, participants in that quintile had a lower BMI, a high prevalence of current/former smoking and current alcohol use, 12 years or longer of school, more physical activity, and higher use of antiosteoporosis medication. They also had less chronic kidney disease, diabetes, prefrailty/frailty, or treatment with lipid-lowering drugs.
In a fully adjusted model, each standard deviation increment in HDL-C level was associated with a 14% higher risk of fractures (hazard ratio, 1.14). When analyzed in quintiles, compared with participants in Q1, those in Q5 had a 33% higher risk for fracture (HR, 1.33).
Prevalence rates were similar between the sexes. The increase in fracture risk appeared to be independent of traditional risk factors for fractures, including age, sex, physical activity, alcohol use, frailty, BMI, smoking status, diabetes, chronic kidney disease, use of lipid-lowering or antiosteoporosis drugs, and education, the authors note.
The results persisted in sensitivity analyses in restricted subgroups of interest and in stratified analyses – including, for example, only minimal fractures; participants not taking antiosteoporosis drugs or statins; never smokers; nondrinkers; and those engaging in minimal physical activity (walking less than 30 minutes per day).
No association was observed between non–HDL-C levels and fractures.
The authors conclude that the study “provides robust evidence that higher levels of HDL-C are associated with incident fractures in both male and female individuals, independent of conventional risk factors.”
Clinically useful?
Commenting on the study for this news organization, Marilyn Tan, MD, clinic chief of the Endocrine Clinic and clinical associate professor of medicine at Stanford (Calif.) University, said, “I certainly would not recommend anyone do anything to actively lower their HDL levels. HDL levels are largely determined by genetics, diet, and lifestyle, with some effects from certain medications/supplements. Studies have demonstrated that moderately higher HDL levels may be protective for atherosclerosis.”
In the current study, she said, “Causation has not been proven, and importantly there is no evidence that reducing HDL levels reduces fracture risk. Also, this association between raised HDL levels and fracture risk has not been demonstrated consistently in other studies.”
Furthermore, she noted, the preclinical trials on which the authors based their hypothesis – that is, an association between HDL and a reduction in the number and function of osteoblasts – “has not been demonstrated widely in human subjects.”
“We have a large armamentarium of FDA-approved treatments for osteoporosis that have been clinically proven to reduce fracture risk very significantly, and these are the tools [in addition to lifestyle changes] we should use to reduce fracture risk,” Dr. Tan concluded.
John Wilkins, MD, of Northwestern University, Chicago, and Anand Rohatgi, MD, MSCS, of UT Southwestern Medical Center, Dallas, also point out some limitations of the study in a related editorial.
They note the inclusion of predominantly healthy adults with a mean age of 75, a population that could yield different findings from middle-aged cohorts with chronic illnesses, as well as a lack of clarity regarding the possible role of alcohol intake among the study participants.
Furthermore, the editorialists write, although significant associations were shown in this study, “models were not adjusted for detailed measures of exercise/activity, triglycerides, or any other lipids, including other HDL compositional measures such as HDL-P or ApoA-I levels. There was no assessment of whether HDL-C improved discrimination, reclassification, or any other validated measures of risk prediction performance.
“Taken together,” they conclude, “this study alone leaves several unanswered questions as to whether high HDL-C could be a useful biomarker to detect fracture risk.”
No commercial funding was disclosed. The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Patients with COPD at higher risk of death 1 year after surgery
Patients with chronic obstructive pulmonary disease (COPD) are more likely to die within a year of undergoing elective surgery and to incur higher health care costs than are similar patients without COPD, data suggest.
An analysis of close to a million patient records found that, after adjustment for sociodemographic factors, procedure type, and comorbidities, patients with COPD were 26% more likely to die in the year after surgery than were those without COPD. Moreover, COPD was associated with a 4.6% increase in health care costs.
Previous studies have evaluated outcomes for the first 30 days after surgery. Those data “may not adequately capture the overall burden of surgery and how long it may take patients to recover,” study author Ashwin Sankar, MD, a clinician-investigator at St. Michael’s Hospital and assistant professor of anesthesia at the University of Toronto, told this news organization.
“We found that COPD often coexists with other conditions, like diabetes, coronary artery disease, and frailty,” Dr. Sankar added.
The study was published online in the Canadian Medical Association Journal.
Additional recovery support
The authors analyzed data from 932,616 patients who underwent intermediate-risk to high-risk elective noncardiac surgeries from 2005 to 2019 in Ontario. Procedures included carotid endarterectomy, open or endovascular abdominal aortic aneurysm repair, peripheral arterial bypass, total hip replacement, total knee replacement, shoulder surgery, large-bowel surgery, partial liver resection, pancreaticoduodenectomy, gastrectomy, esophagectomy, nephrectomy, cystectomy, prostatectomy, and hysterectomy.
The researchers quantified the associations of COPD with survival and costs. Their analyses included partial adjustment for sociodemographic factors and procedure type and full adjustment, which included comorbidities.
The primary outcome was all-cause death in the year after surgery; the secondary outcome was total health care costs in that year.
The mean age of the population was 65 years, and 60% of patients were women. A total of 170,482 (18%) patients had COPD. Compared with those without COPD, the patients with COPD were older and were more likely to be male, to be in a lower income quintile, to be residents of long-term care facilities, and to have been admitted to the hospital before surgery. They were also more likely to have comorbidities, including coronary artery disease, heart failure, and lung cancer.
A larger proportion of patients with COPD had frailty and medium to high comorbidity. They also more frequently underwent orthopedic, open upper abdominal, and vascular surgery.
During the year after surgery, 52,021 (5.6%) patients died, including 18,007 (10.6%) with COPD and 34,014 (4.5%) without. Those with COPD were more likely to die within 30 days of surgery (3.4% vs 1.2%).
For patients with COPD, the partially adjusted hazard ratio (HR) was 1.61 for risk of death; the fully adjusted HR was 1.26. COPD also was associated with a partially adjusted relative increase of 13.1% in health care costs and an increase of 4.6% with full adjustment.
Frailty, cancer, and procedure type were factors that modified the association between COPD and outcomes. “Procedures such as open aortic and upper abdominal surgery are associated with higher postoperative risks irrespective of COPD status, whereas others, such as orthopedic and lower abdominal surgery, may be of significantly greater risk for patients with COPD,” the authors wrote. “Our results suggest that perioperative management of patients with COPD requires careful consideration of the multiple domains that contribute to their elevated perioperative risk.
“Our finding that patients with COPD are at risk beyond 30 days after surgery suggests that it may be worthwhile to additionally support these patients’ recovery well beyond the first month after the procedure,” said Dr. Sankar.
Shared decision-making
Commenting on the study, William Whalen, MD, a pulmonary critical care specialist at Weill Cornell Medicine in New York, said, “I echo the authors’ sentiments that these findings highlight how chronically ill COPD patients are, which may be playing a role in the elevated mortality seen in this study.”
One caveat is in regard to the interpretation of the interaction effects of the study, he said. “Clinicians are unlikely to send patients who are frail or have multiple comorbidities to overly complex surgeries. Therefore, these effects may be misestimated due to selection bias.”
Two questions remain after reading the study, he added. “The first is how the degree of obstruction (i.e., the severity of COPD) impacts long-term mortality. Previous observational studies in nonsurgical COPD patients have shown increased mortality as the severity of obstruction increases. The second is how much of the long-term mortality observed in this study is related to respiratory disease from COPD. Patients with COPD are complex, and many die from nonrespiratory-related causes.”
Dr. Whalen suggests that discussion be held with the surgical team about the long-term morbidity and mortality with and without surgical intervention. Such a discussion could inform a shared decision-making process with the patient.
“Some procedures may be necessary to reduce immediate mortality, such as aortic aneurysmal repair, so [the risk of] longer-term mortality may be more acceptable in this setting,” he said. “Less straightforward are procedures that may improve quality of life. Would a patient accept an increased long-term mortality [risk] if that meant living without orthopedic-related pain?”
The study was funded by the Government of Ontario. Dr. Sankar and Dr. Whalen have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Patients with chronic obstructive pulmonary disease (COPD) are more likely to die within a year of undergoing elective surgery and to incur higher health care costs than are similar patients without COPD, data suggest.
An analysis of close to a million patient records found that, after adjustment for sociodemographic factors, procedure type, and comorbidities, patients with COPD were 26% more likely to die in the year after surgery than were those without COPD. Moreover, COPD was associated with a 4.6% increase in health care costs.
Previous studies have evaluated outcomes for the first 30 days after surgery. Those data “may not adequately capture the overall burden of surgery and how long it may take patients to recover,” study author Ashwin Sankar, MD, a clinician-investigator at St. Michael’s Hospital and assistant professor of anesthesia at the University of Toronto, told this news organization.
“We found that COPD often coexists with other conditions, like diabetes, coronary artery disease, and frailty,” Dr. Sankar added.
The study was published online in the Canadian Medical Association Journal.
Additional recovery support
The authors analyzed data from 932,616 patients who underwent intermediate-risk to high-risk elective noncardiac surgeries from 2005 to 2019 in Ontario. Procedures included carotid endarterectomy, open or endovascular abdominal aortic aneurysm repair, peripheral arterial bypass, total hip replacement, total knee replacement, shoulder surgery, large-bowel surgery, partial liver resection, pancreaticoduodenectomy, gastrectomy, esophagectomy, nephrectomy, cystectomy, prostatectomy, and hysterectomy.
The researchers quantified the associations of COPD with survival and costs. Their analyses included partial adjustment for sociodemographic factors and procedure type and full adjustment, which included comorbidities.
The primary outcome was all-cause death in the year after surgery; the secondary outcome was total health care costs in that year.
The mean age of the population was 65 years, and 60% of patients were women. A total of 170,482 (18%) patients had COPD. Compared with those without COPD, the patients with COPD were older and were more likely to be male, to be in a lower income quintile, to be residents of long-term care facilities, and to have been admitted to the hospital before surgery. They were also more likely to have comorbidities, including coronary artery disease, heart failure, and lung cancer.
A larger proportion of patients with COPD had frailty and medium to high comorbidity. They also more frequently underwent orthopedic, open upper abdominal, and vascular surgery.
During the year after surgery, 52,021 (5.6%) patients died, including 18,007 (10.6%) with COPD and 34,014 (4.5%) without. Those with COPD were more likely to die within 30 days of surgery (3.4% vs 1.2%).
For patients with COPD, the partially adjusted hazard ratio (HR) was 1.61 for risk of death; the fully adjusted HR was 1.26. COPD also was associated with a partially adjusted relative increase of 13.1% in health care costs and an increase of 4.6% with full adjustment.
Frailty, cancer, and procedure type were factors that modified the association between COPD and outcomes. “Procedures such as open aortic and upper abdominal surgery are associated with higher postoperative risks irrespective of COPD status, whereas others, such as orthopedic and lower abdominal surgery, may be of significantly greater risk for patients with COPD,” the authors wrote. “Our results suggest that perioperative management of patients with COPD requires careful consideration of the multiple domains that contribute to their elevated perioperative risk.
“Our finding that patients with COPD are at risk beyond 30 days after surgery suggests that it may be worthwhile to additionally support these patients’ recovery well beyond the first month after the procedure,” said Dr. Sankar.
Shared decision-making
Commenting on the study, William Whalen, MD, a pulmonary critical care specialist at Weill Cornell Medicine in New York, said, “I echo the authors’ sentiments that these findings highlight how chronically ill COPD patients are, which may be playing a role in the elevated mortality seen in this study.”
One caveat is in regard to the interpretation of the interaction effects of the study, he said. “Clinicians are unlikely to send patients who are frail or have multiple comorbidities to overly complex surgeries. Therefore, these effects may be misestimated due to selection bias.”
Two questions remain after reading the study, he added. “The first is how the degree of obstruction (i.e., the severity of COPD) impacts long-term mortality. Previous observational studies in nonsurgical COPD patients have shown increased mortality as the severity of obstruction increases. The second is how much of the long-term mortality observed in this study is related to respiratory disease from COPD. Patients with COPD are complex, and many die from nonrespiratory-related causes.”
Dr. Whalen suggests that discussion be held with the surgical team about the long-term morbidity and mortality with and without surgical intervention. Such a discussion could inform a shared decision-making process with the patient.
“Some procedures may be necessary to reduce immediate mortality, such as aortic aneurysmal repair, so [the risk of] longer-term mortality may be more acceptable in this setting,” he said. “Less straightforward are procedures that may improve quality of life. Would a patient accept an increased long-term mortality [risk] if that meant living without orthopedic-related pain?”
The study was funded by the Government of Ontario. Dr. Sankar and Dr. Whalen have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Patients with chronic obstructive pulmonary disease (COPD) are more likely to die within a year of undergoing elective surgery and to incur higher health care costs than are similar patients without COPD, data suggest.
An analysis of close to a million patient records found that, after adjustment for sociodemographic factors, procedure type, and comorbidities, patients with COPD were 26% more likely to die in the year after surgery than were those without COPD. Moreover, COPD was associated with a 4.6% increase in health care costs.
Previous studies have evaluated outcomes for the first 30 days after surgery. Those data “may not adequately capture the overall burden of surgery and how long it may take patients to recover,” study author Ashwin Sankar, MD, a clinician-investigator at St. Michael’s Hospital and assistant professor of anesthesia at the University of Toronto, told this news organization.
“We found that COPD often coexists with other conditions, like diabetes, coronary artery disease, and frailty,” Dr. Sankar added.
The study was published online in the Canadian Medical Association Journal.
Additional recovery support
The authors analyzed data from 932,616 patients who underwent intermediate-risk to high-risk elective noncardiac surgeries from 2005 to 2019 in Ontario. Procedures included carotid endarterectomy, open or endovascular abdominal aortic aneurysm repair, peripheral arterial bypass, total hip replacement, total knee replacement, shoulder surgery, large-bowel surgery, partial liver resection, pancreaticoduodenectomy, gastrectomy, esophagectomy, nephrectomy, cystectomy, prostatectomy, and hysterectomy.
The researchers quantified the associations of COPD with survival and costs. Their analyses included partial adjustment for sociodemographic factors and procedure type and full adjustment, which included comorbidities.
The primary outcome was all-cause death in the year after surgery; the secondary outcome was total health care costs in that year.
The mean age of the population was 65 years, and 60% of patients were women. A total of 170,482 (18%) patients had COPD. Compared with those without COPD, the patients with COPD were older and were more likely to be male, to be in a lower income quintile, to be residents of long-term care facilities, and to have been admitted to the hospital before surgery. They were also more likely to have comorbidities, including coronary artery disease, heart failure, and lung cancer.
A larger proportion of patients with COPD had frailty and medium to high comorbidity. They also more frequently underwent orthopedic, open upper abdominal, and vascular surgery.
During the year after surgery, 52,021 (5.6%) patients died, including 18,007 (10.6%) with COPD and 34,014 (4.5%) without. Those with COPD were more likely to die within 30 days of surgery (3.4% vs 1.2%).
For patients with COPD, the partially adjusted hazard ratio (HR) was 1.61 for risk of death; the fully adjusted HR was 1.26. COPD also was associated with a partially adjusted relative increase of 13.1% in health care costs and an increase of 4.6% with full adjustment.
Frailty, cancer, and procedure type were factors that modified the association between COPD and outcomes. “Procedures such as open aortic and upper abdominal surgery are associated with higher postoperative risks irrespective of COPD status, whereas others, such as orthopedic and lower abdominal surgery, may be of significantly greater risk for patients with COPD,” the authors wrote. “Our results suggest that perioperative management of patients with COPD requires careful consideration of the multiple domains that contribute to their elevated perioperative risk.
“Our finding that patients with COPD are at risk beyond 30 days after surgery suggests that it may be worthwhile to additionally support these patients’ recovery well beyond the first month after the procedure,” said Dr. Sankar.
Shared decision-making
Commenting on the study, William Whalen, MD, a pulmonary critical care specialist at Weill Cornell Medicine in New York, said, “I echo the authors’ sentiments that these findings highlight how chronically ill COPD patients are, which may be playing a role in the elevated mortality seen in this study.”
One caveat is in regard to the interpretation of the interaction effects of the study, he said. “Clinicians are unlikely to send patients who are frail or have multiple comorbidities to overly complex surgeries. Therefore, these effects may be misestimated due to selection bias.”
Two questions remain after reading the study, he added. “The first is how the degree of obstruction (i.e., the severity of COPD) impacts long-term mortality. Previous observational studies in nonsurgical COPD patients have shown increased mortality as the severity of obstruction increases. The second is how much of the long-term mortality observed in this study is related to respiratory disease from COPD. Patients with COPD are complex, and many die from nonrespiratory-related causes.”
Dr. Whalen suggests that discussion be held with the surgical team about the long-term morbidity and mortality with and without surgical intervention. Such a discussion could inform a shared decision-making process with the patient.
“Some procedures may be necessary to reduce immediate mortality, such as aortic aneurysmal repair, so [the risk of] longer-term mortality may be more acceptable in this setting,” he said. “Less straightforward are procedures that may improve quality of life. Would a patient accept an increased long-term mortality [risk] if that meant living without orthopedic-related pain?”
The study was funded by the Government of Ontario. Dr. Sankar and Dr. Whalen have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Canadian guidance recommends reducing alcohol consumption
“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).
Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:
- Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
- Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
- Three to six drinks raise the risk of developing breast, colon, and other cancers.
- Seven or more increase the risk of heart disease or stroke.
- Each additional drink “radically increases” the risk of these health consequences.
“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”
Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”
“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
Continuum of risk
The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.
That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.
Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).
Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:
- Low for individuals who consume two standard drinks or fewer per week
- Moderate for those who consume from three to six standard drinks per week
- Increasingly high for those who consume seven standard drinks or more per week
The guidance makes the following observations:
- Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
- When pregnant or trying to get pregnant, no amount of alcohol is safe.
- When breastfeeding, not drinking is safest.
- Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
- Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
- Young people should delay alcohol use for as long as possible.
- Individuals should not start to use alcohol or increase their alcohol use for health benefits.
- Any reduction in alcohol use is beneficial.
Other national guidelines
“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”
“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.
“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”
Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”
Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.
Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”
A version of this article originally appeared on Medscape.com.
“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).
Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:
- Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
- Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
- Three to six drinks raise the risk of developing breast, colon, and other cancers.
- Seven or more increase the risk of heart disease or stroke.
- Each additional drink “radically increases” the risk of these health consequences.
“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”
Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”
“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
Continuum of risk
The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.
That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.
Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).
Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:
- Low for individuals who consume two standard drinks or fewer per week
- Moderate for those who consume from three to six standard drinks per week
- Increasingly high for those who consume seven standard drinks or more per week
The guidance makes the following observations:
- Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
- When pregnant or trying to get pregnant, no amount of alcohol is safe.
- When breastfeeding, not drinking is safest.
- Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
- Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
- Young people should delay alcohol use for as long as possible.
- Individuals should not start to use alcohol or increase their alcohol use for health benefits.
- Any reduction in alcohol use is beneficial.
Other national guidelines
“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”
“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.
“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”
Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”
Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.
Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”
A version of this article originally appeared on Medscape.com.
“Drinking less is better,” says the guidance, which replaces Canada’s 2011 Low-Risk Drinking Guidelines (LRDGs).
Developed in consultation with an executive committee from federal, provincial, and territorial governments; national organizations; three scientific expert panels; and an internal evidence review working group, the guidance presents the following findings:
- Consuming no drinks per week has benefits, such as better health and better sleep, and it’s the only safe option during pregnancy.
- Consuming one or two standard drinks weekly will likely not have alcohol-related consequences.
- Three to six drinks raise the risk of developing breast, colon, and other cancers.
- Seven or more increase the risk of heart disease or stroke.
- Each additional drink “radically increases” the risk of these health consequences.
“Alcohol is more harmful than was previously thought and is a key component of the health of your patients,” Adam Sherk, PhD, a scientist at the Canadian Institute for Substance Use Research at the University of Victoria (B.C.), and a member of the scientific expert panel that contributed to the guidance, said in an interview. “Display and discuss the new guidance with your patients with the main message that drinking less is better.”
Peter Butt, MD, a clinical associate professor at the University of Saskatchewan, Saskatoon, and cochair of the guidance project, said in an interview: “The World Health Organization has identified over 200 ICD-coded conditions associated with alcohol use. This creates many opportunities to inquire into quantity and frequency of alcohol use, relate it to the patient’s health and well-being, and provide advice on reduction.”
“Canada’s Guidance on Alcohol and Health: Final Report” and a related infographic were published online Jan. 17.
Continuum of risk
The impetus for the new guidance came from the fact that “our 2011 LRDGs were no longer current, and there was emerging evidence that people drinking within those levels were coming to harm,” said Dr. Butt.
That evidence indicates that alcohol causes at least seven types of cancer, mostly of the breast or colon; is a risk factor for most types of heart disease; and is a main cause of liver disease. Evidence also indicates that avoiding drinking to the point of intoxication will reduce people’s risk of perpetrating alcohol-related violence.
Responding to the need to accurately quantify the risk, the guidance defines a “standard” drink as 12 oz of beer, cooler, or cider (5% alcohol); 5 oz of wine (12% alcohol); and 1.5 oz of spirits such as whiskey, vodka, or gin (40% alcohol).
Using different mortality risk thresholds, the project’s experts developed the following continuum of risk:
- Low for individuals who consume two standard drinks or fewer per week
- Moderate for those who consume from three to six standard drinks per week
- Increasingly high for those who consume seven standard drinks or more per week
The guidance makes the following observations:
- Consuming more than two standard drinks per drinking occasion is associated with an increased risk of harms to self and others, including injuries and violence.
- When pregnant or trying to get pregnant, no amount of alcohol is safe.
- When breastfeeding, not drinking is safest.
- Above the upper limit of the moderate risk zone, health risks increase more steeply for females than males.
- Far more injuries, violence, and deaths result from men’s alcohol use, especially for per occasion drinking, than from women’s alcohol use.
- Young people should delay alcohol use for as long as possible.
- Individuals should not start to use alcohol or increase their alcohol use for health benefits.
- Any reduction in alcohol use is beneficial.
Other national guidelines
“Countries that haven’t updated their alcohol use guidelines recently should do so, as the evidence regarding alcohol and health has advanced considerably in the past 10 years,” said Dr. Sherk. He acknowledged that “any time health guidance changes substantially, it’s reasonable to expect a period of readjustment.”
“Some will be resistant,” Dr. Butt agreed. “Some professionals will need more education than others on the health effects of alcohol. Some patients will also be more invested in drinking than others. The harm-reduction, risk-zone approach should assist in the process of engaging patients and helping them reduce over time.
“Just as we benefited from the updates done in the United Kingdom, France, and especially Australia, so also researchers elsewhere will critique our work and our approach and make their own decisions on how best to communicate with their public,” Dr. Butt said. He noted that Canada’s contributions regarding the association between alcohol and violence, as well as their sex/gender approach to the evidence, “may influence the next country’s review.”
Commenting on whether the United States should consider changing its guidance, Timothy Brennan, MD, MPH, chief of clinical services for the Addiction Institute of Mount Sinai Health System in New York, said in an interview, “A lot of people will be surprised at the recommended limits on alcohol. Most think that they can have one or two glasses of alcohol per day and not have any increased risk to their health. I think the Canadians deserve credit for putting themselves out there.”
Dr. Brennan said there will “certainly be pushback by the drinking lobby, which is very strong both in the U.S. and in Canada.” In fact, the national trade group Beer Canada was recently quoted as stating that it still supports the 2011 guidelines and that the updating process lacked full transparency and expert technical peer review.
Nevertheless, Dr. Brennan said, “it’s overwhelmingly clear that alcohol affects a ton of different parts of our body, so limiting the amount of alcohol we take in is always going to be a good thing. The Canadian graphic is great because it color-codes the risk. I recommend that clinicians put it up in their offices and begin quantifying the units of alcohol that are going into a patient’s body each day.”
A version of this article originally appeared on Medscape.com.
Simulation-based training effective for transesophageal echo
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
FROM JAMA CARDIOLOGY
Pandemic may be limiting ED access for sexual assault
“In 2020, we hoped that the COVID pandemic would only last a few months. However, as it continued, we became increasingly concerned about limited health care access for survivors of sexual assault throughout the ongoing crisis,” study author Katherine A. Muldoon, PhD, MPH, a senior clinical research associate at the Ottawa Hospital Research Institute in Ontario, told this news organization.
“Unexpectedly, we found a 20%-25% increase in the number of survivors of sexual assault presenting for emergency care before the lockdown protocols were enacted,” she added. “After lockdown, the numbers dropped by 50%-60% and fluctuated throughout ... the pandemic.”
As they develop new lockdown protocols, public health officials and governments should incorporate warnings of the risks of violence and state that survivors should still present for urgent care when needed, said Dr. Muldoon. “COVID-19 lockdown protocols have limited access to health care for survivors worldwide, and barriers are likely greater in low-resource settings and those heavily affected by COVID-19.”
The study was published in JAMA Network Open.
Both sexes affected
The researchers analyzed linked health administrative data from 197 EDs in Ontario from January 2019 to September 2021. They used 10 bimonthly time periods to compare differences in the frequency and rates of ED visits for sexual assault in 2020-2021 (during the pandemic), compared with baseline prepandemic rates in 2019.
Sexual assault was defined by 27 ICD-10 procedure and diagnoses codes.
More than 14 million ED presentations occurred during the study period, including 10,523 for sexual assault. The median age was 23 years for female patients and 15 years for males. Most encounters (88.4%) were among females.
During the 2 months before the pandemic (Jan. 11 to Mar. 10, 2020), the rates of ED encounters for sexual assault among females were significantly higher than prepandemic levels (8.4 vs. 6.9 cases per 100,000; age-adjusted rate ratio [aRR], 1.22), whereas during the first 2 months of the pandemic (Mar. 11 to May 10, 2020), rates were significantly lower (4.2 vs. 8.3 cases per 100,000; aRR, 0.51).
Among males, rates were higher during the 2 months before the pandemic, but not significantly different, compared with prepandemic levels (1.2 vs. 1.0 cases per 100,000; aRR, 1.19). However, the rates decreased significantly during the first 2 months of the pandemic (0.5 vs. 1.2 cases per 100,000; aRR, 0.39).
For the 12 months starting July 11, 2020, rates were the same as in 2019. In the final time period (July 11 to Sept. 10, 2021), however, the rates were significantly higher than during prepandemic levels (1.5 vs. 1.1 cases per 100,000; aRR, 1.40).
Further analyses showed a similar pattern for all age groups, community sizes, and income quintiles. Rates were predominantly above prepandemic levels for the 2 months leading up to the pandemic and below expected levels from the beginning of the pandemic onward. However, from July 11 to Sept. 10, 2020 (during a trough in the summer, when sexual assaults are generally higher), and from May 11 to Sept. 10, 2021 (also during a trough and the summer), the rates returned to prepandemic levels.
“The COVID-19 pandemic has caused many changes to society and health care delivery and access,” the authors wrote. “We recommend that the decision-making regarding the management of the COVID-19 pandemic include antiviolence considerations to evaluate how policies and protocols affect the risk of violence and ensure that those who need health care can access services without concern.”
“Specialized and trauma-informed clinics are the best solution for encouraging survivors to come for urgent care following a sexual assault,” said Dr. Muldoon. “Clinicians should be prepared and trained to provide the best possible care for survivors of violence and ensure that getting care is not retraumatizing. Fostering conversations about the common experience of violence and destigmatizing those exposed to violence remain the most important ways to create safer spaces and societies.”
Dedicated care pathways
Commenting on the study, Samuel A. McLean, MD, MPH, director of the Institute for Trauma Recovery and professor of emergency medicine, psychiatry, and anesthesiology at the University of North Carolina at Chapel Hill, said, “This important work documents a reduction in visits by sexual assault survivors for emergency care and forensic evidence collection during times of pandemic surge. It’s impossible to know for certain if this reduction in visits is entirely due to a reduction in sexual assaults, but a number of lines of circumstantial evidence make this unlikely.”
The results highlight the importance of ensuring that sexual assault care is maintained during surges in emergency care volume, added Dr. McLean, who was not involved with the current study. “This can be done via methods such as dedicated care pathways that avoid prolonged survivor wait times for care, and public health messaging that informs the public of the continued ready access to care during surges. Evidence, including data cited by the authors, suggests that these same care-seeking reductions are occurring in the United States and elsewhere.”
The study was supported by the Ontario Ministry of Health and Long-term Care Applied Health Research Question Fund. Dr. Muldoon, study coauthors, and Dr. McLean report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“In 2020, we hoped that the COVID pandemic would only last a few months. However, as it continued, we became increasingly concerned about limited health care access for survivors of sexual assault throughout the ongoing crisis,” study author Katherine A. Muldoon, PhD, MPH, a senior clinical research associate at the Ottawa Hospital Research Institute in Ontario, told this news organization.
“Unexpectedly, we found a 20%-25% increase in the number of survivors of sexual assault presenting for emergency care before the lockdown protocols were enacted,” she added. “After lockdown, the numbers dropped by 50%-60% and fluctuated throughout ... the pandemic.”
As they develop new lockdown protocols, public health officials and governments should incorporate warnings of the risks of violence and state that survivors should still present for urgent care when needed, said Dr. Muldoon. “COVID-19 lockdown protocols have limited access to health care for survivors worldwide, and barriers are likely greater in low-resource settings and those heavily affected by COVID-19.”
The study was published in JAMA Network Open.
Both sexes affected
The researchers analyzed linked health administrative data from 197 EDs in Ontario from January 2019 to September 2021. They used 10 bimonthly time periods to compare differences in the frequency and rates of ED visits for sexual assault in 2020-2021 (during the pandemic), compared with baseline prepandemic rates in 2019.
Sexual assault was defined by 27 ICD-10 procedure and diagnoses codes.
More than 14 million ED presentations occurred during the study period, including 10,523 for sexual assault. The median age was 23 years for female patients and 15 years for males. Most encounters (88.4%) were among females.
During the 2 months before the pandemic (Jan. 11 to Mar. 10, 2020), the rates of ED encounters for sexual assault among females were significantly higher than prepandemic levels (8.4 vs. 6.9 cases per 100,000; age-adjusted rate ratio [aRR], 1.22), whereas during the first 2 months of the pandemic (Mar. 11 to May 10, 2020), rates were significantly lower (4.2 vs. 8.3 cases per 100,000; aRR, 0.51).
Among males, rates were higher during the 2 months before the pandemic, but not significantly different, compared with prepandemic levels (1.2 vs. 1.0 cases per 100,000; aRR, 1.19). However, the rates decreased significantly during the first 2 months of the pandemic (0.5 vs. 1.2 cases per 100,000; aRR, 0.39).
For the 12 months starting July 11, 2020, rates were the same as in 2019. In the final time period (July 11 to Sept. 10, 2021), however, the rates were significantly higher than during prepandemic levels (1.5 vs. 1.1 cases per 100,000; aRR, 1.40).
Further analyses showed a similar pattern for all age groups, community sizes, and income quintiles. Rates were predominantly above prepandemic levels for the 2 months leading up to the pandemic and below expected levels from the beginning of the pandemic onward. However, from July 11 to Sept. 10, 2020 (during a trough in the summer, when sexual assaults are generally higher), and from May 11 to Sept. 10, 2021 (also during a trough and the summer), the rates returned to prepandemic levels.
“The COVID-19 pandemic has caused many changes to society and health care delivery and access,” the authors wrote. “We recommend that the decision-making regarding the management of the COVID-19 pandemic include antiviolence considerations to evaluate how policies and protocols affect the risk of violence and ensure that those who need health care can access services without concern.”
“Specialized and trauma-informed clinics are the best solution for encouraging survivors to come for urgent care following a sexual assault,” said Dr. Muldoon. “Clinicians should be prepared and trained to provide the best possible care for survivors of violence and ensure that getting care is not retraumatizing. Fostering conversations about the common experience of violence and destigmatizing those exposed to violence remain the most important ways to create safer spaces and societies.”
Dedicated care pathways
Commenting on the study, Samuel A. McLean, MD, MPH, director of the Institute for Trauma Recovery and professor of emergency medicine, psychiatry, and anesthesiology at the University of North Carolina at Chapel Hill, said, “This important work documents a reduction in visits by sexual assault survivors for emergency care and forensic evidence collection during times of pandemic surge. It’s impossible to know for certain if this reduction in visits is entirely due to a reduction in sexual assaults, but a number of lines of circumstantial evidence make this unlikely.”
The results highlight the importance of ensuring that sexual assault care is maintained during surges in emergency care volume, added Dr. McLean, who was not involved with the current study. “This can be done via methods such as dedicated care pathways that avoid prolonged survivor wait times for care, and public health messaging that informs the public of the continued ready access to care during surges. Evidence, including data cited by the authors, suggests that these same care-seeking reductions are occurring in the United States and elsewhere.”
The study was supported by the Ontario Ministry of Health and Long-term Care Applied Health Research Question Fund. Dr. Muldoon, study coauthors, and Dr. McLean report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“In 2020, we hoped that the COVID pandemic would only last a few months. However, as it continued, we became increasingly concerned about limited health care access for survivors of sexual assault throughout the ongoing crisis,” study author Katherine A. Muldoon, PhD, MPH, a senior clinical research associate at the Ottawa Hospital Research Institute in Ontario, told this news organization.
“Unexpectedly, we found a 20%-25% increase in the number of survivors of sexual assault presenting for emergency care before the lockdown protocols were enacted,” she added. “After lockdown, the numbers dropped by 50%-60% and fluctuated throughout ... the pandemic.”
As they develop new lockdown protocols, public health officials and governments should incorporate warnings of the risks of violence and state that survivors should still present for urgent care when needed, said Dr. Muldoon. “COVID-19 lockdown protocols have limited access to health care for survivors worldwide, and barriers are likely greater in low-resource settings and those heavily affected by COVID-19.”
The study was published in JAMA Network Open.
Both sexes affected
The researchers analyzed linked health administrative data from 197 EDs in Ontario from January 2019 to September 2021. They used 10 bimonthly time periods to compare differences in the frequency and rates of ED visits for sexual assault in 2020-2021 (during the pandemic), compared with baseline prepandemic rates in 2019.
Sexual assault was defined by 27 ICD-10 procedure and diagnoses codes.
More than 14 million ED presentations occurred during the study period, including 10,523 for sexual assault. The median age was 23 years for female patients and 15 years for males. Most encounters (88.4%) were among females.
During the 2 months before the pandemic (Jan. 11 to Mar. 10, 2020), the rates of ED encounters for sexual assault among females were significantly higher than prepandemic levels (8.4 vs. 6.9 cases per 100,000; age-adjusted rate ratio [aRR], 1.22), whereas during the first 2 months of the pandemic (Mar. 11 to May 10, 2020), rates were significantly lower (4.2 vs. 8.3 cases per 100,000; aRR, 0.51).
Among males, rates were higher during the 2 months before the pandemic, but not significantly different, compared with prepandemic levels (1.2 vs. 1.0 cases per 100,000; aRR, 1.19). However, the rates decreased significantly during the first 2 months of the pandemic (0.5 vs. 1.2 cases per 100,000; aRR, 0.39).
For the 12 months starting July 11, 2020, rates were the same as in 2019. In the final time period (July 11 to Sept. 10, 2021), however, the rates were significantly higher than during prepandemic levels (1.5 vs. 1.1 cases per 100,000; aRR, 1.40).
Further analyses showed a similar pattern for all age groups, community sizes, and income quintiles. Rates were predominantly above prepandemic levels for the 2 months leading up to the pandemic and below expected levels from the beginning of the pandemic onward. However, from July 11 to Sept. 10, 2020 (during a trough in the summer, when sexual assaults are generally higher), and from May 11 to Sept. 10, 2021 (also during a trough and the summer), the rates returned to prepandemic levels.
“The COVID-19 pandemic has caused many changes to society and health care delivery and access,” the authors wrote. “We recommend that the decision-making regarding the management of the COVID-19 pandemic include antiviolence considerations to evaluate how policies and protocols affect the risk of violence and ensure that those who need health care can access services without concern.”
“Specialized and trauma-informed clinics are the best solution for encouraging survivors to come for urgent care following a sexual assault,” said Dr. Muldoon. “Clinicians should be prepared and trained to provide the best possible care for survivors of violence and ensure that getting care is not retraumatizing. Fostering conversations about the common experience of violence and destigmatizing those exposed to violence remain the most important ways to create safer spaces and societies.”
Dedicated care pathways
Commenting on the study, Samuel A. McLean, MD, MPH, director of the Institute for Trauma Recovery and professor of emergency medicine, psychiatry, and anesthesiology at the University of North Carolina at Chapel Hill, said, “This important work documents a reduction in visits by sexual assault survivors for emergency care and forensic evidence collection during times of pandemic surge. It’s impossible to know for certain if this reduction in visits is entirely due to a reduction in sexual assaults, but a number of lines of circumstantial evidence make this unlikely.”
The results highlight the importance of ensuring that sexual assault care is maintained during surges in emergency care volume, added Dr. McLean, who was not involved with the current study. “This can be done via methods such as dedicated care pathways that avoid prolonged survivor wait times for care, and public health messaging that informs the public of the continued ready access to care during surges. Evidence, including data cited by the authors, suggests that these same care-seeking reductions are occurring in the United States and elsewhere.”
The study was supported by the Ontario Ministry of Health and Long-term Care Applied Health Research Question Fund. Dr. Muldoon, study coauthors, and Dr. McLean report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Does EPA lower CV risk? REDUCE-IT revisited
The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.
However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
‘Not all omega-3s created equal’
Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”
REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.
Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”
The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”
Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.
More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
Placebo effects?
Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.
Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”
“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.
“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”
“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
Still room for benefit?
Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.
Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”
Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”
Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”
“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”
Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.
Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”
“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
Clinical inertia?
Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”
Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”
“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”
Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.
Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.
Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”
Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”
Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”
A version of this article first appeared on Medscape.com.
The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.
However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
‘Not all omega-3s created equal’
Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”
REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.
Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”
The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”
Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.
More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
Placebo effects?
Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.
Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”
“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.
“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”
“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
Still room for benefit?
Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.
Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”
Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”
Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”
“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”
Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.
Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”
“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
Clinical inertia?
Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”
Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”
“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”
Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.
Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.
Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”
Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”
Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”
A version of this article first appeared on Medscape.com.
The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.
However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
‘Not all omega-3s created equal’
Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”
REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.
Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”
The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”
Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.
More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
Placebo effects?
Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.
Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”
“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.
“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”
“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
Still room for benefit?
Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.
Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”
Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”
Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”
“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”
Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.
Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”
“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
Clinical inertia?
Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”
Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”
“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”
Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.
Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.
Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”
Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”
Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”
A version of this article first appeared on Medscape.com.
Frail ADHF patients benefit more from early rehab
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.
“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”
Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.
However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”
The study was published online in JAMA Cardiology.
Interpret with caution
Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.
According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.
- The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
- It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
- It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
- It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.
For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.
At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.
The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.
A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.
Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.
“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”
To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
‘Never too old or sick to benefit’
Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”
However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.
Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.
On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”
“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.
The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Genetic test identifies parental source of cancer variant
A new hereditary test can determine whether a cancer-disposing gene was inherited from a patient’s father or mother without the need for parental DNA, potentially improving disease screening and management.
“The presence of parental imprints in regions of the genome has been known for a long time,” study author Peter Lansdorp, MD, PhD, of the BC Cancer Research Centre in Vancouver, said in an interview. In addition, the ability of a specific sequencing technology (Strand-seq) to generate a set of DNA variants that tend to be inherited together from a single parent has been documented in several studies.
“That these two pieces can be put together to assign alleles in a patient to one of the parents without studying the DNA of the parents is a major advance,” said Dr. Lansdorp.
Principal author Steven J.M. Jones, PhD, associate director of bioinformatics at BC Cancer Research Centre, explained, “for directing cascade genetic testing, the test could be used almost immediately, even as a research test. It just guides which side of the family to focus familial genetic testing efforts on and is internally validated by the patient’s variant and later confirmed by clinical testing in the family.”
Dr. Jones added, especially when parents are deceased or unavailable.
The study was published online in Cell Genomics.
Low error rate
Determining a parent of origin for hereditary variants “is essential to evaluate disease risk when a pathogenic variant has PofO effects, that is, when a patient’s risk of disease depends on from which parent it is inherited,” the authors wrote. An example is hereditary paraganglioma-pheochromocytoma syndrome as a result of pathogenic variants in SDHD or SDHAF2 genes. Individuals with the variants are at high risk of developing certain cancers, but only if a defective gene is inherited from their father. If inherited from their mother, there is no increased risk.
The new method relies on a technique called “phased DNA methylation” at maternally and paternally imprinted gene loci, as well as chromosome length phasing of DNA sequences.
The team used five human genome “trios” – two parents and the proband (the first person in a family to receive genetic testing or counseling for a suspected hereditary risk) – to pilot the approach. They showed that the method can correctly identify the PofO with an average mismatch error rate of 0.31% for single nucleotide variants and 1.89% for insertions or deletions (indels).
“We will need to validate this technology for different genes in real-world samples from individuals of diverse backgrounds,” said Dr. Jones. The first step is to validate the technology in scenarios with immediate clinical utility, like with SDHD, where lifelong medical management is affected by knowledge of whether the variant was inherited from the mother or father.
“We would also like to quickly validate this for common hereditary cancer genes, like BRCA1, BRCA2, and Lynch syndrome–associated genes, where prediction of PofO may improve low rates of genetic testing in family members by providing more accurate estimates of their risk to carry the familial variant.”
Challenges to moving the test to the clinic, Dr. Jones said, include scaling up the technology, demonstrating clinical and economic utility, compared with existing testing approaches, “and familiarizing clinicians with a new type of test that will routinely give this added dimension of information.”
‘Tremendously promising technology’
Pathologist Stephen Yip, MD, PhD, of the Vancouver Coastal Health Research Institute, who was not involved in the study but disclosed that he collaborates with the authors on other grant-funded projects, said in a comment that “this is a tremendously promising technology that has immediate practical implications in the investigation of PofO of a pathogenic locus, particularly when genetic material is available only from the proband.”
However, “rigorous validation against the current gold standard of short-reading, next-generation sequencing of trios is needed prior to clinical deployment,” he said. “This will take time and effort. However, the promise of this technology is worth the effort.
“Also, there is the possibility of uncovering novel genetics during testing, which could present an ethical dilemma,” he noted. “A robust consenting and ethical framework and early involvement of an ethicist would be helpful.”
Research in Dr. Lansdorp’s laboratory is funded by the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and the government of British Columbia. Dr. Lansdorp, Dr. Jones, and Dr. Yip reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new hereditary test can determine whether a cancer-disposing gene was inherited from a patient’s father or mother without the need for parental DNA, potentially improving disease screening and management.
“The presence of parental imprints in regions of the genome has been known for a long time,” study author Peter Lansdorp, MD, PhD, of the BC Cancer Research Centre in Vancouver, said in an interview. In addition, the ability of a specific sequencing technology (Strand-seq) to generate a set of DNA variants that tend to be inherited together from a single parent has been documented in several studies.
“That these two pieces can be put together to assign alleles in a patient to one of the parents without studying the DNA of the parents is a major advance,” said Dr. Lansdorp.
Principal author Steven J.M. Jones, PhD, associate director of bioinformatics at BC Cancer Research Centre, explained, “for directing cascade genetic testing, the test could be used almost immediately, even as a research test. It just guides which side of the family to focus familial genetic testing efforts on and is internally validated by the patient’s variant and later confirmed by clinical testing in the family.”
Dr. Jones added, especially when parents are deceased or unavailable.
The study was published online in Cell Genomics.
Low error rate
Determining a parent of origin for hereditary variants “is essential to evaluate disease risk when a pathogenic variant has PofO effects, that is, when a patient’s risk of disease depends on from which parent it is inherited,” the authors wrote. An example is hereditary paraganglioma-pheochromocytoma syndrome as a result of pathogenic variants in SDHD or SDHAF2 genes. Individuals with the variants are at high risk of developing certain cancers, but only if a defective gene is inherited from their father. If inherited from their mother, there is no increased risk.
The new method relies on a technique called “phased DNA methylation” at maternally and paternally imprinted gene loci, as well as chromosome length phasing of DNA sequences.
The team used five human genome “trios” – two parents and the proband (the first person in a family to receive genetic testing or counseling for a suspected hereditary risk) – to pilot the approach. They showed that the method can correctly identify the PofO with an average mismatch error rate of 0.31% for single nucleotide variants and 1.89% for insertions or deletions (indels).
“We will need to validate this technology for different genes in real-world samples from individuals of diverse backgrounds,” said Dr. Jones. The first step is to validate the technology in scenarios with immediate clinical utility, like with SDHD, where lifelong medical management is affected by knowledge of whether the variant was inherited from the mother or father.
“We would also like to quickly validate this for common hereditary cancer genes, like BRCA1, BRCA2, and Lynch syndrome–associated genes, where prediction of PofO may improve low rates of genetic testing in family members by providing more accurate estimates of their risk to carry the familial variant.”
Challenges to moving the test to the clinic, Dr. Jones said, include scaling up the technology, demonstrating clinical and economic utility, compared with existing testing approaches, “and familiarizing clinicians with a new type of test that will routinely give this added dimension of information.”
‘Tremendously promising technology’
Pathologist Stephen Yip, MD, PhD, of the Vancouver Coastal Health Research Institute, who was not involved in the study but disclosed that he collaborates with the authors on other grant-funded projects, said in a comment that “this is a tremendously promising technology that has immediate practical implications in the investigation of PofO of a pathogenic locus, particularly when genetic material is available only from the proband.”
However, “rigorous validation against the current gold standard of short-reading, next-generation sequencing of trios is needed prior to clinical deployment,” he said. “This will take time and effort. However, the promise of this technology is worth the effort.
“Also, there is the possibility of uncovering novel genetics during testing, which could present an ethical dilemma,” he noted. “A robust consenting and ethical framework and early involvement of an ethicist would be helpful.”
Research in Dr. Lansdorp’s laboratory is funded by the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and the government of British Columbia. Dr. Lansdorp, Dr. Jones, and Dr. Yip reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new hereditary test can determine whether a cancer-disposing gene was inherited from a patient’s father or mother without the need for parental DNA, potentially improving disease screening and management.
“The presence of parental imprints in regions of the genome has been known for a long time,” study author Peter Lansdorp, MD, PhD, of the BC Cancer Research Centre in Vancouver, said in an interview. In addition, the ability of a specific sequencing technology (Strand-seq) to generate a set of DNA variants that tend to be inherited together from a single parent has been documented in several studies.
“That these two pieces can be put together to assign alleles in a patient to one of the parents without studying the DNA of the parents is a major advance,” said Dr. Lansdorp.
Principal author Steven J.M. Jones, PhD, associate director of bioinformatics at BC Cancer Research Centre, explained, “for directing cascade genetic testing, the test could be used almost immediately, even as a research test. It just guides which side of the family to focus familial genetic testing efforts on and is internally validated by the patient’s variant and later confirmed by clinical testing in the family.”
Dr. Jones added, especially when parents are deceased or unavailable.
The study was published online in Cell Genomics.
Low error rate
Determining a parent of origin for hereditary variants “is essential to evaluate disease risk when a pathogenic variant has PofO effects, that is, when a patient’s risk of disease depends on from which parent it is inherited,” the authors wrote. An example is hereditary paraganglioma-pheochromocytoma syndrome as a result of pathogenic variants in SDHD or SDHAF2 genes. Individuals with the variants are at high risk of developing certain cancers, but only if a defective gene is inherited from their father. If inherited from their mother, there is no increased risk.
The new method relies on a technique called “phased DNA methylation” at maternally and paternally imprinted gene loci, as well as chromosome length phasing of DNA sequences.
The team used five human genome “trios” – two parents and the proband (the first person in a family to receive genetic testing or counseling for a suspected hereditary risk) – to pilot the approach. They showed that the method can correctly identify the PofO with an average mismatch error rate of 0.31% for single nucleotide variants and 1.89% for insertions or deletions (indels).
“We will need to validate this technology for different genes in real-world samples from individuals of diverse backgrounds,” said Dr. Jones. The first step is to validate the technology in scenarios with immediate clinical utility, like with SDHD, where lifelong medical management is affected by knowledge of whether the variant was inherited from the mother or father.
“We would also like to quickly validate this for common hereditary cancer genes, like BRCA1, BRCA2, and Lynch syndrome–associated genes, where prediction of PofO may improve low rates of genetic testing in family members by providing more accurate estimates of their risk to carry the familial variant.”
Challenges to moving the test to the clinic, Dr. Jones said, include scaling up the technology, demonstrating clinical and economic utility, compared with existing testing approaches, “and familiarizing clinicians with a new type of test that will routinely give this added dimension of information.”
‘Tremendously promising technology’
Pathologist Stephen Yip, MD, PhD, of the Vancouver Coastal Health Research Institute, who was not involved in the study but disclosed that he collaborates with the authors on other grant-funded projects, said in a comment that “this is a tremendously promising technology that has immediate practical implications in the investigation of PofO of a pathogenic locus, particularly when genetic material is available only from the proband.”
However, “rigorous validation against the current gold standard of short-reading, next-generation sequencing of trios is needed prior to clinical deployment,” he said. “This will take time and effort. However, the promise of this technology is worth the effort.
“Also, there is the possibility of uncovering novel genetics during testing, which could present an ethical dilemma,” he noted. “A robust consenting and ethical framework and early involvement of an ethicist would be helpful.”
Research in Dr. Lansdorp’s laboratory is funded by the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and the government of British Columbia. Dr. Lansdorp, Dr. Jones, and Dr. Yip reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CELL GENOMICS