Cardiology

Increases in use of the antipsychotic risperidone (Risperdal) are associated with small dose-related increases in both weight and blood cholesterol levels, new research suggests.

Investigators analyzed 1-year data for more than 400 patients who were taking risperidone and/or its metabolite paliperidone (Invega). Results showed increments of 1 mg of risperidone-equivalent doses were associated with an increase of 0.25% of weight within a year of follow-up.

“Although our findings report a positive and statistically significant dose-dependence of weight gain and cholesterol, both total and LDL [cholesterol], the size of the predicted changes of metabolic effects is clinically nonrelevant,” lead author Marianna Piras, PharmD, Centre for Psychiatric Neuroscience, Lausanne (Switzerland) University Hospital, said in an interview.

“Therefore, dose lowering would not have a beneficial effect on attenuating weight gain or cholesterol increases and could lead to psychiatric decompensation,” said Ms. Piras, who is also a PhD candidate in the unit of pharmacogenetics and clinical psychopharmacology at the University of Lausanne.

However, she added that because dose increments could increase risk for significant weight gain in the first month of treatment – the dose can be increased typically in a range of 1-10 grams – and strong dose increments could contribute to metabolic worsening over time, “risperidone minimum effective doses should be preferred.”

The findings were published online in the Journal of Clinical Psychiatry.
 

‘Serious public health issue’

Compared with the general population, patients with mental illness present with a greater prevalence of metabolic disorders. In addition, several psychotropic medications, including antipsychotics, can induce metabolic alterations such as weight gain, the investigators noted.

Antipsychotic-induced metabolic adverse effects “constitute a serious public health issue” because they are risk factors for cardiovascular diseases such as obesity and/or dyslipidemia, “which have been associated with a 10-year reduced life expectancy in the psychiatric population,” Ms. Piras said.

“The dose-dependence of metabolic adverse effects is a debated subject that needs to be assessed for each psychotropic drug known to induce weight gain,” she added.

Several previous studies have examined whether there is a dose-related effect of antipsychotics on metabolic parameters, “with some results suggesting that [weight gain] seems to develop even when low off-label doses are prescribed,” Ms. Piras noted.

She and her colleagues had already studied dose-related metabolic effects of quetiapine (Seroquel) and olanzapine (Zyprexa).

Risperidone is an antipsychotic with a “medium to high metabolic risk profile,” the researchers note, and few studies have examined the impact of risperidone on metabolic parameters other than weight gain.

For the current analysis, they analyzed data from a longitudinal study that included 438 patients (mean age, 40.7 years; 50.7% men) who started treatment with risperidone and/or paliperidone between 2007 and 2018.

The participants had diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, depression, “other,” or “unknown.”

Clinical follow-up periods were up to a year, but were no shorter than 3 weeks. The investigators also assessed the data at different time intervals at 1, 3, 6, and 12 months “to appreciate the evolution of the metabolic parameters.”

In addition, they collected demographic and clinical information, such as comorbidities, and measured patients’ weight, height, waist circumference, blood pressure, plasma glucose, and lipids at baseline and at 1, 3, and 12 months and then annually. Weight, waist circumference, and BP were also assessed at 2 and 6 months.

Doses of paliperidone were converted into risperidone-equivalent doses.
 

Significant weight gain over time

The mean duration of follow-up for the participants, of whom 374 were being treated with risperidone and 64 with paliperidone, was 153 days. Close to half (48.2%) were taking other psychotropic medications known to be associated with some degree of metabolic risk.

Patients were divided into two cohorts based on their daily dose intake (DDI): less than 3 mg/day (n = 201) and at least 3 mg/day (n = 237).

In the overall cohort, a “significant effect of time on weight change was found for each time point,” the investigators reported.

Small increases, big changes

Commenting on the study, Erika Nurmi, MD, PhD, associate professor in the department of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience, University of California, Los Angeles, said the study is “unique in the field.”

It “leverages real-world data from a large patient registry to ask a long-unanswered question: Are weight and metabolic adverse effects proportional to dose? Big data approaches like these are very powerful, given the large number of participants that can be included,” said Dr. Nurmi, who was not involved with the research.

However, she cautioned, the “biggest drawback [is that] these data are by nature much more complex and prone to confounding effects.”

In this case, a “critical confounder” for the study was that the majority of individuals taking higher risperidone doses were also taking other drugs known to cause weight gain, whereas the majority of those on lower risperidone doses were not. “This difference may explain the dose relationship observed,” she said.

Because real-world, big data are “valuable but also messy, conclusions drawn from them must be interpreted with caution,” Dr. Nurmi said.

She added that it is generally wise to use the lowest effective dose possible.

“Clinicians should appreciate that even small doses of antipsychotics can cause big changes in weight. Risks and benefits of medications must be carefully considered in clinical practice,” Dr. Nurmi said.

The research was funded in part by the Swiss National Research Foundation. Piras reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Nurmi reported no relevant financial relationships, but she is an unpaid member of the Tourette Association of America’s medical advisory board and of the Myriad Genetics scientific advisory board.

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

Increases in use of the antipsychotic risperidone (Risperdal) are associated with small dose-related increases in both weight and blood cholesterol levels, new research suggests.

Investigators analyzed 1-year data for more than 400 patients who were taking risperidone and/or its metabolite paliperidone (Invega). Results showed increments of 1 mg of risperidone-equivalent doses were associated with an increase of 0.25% of weight within a year of follow-up.

“Although our findings report a positive and statistically significant dose-dependence of weight gain and cholesterol, both total and LDL [cholesterol], the size of the predicted changes of metabolic effects is clinically nonrelevant,” lead author Marianna Piras, PharmD, Centre for Psychiatric Neuroscience, Lausanne (Switzerland) University Hospital, said in an interview.

“Therefore, dose lowering would not have a beneficial effect on attenuating weight gain or cholesterol increases and could lead to psychiatric decompensation,” said Ms. Piras, who is also a PhD candidate in the unit of pharmacogenetics and clinical psychopharmacology at the University of Lausanne.

However, she added that because dose increments could increase risk for significant weight gain in the first month of treatment – the dose can be increased typically in a range of 1-10 grams – and strong dose increments could contribute to metabolic worsening over time, “risperidone minimum effective doses should be preferred.”

The findings were published online in the Journal of Clinical Psychiatry.
 

‘Serious public health issue’

Compared with the general population, patients with mental illness present with a greater prevalence of metabolic disorders. In addition, several psychotropic medications, including antipsychotics, can induce metabolic alterations such as weight gain, the investigators noted.

Antipsychotic-induced metabolic adverse effects “constitute a serious public health issue” because they are risk factors for cardiovascular diseases such as obesity and/or dyslipidemia, “which have been associated with a 10-year reduced life expectancy in the psychiatric population,” Ms. Piras said.

“The dose-dependence of metabolic adverse effects is a debated subject that needs to be assessed for each psychotropic drug known to induce weight gain,” she added.

Several previous studies have examined whether there is a dose-related effect of antipsychotics on metabolic parameters, “with some results suggesting that [weight gain] seems to develop even when low off-label doses are prescribed,” Ms. Piras noted.

She and her colleagues had already studied dose-related metabolic effects of quetiapine (Seroquel) and olanzapine (Zyprexa).

Risperidone is an antipsychotic with a “medium to high metabolic risk profile,” the researchers note, and few studies have examined the impact of risperidone on metabolic parameters other than weight gain.

For the current analysis, they analyzed data from a longitudinal study that included 438 patients (mean age, 40.7 years; 50.7% men) who started treatment with risperidone and/or paliperidone between 2007 and 2018.

The participants had diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, depression, “other,” or “unknown.”

Clinical follow-up periods were up to a year, but were no shorter than 3 weeks. The investigators also assessed the data at different time intervals at 1, 3, 6, and 12 months “to appreciate the evolution of the metabolic parameters.”

In addition, they collected demographic and clinical information, such as comorbidities, and measured patients’ weight, height, waist circumference, blood pressure, plasma glucose, and lipids at baseline and at 1, 3, and 12 months and then annually. Weight, waist circumference, and BP were also assessed at 2 and 6 months.

Doses of paliperidone were converted into risperidone-equivalent doses.
 

Significant weight gain over time

The mean duration of follow-up for the participants, of whom 374 were being treated with risperidone and 64 with paliperidone, was 153 days. Close to half (48.2%) were taking other psychotropic medications known to be associated with some degree of metabolic risk.

Patients were divided into two cohorts based on their daily dose intake (DDI): less than 3 mg/day (n = 201) and at least 3 mg/day (n = 237).

In the overall cohort, a “significant effect of time on weight change was found for each time point,” the investigators reported.

Small increases, big changes

Commenting on the study, Erika Nurmi, MD, PhD, associate professor in the department of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience, University of California, Los Angeles, said the study is “unique in the field.”

It “leverages real-world data from a large patient registry to ask a long-unanswered question: Are weight and metabolic adverse effects proportional to dose? Big data approaches like these are very powerful, given the large number of participants that can be included,” said Dr. Nurmi, who was not involved with the research.

However, she cautioned, the “biggest drawback [is that] these data are by nature much more complex and prone to confounding effects.”

In this case, a “critical confounder” for the study was that the majority of individuals taking higher risperidone doses were also taking other drugs known to cause weight gain, whereas the majority of those on lower risperidone doses were not. “This difference may explain the dose relationship observed,” she said.

Because real-world, big data are “valuable but also messy, conclusions drawn from them must be interpreted with caution,” Dr. Nurmi said.

She added that it is generally wise to use the lowest effective dose possible.

“Clinicians should appreciate that even small doses of antipsychotics can cause big changes in weight. Risks and benefits of medications must be carefully considered in clinical practice,” Dr. Nurmi said.

The research was funded in part by the Swiss National Research Foundation. Piras reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Nurmi reported no relevant financial relationships, but she is an unpaid member of the Tourette Association of America’s medical advisory board and of the Myriad Genetics scientific advisory board.

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

Increases in use of the antipsychotic risperidone (Risperdal) are associated with small dose-related increases in both weight and blood cholesterol levels, new research suggests.

Investigators analyzed 1-year data for more than 400 patients who were taking risperidone and/or its metabolite paliperidone (Invega). Results showed increments of 1 mg of risperidone-equivalent doses were associated with an increase of 0.25% of weight within a year of follow-up.

“Although our findings report a positive and statistically significant dose-dependence of weight gain and cholesterol, both total and LDL [cholesterol], the size of the predicted changes of metabolic effects is clinically nonrelevant,” lead author Marianna Piras, PharmD, Centre for Psychiatric Neuroscience, Lausanne (Switzerland) University Hospital, said in an interview.

“Therefore, dose lowering would not have a beneficial effect on attenuating weight gain or cholesterol increases and could lead to psychiatric decompensation,” said Ms. Piras, who is also a PhD candidate in the unit of pharmacogenetics and clinical psychopharmacology at the University of Lausanne.

However, she added that because dose increments could increase risk for significant weight gain in the first month of treatment – the dose can be increased typically in a range of 1-10 grams – and strong dose increments could contribute to metabolic worsening over time, “risperidone minimum effective doses should be preferred.”

The findings were published online in the Journal of Clinical Psychiatry.
 

‘Serious public health issue’

Compared with the general population, patients with mental illness present with a greater prevalence of metabolic disorders. In addition, several psychotropic medications, including antipsychotics, can induce metabolic alterations such as weight gain, the investigators noted.

Antipsychotic-induced metabolic adverse effects “constitute a serious public health issue” because they are risk factors for cardiovascular diseases such as obesity and/or dyslipidemia, “which have been associated with a 10-year reduced life expectancy in the psychiatric population,” Ms. Piras said.

“The dose-dependence of metabolic adverse effects is a debated subject that needs to be assessed for each psychotropic drug known to induce weight gain,” she added.

Several previous studies have examined whether there is a dose-related effect of antipsychotics on metabolic parameters, “with some results suggesting that [weight gain] seems to develop even when low off-label doses are prescribed,” Ms. Piras noted.

She and her colleagues had already studied dose-related metabolic effects of quetiapine (Seroquel) and olanzapine (Zyprexa).

Risperidone is an antipsychotic with a “medium to high metabolic risk profile,” the researchers note, and few studies have examined the impact of risperidone on metabolic parameters other than weight gain.

For the current analysis, they analyzed data from a longitudinal study that included 438 patients (mean age, 40.7 years; 50.7% men) who started treatment with risperidone and/or paliperidone between 2007 and 2018.

The participants had diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, depression, “other,” or “unknown.”

Clinical follow-up periods were up to a year, but were no shorter than 3 weeks. The investigators also assessed the data at different time intervals at 1, 3, 6, and 12 months “to appreciate the evolution of the metabolic parameters.”

In addition, they collected demographic and clinical information, such as comorbidities, and measured patients’ weight, height, waist circumference, blood pressure, plasma glucose, and lipids at baseline and at 1, 3, and 12 months and then annually. Weight, waist circumference, and BP were also assessed at 2 and 6 months.

Doses of paliperidone were converted into risperidone-equivalent doses.
 

Significant weight gain over time

The mean duration of follow-up for the participants, of whom 374 were being treated with risperidone and 64 with paliperidone, was 153 days. Close to half (48.2%) were taking other psychotropic medications known to be associated with some degree of metabolic risk.

Patients were divided into two cohorts based on their daily dose intake (DDI): less than 3 mg/day (n = 201) and at least 3 mg/day (n = 237).

In the overall cohort, a “significant effect of time on weight change was found for each time point,” the investigators reported.

Small increases, big changes

Commenting on the study, Erika Nurmi, MD, PhD, associate professor in the department of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience, University of California, Los Angeles, said the study is “unique in the field.”

It “leverages real-world data from a large patient registry to ask a long-unanswered question: Are weight and metabolic adverse effects proportional to dose? Big data approaches like these are very powerful, given the large number of participants that can be included,” said Dr. Nurmi, who was not involved with the research.

However, she cautioned, the “biggest drawback [is that] these data are by nature much more complex and prone to confounding effects.”

In this case, a “critical confounder” for the study was that the majority of individuals taking higher risperidone doses were also taking other drugs known to cause weight gain, whereas the majority of those on lower risperidone doses were not. “This difference may explain the dose relationship observed,” she said.

Because real-world, big data are “valuable but also messy, conclusions drawn from them must be interpreted with caution,” Dr. Nurmi said.

She added that it is generally wise to use the lowest effective dose possible.

“Clinicians should appreciate that even small doses of antipsychotics can cause big changes in weight. Risks and benefits of medications must be carefully considered in clinical practice,” Dr. Nurmi said.

The research was funded in part by the Swiss National Research Foundation. Piras reports no relevant financial relationships. The other investigators’ disclosures are listed in the original article. Dr. Nurmi reported no relevant financial relationships, but she is an unpaid member of the Tourette Association of America’s medical advisory board and of the Myriad Genetics scientific advisory board.

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

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.

The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.

“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.

Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.

When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.

Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.

However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.

High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.

In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”

©Clayton Hansen/iStockphoto

“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.

The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”

They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”

The investigators and editorialists have no disclosures.

A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.

The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.

“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.

Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.

When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.

Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.

However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.

High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.

In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”

©Clayton Hansen/iStockphoto

“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.

The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”

They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”

The investigators and editorialists have no disclosures.

A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.

The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.

“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.

Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.

When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.

Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.

However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.

High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.

In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”

©Clayton Hansen/iStockphoto

“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.

The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”

They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”

The investigators and editorialists have no disclosures.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

The 2022 Pediatric Academic Societies meeting included an excellent session on the acute and delayed effects of COVID-19 on children’s hearts. Data on the risk for cardiac injury during acute COVID-19, return-to-play guidelines after COVID-19–related heart injury, and post–vaccine-associated myocarditis were reviewed.

COVID-induced cardiac injury

The risk for COVID-induced cardiac injury is directly associated with age. Recent Centers for Disease Control and Prevention data revealed a “myocarditis or pericarditis” rate in the range of 12-17 cases per 100,000 SARS-CoV-2 infections among male children aged 5-11 years (lower rates for females); the rate jumps to 50-65 cases per 100,000 infections among male children aged 12-17 years. So cardiac injury caused by acute COVID-19 appears rare, but the risk is clearly associated with male sex and adolescent age.

Return to play after COVID-19

Clinicians may be pressed by patients and parents for advice on return to play after illness with COVID-19. In July 2020, the American College of Cardiology published an algorithm that has been adjusted over time, most recently in 2022 by the American Academy of Pediatrics. These algorithms stratify recommendations by degree of illness. One rule of thumb: Patients with severe COVID-19 (ICU care or multisystem inflammatory syndrome in children [MIS-C]) have only one box on the algorithm, and that is to rest for 3-6 months and only return to usual activity after cardiac clearance. Moderate disease (defined as ≥ 4 days of fever > 100.4 °F; ≥ 1 week of myalgia, chills, lethargy, or any non-ICU hospital stay; and no evidence of MIS-C) require undergoing an ECG to look for cardiac dysfunction, followed by at least 10 days of rest if the ECG is negative or referral for cardiac evaluation if either ECG or exam by a pediatric cardiologist is abnormal.

Clinicians can perhaps be more permissible with patients who are younger or who have had less severe disease. For example, if a patient aged younger than 12 years is asymptomatic with routine activity at the time of evaluation, an ECG is not indicated. For patients aged 12-15 years who are asymptomatic at the time of evaluation but participate in a high-intensity sport, clinicians might consider obtaining an ECG. As few as 3 days of rest might be enough for select patients who are asymptomatic at presentation. For other patients, clinicians should work with parents to introduce activity gradually and make it clear to parents that any activity intolerance requires quick reevaluation. On existing athlete registries, no deaths that are attributable to post–COVID-19 cardiac effects have been confirmed in children; however, all data presented during the session were from prior to the Omicron variant surge in early 2022, so more information may be forthcoming.
 

Considerations for MIS-C

Among children experiencing MIS-C, 35% had ECG changes, 40% exhibited left ventricular systolic or diastolic dysfunction, and 30% had mitral regurgitation, meaning that a large percentage of patients with MIS-C show some degree of cardiac dysfunction. Unfortunately, we are still in the data-gathering phase for long-term outcomes. Functional parameters tend to improve within a week, and most patients will return to normal cardiac function by 3-4 months.

Return to play after MIS-C is quite different from that for acute COVID-19. Patients with MIS-C should be treated much like other patients with myocarditis with an expected return to play in 3-6 months and only after cardiac follow-up. Another good-to-remember recommendation is to delay COVID-19 vaccination for at least 90 days after an episode of MIS-C.
 

Vaccine-related myocarditis

Once again, older age appears to be a risk factor because most patients with postvaccine myocarditis have been in their mid-teens to early 20s, with events more likely after the second vaccine dose and also more likely in male children (4:1 ratio to female children). No deaths have occurred from postvaccination myocarditis in patients younger than 30 years. Still, many individuals have exhibited residual MRI enhancement in the cardiac tissue for some time after experiencing postvaccination myocarditis; it’s currently unclear whether that has clinical implications. By comparison, CDC data demonstrates convincingly that the risk for cardiac effects is much greater after acute COVID-19 than after COVID-19 vaccination, with risk ratios often higher than 20, depending on age and condition (for example, myocarditis vs. pericarditis). Data are still insufficient to determine whether clinicians should recommend or avoid COVID-19 vaccination in children with congenital heart disease.

In summary, administering COVID-19 vaccines requires a great deal of shared decision-making with parents, and the clinician’s role is to educate parents about all potential risks related to both the vaccine and COVID-19 illness. Research has consistently shown that acute COVID-19 myocarditis and myocarditis associated with MIS-C are much more likely to occur in unvaccinated youth and more likely than postvaccination myocarditis, regardless of age.

William T. Basco, Jr., MD, MS, is a professor of pediatrics at the Medical University of South Carolina, Charleston, and director of the division of general pediatrics. He is an active health services researcher and has published more than 60 manuscripts in the peer-reviewed literature.

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

MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.

The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.

Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).

This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”

Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”

The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.

In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.

It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.

“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.

“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”

In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).

Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.

For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.

“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
 

Handy tool

The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.

“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.

He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.

Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.

During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.

“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.

“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”

However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”

Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.

They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.

The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.

The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.

When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.

For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.

Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.

For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.

This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”

No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.

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

MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.

The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.

Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).

This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”

Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”

The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.

In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.

It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.

“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.

“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”

In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).

Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.

For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.

“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
 

Handy tool

The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.

“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.

He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.

Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.

During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.

“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.

“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”

However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”

Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.

They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.

The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.

The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.

When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.

For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.

Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.

For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.

This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”

No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.

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

MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.

The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.

Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).

This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”

Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”

The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.

In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.

It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.

“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.

“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”

In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).

Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.

For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.

“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
 

Handy tool

The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.

“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.

He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.

Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.

During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.

“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.

“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”

However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”

Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.

They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.

The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.

The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.

When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.

For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.

Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.

For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.

This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”

No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.

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

Time-restricted eating reduced cardiovascular risk among older breast cancer survivors, a single-group feasibility study suggests.

The results show a 15% relative decline in cardiovascular risk, measured using the Framingham Risk Score, among at-risk breast cancer survivors (BCS) after only 8 weeks of following a time-restricted eating regimen, reported Amy A. Kirkham, PhD, assistant professor of kinesiology and physical education, University of Toronto, and colleagues.

“Time-restricted eating also significantly decreased visceral adipose tissue (VAT), which our team has previously found to accumulate rapidly with cardiotoxic treatment and predict later cardiac events among BCS,” the researchers add.

The findings were published online in the Journal of the American College of Cardiology: Cardiac Onco.

Physical activity is one of the main modalities for lowering cardiovascular risk, but it is not feasible for everyone because of physical limitations and other factors, noted Dr. Kirkham.

“I became interested in time-restricted eating when I came across the literature, which has really exploded in the last 5 years, showing that it can reduce the number of cardiovascular risk factors,” she said in an interview.

“However, most of these populations studied have had cardiometabolic conditions, like obesity, type 2 diabetes, prediabetes, and metabolic syndrome, and no one has looked at this” in either the population specifically at high risk for cardiovascular disease or in patients with overt cardiovascular disease, she said.

This approach is easy for patients to follow and is much simpler than many of the other dietary patterns, noted Dr. Kirkham. “It simply consists of having a start time or end time to your eating, so it is easy to prescribe,” she said. “You can see how that is much easier for a doctor to explain to a patient than trying to explain how to meet the physical activity guidelines each week.”

“This particular study definitely shows that time-restricted eating can decrease the calorie intake, and I think by decreasing the calorie intake you definitely would improve the body weight, which has numerous benefits irrespective of how we arrive at the end goal which is including the cardiovascular risk factors,” said Ajay Vallakati, MBBS, physician and clinical assistant professor of internal medicine, the Ohio State University, Columbus, commenting on the study.

“I think time-restricted eating is a tool we should look at, and a bigger study would help us to recommend this for our patients,” Dr. Vallakati told this news organization.

The study involved 22 participants. Mean age was 66 years. Mean body mass index was 31 ± 5 kg/m². In the cohort, 91% of participants were taking aromatase inhibitors and tamoxifen at the time of the study, and 50% underwent left-sided radiation.

The study group included breast cancer survivors who had risk factors for cardiovascular disease mortality, including completion of cardiotoxic therapy, like anthracyclines, within 1-6 years, obesity/overweight, and older age, defined as 60 years of age or older.

Participants were allowed to eat freely between 12 PM and 8 PM on weekdays and any time during weekends. Outside of the allotted hours, they could only drink black coffee, water, or black tea for the 8-week study period. They were not under any other physical activity or dietary restrictions.

All were provided with behavioral support, such as check-in phone calls with the research team at 1-, 3-, and 6-week follow-up and pre-interventional calls from a registered dietitian. During weekdays, they also received automated text messages twice a day asking what time they started and stopped eating.

Irritability and headaches were among the transient, minor symptoms reported, the researchers say. The study group responded to nearly all of the text messages that they received from the researchers. The participants also followed through with the fast for a median 98% of the prescribed days by fasting for 16 or more hours.

The results showed that after 8 weeks, median Framingham cardiovascular risk declined from 10.9% to 8.6%, a 15% relative reduction (P = .037). Modifiable aspects of Framingham, such as systolic blood pressure, total cholesterol, and high-density lipoprotein, remained relatively consistent overall, however, suggesting variation between individuals in the etiology of the risk decline.

Caloric intake fell by a median of 450 kcal, representing a relative reduction of about 22% (P < .001), they note.

The findings also showed a decline in median derived whole-body fat mass (–0.9 kg; P = .046), body mass (–1.0 kg; P = .025), and mean MRI-derived VAT (–5%; P = .009).

Other data showed that the average BMI remained the same (P = .10).

At the beginning of the study, 68% of the cohort was considered cardiometabolically unhealthy, given the benchmarks for pharmacologic preventive therapy of cardiovascular risk or metabolic syndrome based on Canadian Cardiovascular Society recommendations.

Notably, 53% of the cohort was no longer classified as meeting the criteria for metabolic syndrome or for the therapeutic treatment of cardiovascular risk after the intervention.

The study’s limitations include its short duration, selection bias, and that it did not involve a control group, the researchers acknowledge.

“Randomized controlled trials are needed to confirm these findings and to evaluate the health benefits, including potential health care cost savings and safety of longer-term time-restricted eating,” the researchers conclude.

Dr. Vallakati and Dr. Kirkham report no relevant conflicts of interest.

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

Time-restricted eating reduced cardiovascular risk among older breast cancer survivors, a single-group feasibility study suggests.

The results show a 15% relative decline in cardiovascular risk, measured using the Framingham Risk Score, among at-risk breast cancer survivors (BCS) after only 8 weeks of following a time-restricted eating regimen, reported Amy A. Kirkham, PhD, assistant professor of kinesiology and physical education, University of Toronto, and colleagues.

“Time-restricted eating also significantly decreased visceral adipose tissue (VAT), which our team has previously found to accumulate rapidly with cardiotoxic treatment and predict later cardiac events among BCS,” the researchers add.

The findings were published online in the Journal of the American College of Cardiology: Cardiac Onco.

Physical activity is one of the main modalities for lowering cardiovascular risk, but it is not feasible for everyone because of physical limitations and other factors, noted Dr. Kirkham.

“I became interested in time-restricted eating when I came across the literature, which has really exploded in the last 5 years, showing that it can reduce the number of cardiovascular risk factors,” she said in an interview.

“However, most of these populations studied have had cardiometabolic conditions, like obesity, type 2 diabetes, prediabetes, and metabolic syndrome, and no one has looked at this” in either the population specifically at high risk for cardiovascular disease or in patients with overt cardiovascular disease, she said.

This approach is easy for patients to follow and is much simpler than many of the other dietary patterns, noted Dr. Kirkham. “It simply consists of having a start time or end time to your eating, so it is easy to prescribe,” she said. “You can see how that is much easier for a doctor to explain to a patient than trying to explain how to meet the physical activity guidelines each week.”

“This particular study definitely shows that time-restricted eating can decrease the calorie intake, and I think by decreasing the calorie intake you definitely would improve the body weight, which has numerous benefits irrespective of how we arrive at the end goal which is including the cardiovascular risk factors,” said Ajay Vallakati, MBBS, physician and clinical assistant professor of internal medicine, the Ohio State University, Columbus, commenting on the study.

“I think time-restricted eating is a tool we should look at, and a bigger study would help us to recommend this for our patients,” Dr. Vallakati told this news organization.

The study involved 22 participants. Mean age was 66 years. Mean body mass index was 31 ± 5 kg/m². In the cohort, 91% of participants were taking aromatase inhibitors and tamoxifen at the time of the study, and 50% underwent left-sided radiation.

The study group included breast cancer survivors who had risk factors for cardiovascular disease mortality, including completion of cardiotoxic therapy, like anthracyclines, within 1-6 years, obesity/overweight, and older age, defined as 60 years of age or older.

Participants were allowed to eat freely between 12 PM and 8 PM on weekdays and any time during weekends. Outside of the allotted hours, they could only drink black coffee, water, or black tea for the 8-week study period. They were not under any other physical activity or dietary restrictions.

All were provided with behavioral support, such as check-in phone calls with the research team at 1-, 3-, and 6-week follow-up and pre-interventional calls from a registered dietitian. During weekdays, they also received automated text messages twice a day asking what time they started and stopped eating.

Irritability and headaches were among the transient, minor symptoms reported, the researchers say. The study group responded to nearly all of the text messages that they received from the researchers. The participants also followed through with the fast for a median 98% of the prescribed days by fasting for 16 or more hours.

The results showed that after 8 weeks, median Framingham cardiovascular risk declined from 10.9% to 8.6%, a 15% relative reduction (P = .037). Modifiable aspects of Framingham, such as systolic blood pressure, total cholesterol, and high-density lipoprotein, remained relatively consistent overall, however, suggesting variation between individuals in the etiology of the risk decline.

Caloric intake fell by a median of 450 kcal, representing a relative reduction of about 22% (P < .001), they note.

The findings also showed a decline in median derived whole-body fat mass (–0.9 kg; P = .046), body mass (–1.0 kg; P = .025), and mean MRI-derived VAT (–5%; P = .009).

Other data showed that the average BMI remained the same (P = .10).

At the beginning of the study, 68% of the cohort was considered cardiometabolically unhealthy, given the benchmarks for pharmacologic preventive therapy of cardiovascular risk or metabolic syndrome based on Canadian Cardiovascular Society recommendations.

Notably, 53% of the cohort was no longer classified as meeting the criteria for metabolic syndrome or for the therapeutic treatment of cardiovascular risk after the intervention.

The study’s limitations include its short duration, selection bias, and that it did not involve a control group, the researchers acknowledge.

“Randomized controlled trials are needed to confirm these findings and to evaluate the health benefits, including potential health care cost savings and safety of longer-term time-restricted eating,” the researchers conclude.

Dr. Vallakati and Dr. Kirkham report no relevant conflicts of interest.

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

Time-restricted eating reduced cardiovascular risk among older breast cancer survivors, a single-group feasibility study suggests.

The results show a 15% relative decline in cardiovascular risk, measured using the Framingham Risk Score, among at-risk breast cancer survivors (BCS) after only 8 weeks of following a time-restricted eating regimen, reported Amy A. Kirkham, PhD, assistant professor of kinesiology and physical education, University of Toronto, and colleagues.

“Time-restricted eating also significantly decreased visceral adipose tissue (VAT), which our team has previously found to accumulate rapidly with cardiotoxic treatment and predict later cardiac events among BCS,” the researchers add.

The findings were published online in the Journal of the American College of Cardiology: Cardiac Onco.

Physical activity is one of the main modalities for lowering cardiovascular risk, but it is not feasible for everyone because of physical limitations and other factors, noted Dr. Kirkham.

“I became interested in time-restricted eating when I came across the literature, which has really exploded in the last 5 years, showing that it can reduce the number of cardiovascular risk factors,” she said in an interview.

“However, most of these populations studied have had cardiometabolic conditions, like obesity, type 2 diabetes, prediabetes, and metabolic syndrome, and no one has looked at this” in either the population specifically at high risk for cardiovascular disease or in patients with overt cardiovascular disease, she said.

This approach is easy for patients to follow and is much simpler than many of the other dietary patterns, noted Dr. Kirkham. “It simply consists of having a start time or end time to your eating, so it is easy to prescribe,” she said. “You can see how that is much easier for a doctor to explain to a patient than trying to explain how to meet the physical activity guidelines each week.”

“This particular study definitely shows that time-restricted eating can decrease the calorie intake, and I think by decreasing the calorie intake you definitely would improve the body weight, which has numerous benefits irrespective of how we arrive at the end goal which is including the cardiovascular risk factors,” said Ajay Vallakati, MBBS, physician and clinical assistant professor of internal medicine, the Ohio State University, Columbus, commenting on the study.

“I think time-restricted eating is a tool we should look at, and a bigger study would help us to recommend this for our patients,” Dr. Vallakati told this news organization.

The study involved 22 participants. Mean age was 66 years. Mean body mass index was 31 ± 5 kg/m². In the cohort, 91% of participants were taking aromatase inhibitors and tamoxifen at the time of the study, and 50% underwent left-sided radiation.

The study group included breast cancer survivors who had risk factors for cardiovascular disease mortality, including completion of cardiotoxic therapy, like anthracyclines, within 1-6 years, obesity/overweight, and older age, defined as 60 years of age or older.

Participants were allowed to eat freely between 12 PM and 8 PM on weekdays and any time during weekends. Outside of the allotted hours, they could only drink black coffee, water, or black tea for the 8-week study period. They were not under any other physical activity or dietary restrictions.

All were provided with behavioral support, such as check-in phone calls with the research team at 1-, 3-, and 6-week follow-up and pre-interventional calls from a registered dietitian. During weekdays, they also received automated text messages twice a day asking what time they started and stopped eating.

Irritability and headaches were among the transient, minor symptoms reported, the researchers say. The study group responded to nearly all of the text messages that they received from the researchers. The participants also followed through with the fast for a median 98% of the prescribed days by fasting for 16 or more hours.

The results showed that after 8 weeks, median Framingham cardiovascular risk declined from 10.9% to 8.6%, a 15% relative reduction (P = .037). Modifiable aspects of Framingham, such as systolic blood pressure, total cholesterol, and high-density lipoprotein, remained relatively consistent overall, however, suggesting variation between individuals in the etiology of the risk decline.

Caloric intake fell by a median of 450 kcal, representing a relative reduction of about 22% (P < .001), they note.

The findings also showed a decline in median derived whole-body fat mass (–0.9 kg; P = .046), body mass (–1.0 kg; P = .025), and mean MRI-derived VAT (–5%; P = .009).

Other data showed that the average BMI remained the same (P = .10).

At the beginning of the study, 68% of the cohort was considered cardiometabolically unhealthy, given the benchmarks for pharmacologic preventive therapy of cardiovascular risk or metabolic syndrome based on Canadian Cardiovascular Society recommendations.

Notably, 53% of the cohort was no longer classified as meeting the criteria for metabolic syndrome or for the therapeutic treatment of cardiovascular risk after the intervention.

The study’s limitations include its short duration, selection bias, and that it did not involve a control group, the researchers acknowledge.

“Randomized controlled trials are needed to confirm these findings and to evaluate the health benefits, including potential health care cost savings and safety of longer-term time-restricted eating,” the researchers conclude.

Dr. Vallakati and Dr. Kirkham report no relevant conflicts of interest.

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

From the Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.

Abstract

Complex cardiac patients are often referred for surgery or palliative care based on the risk of perioperative mortality. This decision ignores factors such as quality of life or duration of life in either surgery or the palliative path. Here, we propose a model to numerically assess and compare the value of surgery vs palliation. This model includes quality and duration of life, as well as risk of perioperative mortality, and involves a patient’s preferences in the decision-making process.

For each pathway, surgery or palliative care, a value is calculated and compared to a normal life value (no disease symptoms and normal life expectancy). The formula is adjusted for the risk of operative mortality. The model produces a ratio of the value of surgery to the value of palliative care that signifies the superiority of one or another. This model calculation presents an objective estimated numerical value to compare the value of surgery and palliative care. It can be applied to every decision-making process before surgery. In general, if a procedure has the potential to significantly extend life in a patient who otherwise has a very short life expectancy with palliation only, performing high-risk surgery would be a reasonable option. A model that provides a numerical value for surgery vs palliative care and includes quality and duration of life in each pathway could be a useful tool for cardiac surgeons in decision making regarding high-risk surgery.

Keywords: high-risk surgery, palliative care, quality of life, life expectancy.

Patients with complex cardiovascular disease are occasionally considered inoperable due to the high risk of surgical mortality. When the risk of perioperative mortality (POM) is predicted to be too high, surgical intervention is denied, and patients are often referred to palliative care. The risk of POM in cardiac surgery is often calculated using large-scale databases, such as the Society of Thoracic Surgeons (STS) records. The STS risk models, which are regularly updated, are based on large data sets and incorporate precise statistical methods for risk adjustment.¹ In general, these calculators provide a percentage value that defines the magnitude of the risk of death, and then an arbitrary range is selected to categorize the procedure as low, medium, or high risk or inoperable status. The STS database does not set a cutoff point or range to define “operability.” Assigning inoperable status to a certain risk rate is problematic, with many ethical, legal, and moral implications, and for this reason, it has mostly remained undefined. In contrast, the low- and medium-risk ranges are easier to define. Another limitation encountered in the STS database is the lack of risk data for less common but very high-risk procedures, such as a triple valve replacement.

A common example where risk classification has been defined is in patients who are candidates for surgical vs transcatheter aortic valve replacement. Some groups have described a risk of <4% as low risk, 4% to 8% as intermediate risk, >8% as high risk, and >15% as inoperable²; for some other groups, a risk of POM >50% is considered extreme risk or inoperable.^3,4 This procedure-specific classification is a useful decision-making tool and helps the surgeon perform an initial risk assessment to allocate a specific patient to a group—operable or nonoperable—only by calculating the risk of surgical death. However, this allocation method does not provide any information on how and when death occurs in either group. These 2 parameters of how and when death occurs define the quality of life (QOL) and the duration of life (DOL), respectively, and together could be considered as the value of life in each pathway. A survivor of a high-risk surgery may benefit from good quality and extended life (a high value), or, on the other end of the spectrum, a high-risk patient who does not undergo surgery is spared the mortality risk of the surgery but dies sooner (low value) with symptoms due to the natural course of the untreated disease.

The central question is, if a surgery is high risk but has the potential of providing a good value (for those who survive it), what QOL and DOL values are acceptable to risk or to justify accepting and proceeding with a risky surgery? Or how high a POM risk is justified to proceed with surgery rather than the alternative palliative care with a certain quality and duration? It is obvious that a decision-making process that is based on POM cannot compare the value of surgery (Vs) and the value of palliation (Vp). Furthermore, it ignores patient preferences and their input, as these are excluded from this decision-making process.

To be able to include QOL and DOL in any decision making, one must precisely describe these parameters. Both QOL and DOL are used for estimation of disease burden by health care administrators, public health experts, insurance agencies, and others. Multiple models have been proposed and used to estimate the overall burden of the disease. Most of the models for this purpose are created for large-scale economic purposes and not for decision making in individual cases.

An important measure is the quality-adjusted life year (QALY). This is an important parameter since it includes both measures of quality and quantity of life.^5,6 QALY is a simplified measure to assess the value of health outcomes, and it has been used in economic calculations to assess mainly the cost-effectiveness of various interventions. We sought to evaluate the utility of a similar method in adding further insight into the surgical decision-making process. In this article, we propose a simple model to compare the value of surgery vs palliative care, similar to QALY. This model includes and adjusts for the quality and the quantity of life, in addition to the risk of POM, in the decision-making process for high-risk patients.

The Model

The 2 decision pathways, surgery and palliative care, are compared for their value. We define the value as the product of QOL and DOL in each pathway and use the severity of the symptoms as a surrogate for QOL. If duration and quality were depicted on the x and y axes of a graph (Figure 1), then the area under the curve would represent the collective value in each situation. Figure 2 shows the timeline and the different pathways with each decision. The value in each situation is calculated in relation to the full value, which is represented as the value of normal life (Vn), that is, life without disease and with normal life expectancy. The values of each decision pathway, the value of surgery (Vs) and the value of palliation (Vp), are then compared to define the benefit for each decision as follows:

If Vs/Vp > 1, the benefit is toward surgery;

If Vs/Vp < 1, the benefit is for palliative care.

Definitions

Both quality and duration of life are presented on a 1-10 scale, 1 being the lowest and 10 the highest value, to yield a product with a value of 100 in normal, disease-free life. Any lower value is presented as a percentage to represent the comparison to the full value. QOL is determined by degradation of full quality with the average level of symptoms. DOL is calculated as a lost time (period of time from death after a specific intervention [surgery or palliation] until death at normal life expectancy) in fraction of full life (death at life expectancy). The Vs is adjusted to exclude the nonsurvivors using the chance of survival (100 – POM risk).

For the DOL under any condition, a 10-year survival rate could be used as a surrogate in this formula. Compared to life expectancy value, using the 10-year survival rate simplifies the calculation since cardiac diseases are more prevalent in older age, close to or beyond the average life expectancy value.

Using the time intervals from the timeline in Figure 2:

dh = time interval from diagnosis to death at life expectancy

dg = time interval from diagnosis to death after successful surgery

df = time interval from diagnosis to death after palliative care

Duration for palliative care:

Duration for surgery:

Adjustment: This value is calculated for those who survive the surgery. To adjust for the POM, it is multiplied by the 100 − POM risk.

Since value is the base for comparison in this model, and it is the product of 2 equally important factors in the formula (severity and duration of symptoms), a factor of 10 was chosen to yield a value of 100, which represents 100% health or absence of symptoms for any duration.

After elimination of normal life expectancy, form the numerator and denominator:

To adjust for surgical outcomes in special circumstances where less than optimal or standard surgical results are expected (eg, in very rare surgeries, limited resource institutions, or suboptimal postoperative surgical care), an optional coefficient R can be added to the numerator (surgical value). This optional coefficient, with values such as 0.8, 0.9 (to degrade the value of surgery) or 1 (standard surgical outcome), adjusts for variability in interinstitutional surgical results or surgeon variability. No coefficient is added to the denominator since palliative care provides minimal differences between clinicians and hospitals. Thus, the final adjusted formula would be as follows:

Example

A 60-year-old patient with a 10% POM risk needs to be allocated to surgical or palliative care. With palliative care, if this patient lived 6 years with average symptoms grade 4, the Vp would be 20; that is, 20% of the normal life value (if he lived 18 years instead without the disease).

Using the formula for calculation of value in each pathway:

With adjustment of 90% survival chance in surgery, 53 × 90% = 48%. In this example, Vs/Vp = 48/20 = 2.4, showing a significant benefit for surgical care. Notably, the unknown value of normal life expectancy is not needed for the calculation of Vs/Vp, since it is the same in both pathways and it is eliminated by calculation in fraction.

Based on this formula, since the duration of surgical symptoms is short, no matter how severe these are, if the potential duration of life after surgery is high (represented by smaller area under the curve in Figure 1), the numerator becomes larger and the value of the surgery grows. For example, if a patient with a 15% risk of POM, which is generally considered inoperable, lives 5 years, as opposed to 2 years with palliative care with mild symptoms (eg 3/10), Vs/Vp would be 2.7, still showing a significant benefit for surgical care.

Discussion

Any surgical intervention is offered with 2 goals in mind, improving QOL and extending DOL. In a high-risk patient, surgery might be declined due to a high risk of POM, and the patient is offered palliative care, which other than providing symptom relief does not change the course of disease and eventually the patient will die due to the untreated disease. In this decision-making method, mostly completed by a care team only, a potential risk of death due to surgery which possibly could cure the patient is traded for immediate survival; however, the symptomatic course ensues until death. This mostly unilateral decision-making process by a care team, which incorporates minimal input from the patient or ignores patient preferences altogether, is based only on POM risk, and roughly includes a single parameter: years of potential life lost (YPLL). YPLL is a measure of premature mortality, and in the setting of surgical intervention, YPLL is the number of years a patient would lose unless a successful surgery were undertaken. Obviously, patients would live longer if a surgery that was intended to save them failed.

In this article, we proposed a simple method to quantify each decision to decide whether to operate or choose surgical care vs palliative care. Since quality and duration of life are both end factors clinicians and patients aspire to in each decision, they can be considered together as the value of each decision. We believe a numerical framework would provide an objective way to assist both the patient at high risk and the care team in the decision-making process.

The 2 parameters we consider are DOL and QOL. DOL, or survival, can be extracted from large-scale data using statistical methods that have been developed to predict survival under various conditions, such as Kaplan-Meier curves. These methods present the chance of survival in percentages in a defined time frame, such as a 5- or 10-year period.

While the DOL is a numerical parameter and quantifiable, the QOL is a more complex entity. This subjective parameter bears multiple definitions, aspects, and categories, and therefore multiple scales for quantification of QOL have been proposed. These scales have been used extensively for the purpose of health determination in health care policy and economic planning. Most scales acknowledge that QOL is multifactorial and includes interrelated aspects such as mental and socioeconomic factors. We have also noticed that QOL is better determined by the palliative care team than surgeons, so including these care providers in the decision-making process might reduce surgeon bias.

Since our purpose here is only to assist with the decision on medical intervention, we focus on physical QOL. Multiple scales are used to assess health-related QOL, such as the Assessment of Quality of Life (AQoL)-8D,⁷ EuroQol-5 Dimension (EQ-5D),⁸ 15D,⁹ and the 36-Item Short Form Survey (SF-36).¹⁰ These complex scales are built for systematic reviews, and they are not practical for a clinical user. To simplify and keep this practical, we define QOL by using the severity or grade of symptoms related to the disease the patient has on a scale of 0 to 10. The severity of symptoms can be easily determined using available scales. An applicable scale for this purpose is the Edmonton Symptom Assessment Scale (ESAS), which has been in use for years and has evolved as a useful tool in the medical field.¹¹

Once DOL and QOL are determined on a 1-10 scale, the multiplied value then provides a product that we consider a value. The highest value hoped for in each decision is the achievement of the best QOL and DOL, a value of 100. In Figure 1, a graphic presentation of value in each decision is best seen as the area under the curve. As shown, a successful surgery, even when accompanied by significant symptoms during initial recovery, has a chance (100 – risk of POM%) to gain a larger area under curve (value) by achieving a longer life with no or fewer symptoms. However, in palliative care, progressing disease and even palliated symptoms with a shorter life expectancy impose a large burden on the patient and a much lower value. Note that in this calculation, life expectancy, which is an important but unpredictable factor, is initially included; however, by ratio comparison, it is eliminated, simplifying the calculation further.

Using this formula in different settings reveals that high-risk surgery has a greater potential to reduce YPLL in the general population. Based on this formula, compared to a surgery with potential to significantly extend DOL, a definite shorter and symptomatic life course with palliative care makes it a significantly less favorable option. In fact, in the cardiovascular field, palliative care has minimal or no effect on natural history, as the mechanism of illness is mechanical, such as occlusion of coronary arteries or valve dysfunction, leading eventually to heart failure and death. In a study by Xu et al, although palliative care reduced readmission rates and improved symptoms on a variety of scales, there was no effect on mortality and QOL in patients with heart failure.¹²

No model in this field has proven to be ideal, and this model bears multiple limitations as well. We have used severity of symptoms as a surrogate for QOL based on the fact that cardiac patients with different pathologies who are untreated will have a common final pathway with development of heart failure symptoms that dictate their QOL. Also, grading QOL is a difficult task at times. Even a model such as QALY, which is one of the most used, is not a perfect model and is not free of problems.⁶ The difference in surgical results and life expectancy between sexes and ethnic groups might be a source of bias in this formula. Also, multiple factors directly and indirectly affect QOL and DOL and create inaccuracies; therefore, making an exact science from an inexact one naturally relies on multiple assumptions. Although it has previously been shown that most POM occurs in a short period of time after cardiac surgery,¹³ long-term complications that potentially degrade QOL are not included in this model. By applying this model, one must assume indefinite economic resources. Moreover, applying a single mathematical model in a biologic system and in the general population has intrinsic shortcomings, and it must overlook many other factors (eg, ethical, legal). For example, it will be hard to justify a failed surgery with 15% risk of POM undertaken to eliminate the severe long-lasting symptoms of a disease, while the outcome of a successful surgery with a 20% risk of POM that adds life and quality would be ignored in the current health care system. Thus, regardless of the significant potential, most surgeons would waive a surgery based solely on the percentage rate of POM, perhaps using other terms such as ”peri-nonoperative mortality.”

Conclusion

We have proposed a simple and practical formula for decision making regarding surgical vs palliative care in high-risk patients. By assigning a value that is composed of QOL and DOL in each pathway and including the risk of POM, a ratio of values provides a numerical estimation that can be used to show preference over a specific decision. An advantage of this formula, in addition to presenting an arithmetic value that is easier to understand, is that it can be used in shared decision making with patients. We emphasize that this model is only a preliminary concept at this time and has not been tested or validated for clinical use. Validation of such a model will require extensive work and testing within a large-scale population. We hope that this article will serve as a starting point for the development of other models, and that this formula will become more sophisticated with fewer limitations through larger multidisciplinary efforts in the future.

Corresponding author: Rabin Gerrah, MD, Good Samaritan Regional Medical Center, 3640 NW Samaritan Drive, Suite 100B, Corvallis, OR 97330; rgerrah@stanford.edu.

Disclosures: None reported.

From the Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.

Abstract

Complex cardiac patients are often referred for surgery or palliative care based on the risk of perioperative mortality. This decision ignores factors such as quality of life or duration of life in either surgery or the palliative path. Here, we propose a model to numerically assess and compare the value of surgery vs palliation. This model includes quality and duration of life, as well as risk of perioperative mortality, and involves a patient’s preferences in the decision-making process.

For each pathway, surgery or palliative care, a value is calculated and compared to a normal life value (no disease symptoms and normal life expectancy). The formula is adjusted for the risk of operative mortality. The model produces a ratio of the value of surgery to the value of palliative care that signifies the superiority of one or another. This model calculation presents an objective estimated numerical value to compare the value of surgery and palliative care. It can be applied to every decision-making process before surgery. In general, if a procedure has the potential to significantly extend life in a patient who otherwise has a very short life expectancy with palliation only, performing high-risk surgery would be a reasonable option. A model that provides a numerical value for surgery vs palliative care and includes quality and duration of life in each pathway could be a useful tool for cardiac surgeons in decision making regarding high-risk surgery.

Keywords: high-risk surgery, palliative care, quality of life, life expectancy.

Patients with complex cardiovascular disease are occasionally considered inoperable due to the high risk of surgical mortality. When the risk of perioperative mortality (POM) is predicted to be too high, surgical intervention is denied, and patients are often referred to palliative care. The risk of POM in cardiac surgery is often calculated using large-scale databases, such as the Society of Thoracic Surgeons (STS) records. The STS risk models, which are regularly updated, are based on large data sets and incorporate precise statistical methods for risk adjustment.¹ In general, these calculators provide a percentage value that defines the magnitude of the risk of death, and then an arbitrary range is selected to categorize the procedure as low, medium, or high risk or inoperable status. The STS database does not set a cutoff point or range to define “operability.” Assigning inoperable status to a certain risk rate is problematic, with many ethical, legal, and moral implications, and for this reason, it has mostly remained undefined. In contrast, the low- and medium-risk ranges are easier to define. Another limitation encountered in the STS database is the lack of risk data for less common but very high-risk procedures, such as a triple valve replacement.

A common example where risk classification has been defined is in patients who are candidates for surgical vs transcatheter aortic valve replacement. Some groups have described a risk of <4% as low risk, 4% to 8% as intermediate risk, >8% as high risk, and >15% as inoperable²; for some other groups, a risk of POM >50% is considered extreme risk or inoperable.^3,4 This procedure-specific classification is a useful decision-making tool and helps the surgeon perform an initial risk assessment to allocate a specific patient to a group—operable or nonoperable—only by calculating the risk of surgical death. However, this allocation method does not provide any information on how and when death occurs in either group. These 2 parameters of how and when death occurs define the quality of life (QOL) and the duration of life (DOL), respectively, and together could be considered as the value of life in each pathway. A survivor of a high-risk surgery may benefit from good quality and extended life (a high value), or, on the other end of the spectrum, a high-risk patient who does not undergo surgery is spared the mortality risk of the surgery but dies sooner (low value) with symptoms due to the natural course of the untreated disease.

The central question is, if a surgery is high risk but has the potential of providing a good value (for those who survive it), what QOL and DOL values are acceptable to risk or to justify accepting and proceeding with a risky surgery? Or how high a POM risk is justified to proceed with surgery rather than the alternative palliative care with a certain quality and duration? It is obvious that a decision-making process that is based on POM cannot compare the value of surgery (Vs) and the value of palliation (Vp). Furthermore, it ignores patient preferences and their input, as these are excluded from this decision-making process.

To be able to include QOL and DOL in any decision making, one must precisely describe these parameters. Both QOL and DOL are used for estimation of disease burden by health care administrators, public health experts, insurance agencies, and others. Multiple models have been proposed and used to estimate the overall burden of the disease. Most of the models for this purpose are created for large-scale economic purposes and not for decision making in individual cases.

An important measure is the quality-adjusted life year (QALY). This is an important parameter since it includes both measures of quality and quantity of life.^5,6 QALY is a simplified measure to assess the value of health outcomes, and it has been used in economic calculations to assess mainly the cost-effectiveness of various interventions. We sought to evaluate the utility of a similar method in adding further insight into the surgical decision-making process. In this article, we propose a simple model to compare the value of surgery vs palliative care, similar to QALY. This model includes and adjusts for the quality and the quantity of life, in addition to the risk of POM, in the decision-making process for high-risk patients.

The Model

The 2 decision pathways, surgery and palliative care, are compared for their value. We define the value as the product of QOL and DOL in each pathway and use the severity of the symptoms as a surrogate for QOL. If duration and quality were depicted on the x and y axes of a graph (Figure 1), then the area under the curve would represent the collective value in each situation. Figure 2 shows the timeline and the different pathways with each decision. The value in each situation is calculated in relation to the full value, which is represented as the value of normal life (Vn), that is, life without disease and with normal life expectancy. The values of each decision pathway, the value of surgery (Vs) and the value of palliation (Vp), are then compared to define the benefit for each decision as follows:

If Vs/Vp > 1, the benefit is toward surgery;

If Vs/Vp < 1, the benefit is for palliative care.

Definitions

Both quality and duration of life are presented on a 1-10 scale, 1 being the lowest and 10 the highest value, to yield a product with a value of 100 in normal, disease-free life. Any lower value is presented as a percentage to represent the comparison to the full value. QOL is determined by degradation of full quality with the average level of symptoms. DOL is calculated as a lost time (period of time from death after a specific intervention [surgery or palliation] until death at normal life expectancy) in fraction of full life (death at life expectancy). The Vs is adjusted to exclude the nonsurvivors using the chance of survival (100 – POM risk).

For the DOL under any condition, a 10-year survival rate could be used as a surrogate in this formula. Compared to life expectancy value, using the 10-year survival rate simplifies the calculation since cardiac diseases are more prevalent in older age, close to or beyond the average life expectancy value.

Using the time intervals from the timeline in Figure 2:

dh = time interval from diagnosis to death at life expectancy

dg = time interval from diagnosis to death after successful surgery

df = time interval from diagnosis to death after palliative care

Duration for palliative care:

Duration for surgery:

Adjustment: This value is calculated for those who survive the surgery. To adjust for the POM, it is multiplied by the 100 − POM risk.

Since value is the base for comparison in this model, and it is the product of 2 equally important factors in the formula (severity and duration of symptoms), a factor of 10 was chosen to yield a value of 100, which represents 100% health or absence of symptoms for any duration.

After elimination of normal life expectancy, form the numerator and denominator:

To adjust for surgical outcomes in special circumstances where less than optimal or standard surgical results are expected (eg, in very rare surgeries, limited resource institutions, or suboptimal postoperative surgical care), an optional coefficient R can be added to the numerator (surgical value). This optional coefficient, with values such as 0.8, 0.9 (to degrade the value of surgery) or 1 (standard surgical outcome), adjusts for variability in interinstitutional surgical results or surgeon variability. No coefficient is added to the denominator since palliative care provides minimal differences between clinicians and hospitals. Thus, the final adjusted formula would be as follows:

Example

A 60-year-old patient with a 10% POM risk needs to be allocated to surgical or palliative care. With palliative care, if this patient lived 6 years with average symptoms grade 4, the Vp would be 20; that is, 20% of the normal life value (if he lived 18 years instead without the disease).

Using the formula for calculation of value in each pathway:

With adjustment of 90% survival chance in surgery, 53 × 90% = 48%. In this example, Vs/Vp = 48/20 = 2.4, showing a significant benefit for surgical care. Notably, the unknown value of normal life expectancy is not needed for the calculation of Vs/Vp, since it is the same in both pathways and it is eliminated by calculation in fraction.

Based on this formula, since the duration of surgical symptoms is short, no matter how severe these are, if the potential duration of life after surgery is high (represented by smaller area under the curve in Figure 1), the numerator becomes larger and the value of the surgery grows. For example, if a patient with a 15% risk of POM, which is generally considered inoperable, lives 5 years, as opposed to 2 years with palliative care with mild symptoms (eg 3/10), Vs/Vp would be 2.7, still showing a significant benefit for surgical care.

Discussion

Any surgical intervention is offered with 2 goals in mind, improving QOL and extending DOL. In a high-risk patient, surgery might be declined due to a high risk of POM, and the patient is offered palliative care, which other than providing symptom relief does not change the course of disease and eventually the patient will die due to the untreated disease. In this decision-making method, mostly completed by a care team only, a potential risk of death due to surgery which possibly could cure the patient is traded for immediate survival; however, the symptomatic course ensues until death. This mostly unilateral decision-making process by a care team, which incorporates minimal input from the patient or ignores patient preferences altogether, is based only on POM risk, and roughly includes a single parameter: years of potential life lost (YPLL). YPLL is a measure of premature mortality, and in the setting of surgical intervention, YPLL is the number of years a patient would lose unless a successful surgery were undertaken. Obviously, patients would live longer if a surgery that was intended to save them failed.

In this article, we proposed a simple method to quantify each decision to decide whether to operate or choose surgical care vs palliative care. Since quality and duration of life are both end factors clinicians and patients aspire to in each decision, they can be considered together as the value of each decision. We believe a numerical framework would provide an objective way to assist both the patient at high risk and the care team in the decision-making process.

The 2 parameters we consider are DOL and QOL. DOL, or survival, can be extracted from large-scale data using statistical methods that have been developed to predict survival under various conditions, such as Kaplan-Meier curves. These methods present the chance of survival in percentages in a defined time frame, such as a 5- or 10-year period.

While the DOL is a numerical parameter and quantifiable, the QOL is a more complex entity. This subjective parameter bears multiple definitions, aspects, and categories, and therefore multiple scales for quantification of QOL have been proposed. These scales have been used extensively for the purpose of health determination in health care policy and economic planning. Most scales acknowledge that QOL is multifactorial and includes interrelated aspects such as mental and socioeconomic factors. We have also noticed that QOL is better determined by the palliative care team than surgeons, so including these care providers in the decision-making process might reduce surgeon bias.

Since our purpose here is only to assist with the decision on medical intervention, we focus on physical QOL. Multiple scales are used to assess health-related QOL, such as the Assessment of Quality of Life (AQoL)-8D,⁷ EuroQol-5 Dimension (EQ-5D),⁸ 15D,⁹ and the 36-Item Short Form Survey (SF-36).¹⁰ These complex scales are built for systematic reviews, and they are not practical for a clinical user. To simplify and keep this practical, we define QOL by using the severity or grade of symptoms related to the disease the patient has on a scale of 0 to 10. The severity of symptoms can be easily determined using available scales. An applicable scale for this purpose is the Edmonton Symptom Assessment Scale (ESAS), which has been in use for years and has evolved as a useful tool in the medical field.¹¹

Once DOL and QOL are determined on a 1-10 scale, the multiplied value then provides a product that we consider a value. The highest value hoped for in each decision is the achievement of the best QOL and DOL, a value of 100. In Figure 1, a graphic presentation of value in each decision is best seen as the area under the curve. As shown, a successful surgery, even when accompanied by significant symptoms during initial recovery, has a chance (100 – risk of POM%) to gain a larger area under curve (value) by achieving a longer life with no or fewer symptoms. However, in palliative care, progressing disease and even palliated symptoms with a shorter life expectancy impose a large burden on the patient and a much lower value. Note that in this calculation, life expectancy, which is an important but unpredictable factor, is initially included; however, by ratio comparison, it is eliminated, simplifying the calculation further.

Using this formula in different settings reveals that high-risk surgery has a greater potential to reduce YPLL in the general population. Based on this formula, compared to a surgery with potential to significantly extend DOL, a definite shorter and symptomatic life course with palliative care makes it a significantly less favorable option. In fact, in the cardiovascular field, palliative care has minimal or no effect on natural history, as the mechanism of illness is mechanical, such as occlusion of coronary arteries or valve dysfunction, leading eventually to heart failure and death. In a study by Xu et al, although palliative care reduced readmission rates and improved symptoms on a variety of scales, there was no effect on mortality and QOL in patients with heart failure.¹²

No model in this field has proven to be ideal, and this model bears multiple limitations as well. We have used severity of symptoms as a surrogate for QOL based on the fact that cardiac patients with different pathologies who are untreated will have a common final pathway with development of heart failure symptoms that dictate their QOL. Also, grading QOL is a difficult task at times. Even a model such as QALY, which is one of the most used, is not a perfect model and is not free of problems.⁶ The difference in surgical results and life expectancy between sexes and ethnic groups might be a source of bias in this formula. Also, multiple factors directly and indirectly affect QOL and DOL and create inaccuracies; therefore, making an exact science from an inexact one naturally relies on multiple assumptions. Although it has previously been shown that most POM occurs in a short period of time after cardiac surgery,¹³ long-term complications that potentially degrade QOL are not included in this model. By applying this model, one must assume indefinite economic resources. Moreover, applying a single mathematical model in a biologic system and in the general population has intrinsic shortcomings, and it must overlook many other factors (eg, ethical, legal). For example, it will be hard to justify a failed surgery with 15% risk of POM undertaken to eliminate the severe long-lasting symptoms of a disease, while the outcome of a successful surgery with a 20% risk of POM that adds life and quality would be ignored in the current health care system. Thus, regardless of the significant potential, most surgeons would waive a surgery based solely on the percentage rate of POM, perhaps using other terms such as ”peri-nonoperative mortality.”

Conclusion

We have proposed a simple and practical formula for decision making regarding surgical vs palliative care in high-risk patients. By assigning a value that is composed of QOL and DOL in each pathway and including the risk of POM, a ratio of values provides a numerical estimation that can be used to show preference over a specific decision. An advantage of this formula, in addition to presenting an arithmetic value that is easier to understand, is that it can be used in shared decision making with patients. We emphasize that this model is only a preliminary concept at this time and has not been tested or validated for clinical use. Validation of such a model will require extensive work and testing within a large-scale population. We hope that this article will serve as a starting point for the development of other models, and that this formula will become more sophisticated with fewer limitations through larger multidisciplinary efforts in the future.

Corresponding author: Rabin Gerrah, MD, Good Samaritan Regional Medical Center, 3640 NW Samaritan Drive, Suite 100B, Corvallis, OR 97330; rgerrah@stanford.edu.

Disclosures: None reported.

From the Department of Cardiothoracic Surgery, Stanford University, Stanford, CA.

Abstract

Complex cardiac patients are often referred for surgery or palliative care based on the risk of perioperative mortality. This decision ignores factors such as quality of life or duration of life in either surgery or the palliative path. Here, we propose a model to numerically assess and compare the value of surgery vs palliation. This model includes quality and duration of life, as well as risk of perioperative mortality, and involves a patient’s preferences in the decision-making process.

For each pathway, surgery or palliative care, a value is calculated and compared to a normal life value (no disease symptoms and normal life expectancy). The formula is adjusted for the risk of operative mortality. The model produces a ratio of the value of surgery to the value of palliative care that signifies the superiority of one or another. This model calculation presents an objective estimated numerical value to compare the value of surgery and palliative care. It can be applied to every decision-making process before surgery. In general, if a procedure has the potential to significantly extend life in a patient who otherwise has a very short life expectancy with palliation only, performing high-risk surgery would be a reasonable option. A model that provides a numerical value for surgery vs palliative care and includes quality and duration of life in each pathway could be a useful tool for cardiac surgeons in decision making regarding high-risk surgery.

Keywords: high-risk surgery, palliative care, quality of life, life expectancy.

Patients with complex cardiovascular disease are occasionally considered inoperable due to the high risk of surgical mortality. When the risk of perioperative mortality (POM) is predicted to be too high, surgical intervention is denied, and patients are often referred to palliative care. The risk of POM in cardiac surgery is often calculated using large-scale databases, such as the Society of Thoracic Surgeons (STS) records. The STS risk models, which are regularly updated, are based on large data sets and incorporate precise statistical methods for risk adjustment.¹ In general, these calculators provide a percentage value that defines the magnitude of the risk of death, and then an arbitrary range is selected to categorize the procedure as low, medium, or high risk or inoperable status. The STS database does not set a cutoff point or range to define “operability.” Assigning inoperable status to a certain risk rate is problematic, with many ethical, legal, and moral implications, and for this reason, it has mostly remained undefined. In contrast, the low- and medium-risk ranges are easier to define. Another limitation encountered in the STS database is the lack of risk data for less common but very high-risk procedures, such as a triple valve replacement.

A common example where risk classification has been defined is in patients who are candidates for surgical vs transcatheter aortic valve replacement. Some groups have described a risk of <4% as low risk, 4% to 8% as intermediate risk, >8% as high risk, and >15% as inoperable²; for some other groups, a risk of POM >50% is considered extreme risk or inoperable.^3,4 This procedure-specific classification is a useful decision-making tool and helps the surgeon perform an initial risk assessment to allocate a specific patient to a group—operable or nonoperable—only by calculating the risk of surgical death. However, this allocation method does not provide any information on how and when death occurs in either group. These 2 parameters of how and when death occurs define the quality of life (QOL) and the duration of life (DOL), respectively, and together could be considered as the value of life in each pathway. A survivor of a high-risk surgery may benefit from good quality and extended life (a high value), or, on the other end of the spectrum, a high-risk patient who does not undergo surgery is spared the mortality risk of the surgery but dies sooner (low value) with symptoms due to the natural course of the untreated disease.

The central question is, if a surgery is high risk but has the potential of providing a good value (for those who survive it), what QOL and DOL values are acceptable to risk or to justify accepting and proceeding with a risky surgery? Or how high a POM risk is justified to proceed with surgery rather than the alternative palliative care with a certain quality and duration? It is obvious that a decision-making process that is based on POM cannot compare the value of surgery (Vs) and the value of palliation (Vp). Furthermore, it ignores patient preferences and their input, as these are excluded from this decision-making process.

To be able to include QOL and DOL in any decision making, one must precisely describe these parameters. Both QOL and DOL are used for estimation of disease burden by health care administrators, public health experts, insurance agencies, and others. Multiple models have been proposed and used to estimate the overall burden of the disease. Most of the models for this purpose are created for large-scale economic purposes and not for decision making in individual cases.

An important measure is the quality-adjusted life year (QALY). This is an important parameter since it includes both measures of quality and quantity of life.^5,6 QALY is a simplified measure to assess the value of health outcomes, and it has been used in economic calculations to assess mainly the cost-effectiveness of various interventions. We sought to evaluate the utility of a similar method in adding further insight into the surgical decision-making process. In this article, we propose a simple model to compare the value of surgery vs palliative care, similar to QALY. This model includes and adjusts for the quality and the quantity of life, in addition to the risk of POM, in the decision-making process for high-risk patients.

The Model

The 2 decision pathways, surgery and palliative care, are compared for their value. We define the value as the product of QOL and DOL in each pathway and use the severity of the symptoms as a surrogate for QOL. If duration and quality were depicted on the x and y axes of a graph (Figure 1), then the area under the curve would represent the collective value in each situation. Figure 2 shows the timeline and the different pathways with each decision. The value in each situation is calculated in relation to the full value, which is represented as the value of normal life (Vn), that is, life without disease and with normal life expectancy. The values of each decision pathway, the value of surgery (Vs) and the value of palliation (Vp), are then compared to define the benefit for each decision as follows:

If Vs/Vp > 1, the benefit is toward surgery;

If Vs/Vp < 1, the benefit is for palliative care.

Definitions

Both quality and duration of life are presented on a 1-10 scale, 1 being the lowest and 10 the highest value, to yield a product with a value of 100 in normal, disease-free life. Any lower value is presented as a percentage to represent the comparison to the full value. QOL is determined by degradation of full quality with the average level of symptoms. DOL is calculated as a lost time (period of time from death after a specific intervention [surgery or palliation] until death at normal life expectancy) in fraction of full life (death at life expectancy). The Vs is adjusted to exclude the nonsurvivors using the chance of survival (100 – POM risk).

For the DOL under any condition, a 10-year survival rate could be used as a surrogate in this formula. Compared to life expectancy value, using the 10-year survival rate simplifies the calculation since cardiac diseases are more prevalent in older age, close to or beyond the average life expectancy value.

Using the time intervals from the timeline in Figure 2:

dh = time interval from diagnosis to death at life expectancy

dg = time interval from diagnosis to death after successful surgery

df = time interval from diagnosis to death after palliative care

Duration for palliative care:

Duration for surgery:

Adjustment: This value is calculated for those who survive the surgery. To adjust for the POM, it is multiplied by the 100 − POM risk.

Since value is the base for comparison in this model, and it is the product of 2 equally important factors in the formula (severity and duration of symptoms), a factor of 10 was chosen to yield a value of 100, which represents 100% health or absence of symptoms for any duration.

After elimination of normal life expectancy, form the numerator and denominator:

To adjust for surgical outcomes in special circumstances where less than optimal or standard surgical results are expected (eg, in very rare surgeries, limited resource institutions, or suboptimal postoperative surgical care), an optional coefficient R can be added to the numerator (surgical value). This optional coefficient, with values such as 0.8, 0.9 (to degrade the value of surgery) or 1 (standard surgical outcome), adjusts for variability in interinstitutional surgical results or surgeon variability. No coefficient is added to the denominator since palliative care provides minimal differences between clinicians and hospitals. Thus, the final adjusted formula would be as follows:

Example

A 60-year-old patient with a 10% POM risk needs to be allocated to surgical or palliative care. With palliative care, if this patient lived 6 years with average symptoms grade 4, the Vp would be 20; that is, 20% of the normal life value (if he lived 18 years instead without the disease).

Using the formula for calculation of value in each pathway:

With adjustment of 90% survival chance in surgery, 53 × 90% = 48%. In this example, Vs/Vp = 48/20 = 2.4, showing a significant benefit for surgical care. Notably, the unknown value of normal life expectancy is not needed for the calculation of Vs/Vp, since it is the same in both pathways and it is eliminated by calculation in fraction.

Based on this formula, since the duration of surgical symptoms is short, no matter how severe these are, if the potential duration of life after surgery is high (represented by smaller area under the curve in Figure 1), the numerator becomes larger and the value of the surgery grows. For example, if a patient with a 15% risk of POM, which is generally considered inoperable, lives 5 years, as opposed to 2 years with palliative care with mild symptoms (eg 3/10), Vs/Vp would be 2.7, still showing a significant benefit for surgical care.

Discussion

Any surgical intervention is offered with 2 goals in mind, improving QOL and extending DOL. In a high-risk patient, surgery might be declined due to a high risk of POM, and the patient is offered palliative care, which other than providing symptom relief does not change the course of disease and eventually the patient will die due to the untreated disease. In this decision-making method, mostly completed by a care team only, a potential risk of death due to surgery which possibly could cure the patient is traded for immediate survival; however, the symptomatic course ensues until death. This mostly unilateral decision-making process by a care team, which incorporates minimal input from the patient or ignores patient preferences altogether, is based only on POM risk, and roughly includes a single parameter: years of potential life lost (YPLL). YPLL is a measure of premature mortality, and in the setting of surgical intervention, YPLL is the number of years a patient would lose unless a successful surgery were undertaken. Obviously, patients would live longer if a surgery that was intended to save them failed.

In this article, we proposed a simple method to quantify each decision to decide whether to operate or choose surgical care vs palliative care. Since quality and duration of life are both end factors clinicians and patients aspire to in each decision, they can be considered together as the value of each decision. We believe a numerical framework would provide an objective way to assist both the patient at high risk and the care team in the decision-making process.

The 2 parameters we consider are DOL and QOL. DOL, or survival, can be extracted from large-scale data using statistical methods that have been developed to predict survival under various conditions, such as Kaplan-Meier curves. These methods present the chance of survival in percentages in a defined time frame, such as a 5- or 10-year period.

While the DOL is a numerical parameter and quantifiable, the QOL is a more complex entity. This subjective parameter bears multiple definitions, aspects, and categories, and therefore multiple scales for quantification of QOL have been proposed. These scales have been used extensively for the purpose of health determination in health care policy and economic planning. Most scales acknowledge that QOL is multifactorial and includes interrelated aspects such as mental and socioeconomic factors. We have also noticed that QOL is better determined by the palliative care team than surgeons, so including these care providers in the decision-making process might reduce surgeon bias.

Since our purpose here is only to assist with the decision on medical intervention, we focus on physical QOL. Multiple scales are used to assess health-related QOL, such as the Assessment of Quality of Life (AQoL)-8D,⁷ EuroQol-5 Dimension (EQ-5D),⁸ 15D,⁹ and the 36-Item Short Form Survey (SF-36).¹⁰ These complex scales are built for systematic reviews, and they are not practical for a clinical user. To simplify and keep this practical, we define QOL by using the severity or grade of symptoms related to the disease the patient has on a scale of 0 to 10. The severity of symptoms can be easily determined using available scales. An applicable scale for this purpose is the Edmonton Symptom Assessment Scale (ESAS), which has been in use for years and has evolved as a useful tool in the medical field.¹¹

Once DOL and QOL are determined on a 1-10 scale, the multiplied value then provides a product that we consider a value. The highest value hoped for in each decision is the achievement of the best QOL and DOL, a value of 100. In Figure 1, a graphic presentation of value in each decision is best seen as the area under the curve. As shown, a successful surgery, even when accompanied by significant symptoms during initial recovery, has a chance (100 – risk of POM%) to gain a larger area under curve (value) by achieving a longer life with no or fewer symptoms. However, in palliative care, progressing disease and even palliated symptoms with a shorter life expectancy impose a large burden on the patient and a much lower value. Note that in this calculation, life expectancy, which is an important but unpredictable factor, is initially included; however, by ratio comparison, it is eliminated, simplifying the calculation further.

Using this formula in different settings reveals that high-risk surgery has a greater potential to reduce YPLL in the general population. Based on this formula, compared to a surgery with potential to significantly extend DOL, a definite shorter and symptomatic life course with palliative care makes it a significantly less favorable option. In fact, in the cardiovascular field, palliative care has minimal or no effect on natural history, as the mechanism of illness is mechanical, such as occlusion of coronary arteries or valve dysfunction, leading eventually to heart failure and death. In a study by Xu et al, although palliative care reduced readmission rates and improved symptoms on a variety of scales, there was no effect on mortality and QOL in patients with heart failure.¹²

No model in this field has proven to be ideal, and this model bears multiple limitations as well. We have used severity of symptoms as a surrogate for QOL based on the fact that cardiac patients with different pathologies who are untreated will have a common final pathway with development of heart failure symptoms that dictate their QOL. Also, grading QOL is a difficult task at times. Even a model such as QALY, which is one of the most used, is not a perfect model and is not free of problems.⁶ The difference in surgical results and life expectancy between sexes and ethnic groups might be a source of bias in this formula. Also, multiple factors directly and indirectly affect QOL and DOL and create inaccuracies; therefore, making an exact science from an inexact one naturally relies on multiple assumptions. Although it has previously been shown that most POM occurs in a short period of time after cardiac surgery,¹³ long-term complications that potentially degrade QOL are not included in this model. By applying this model, one must assume indefinite economic resources. Moreover, applying a single mathematical model in a biologic system and in the general population has intrinsic shortcomings, and it must overlook many other factors (eg, ethical, legal). For example, it will be hard to justify a failed surgery with 15% risk of POM undertaken to eliminate the severe long-lasting symptoms of a disease, while the outcome of a successful surgery with a 20% risk of POM that adds life and quality would be ignored in the current health care system. Thus, regardless of the significant potential, most surgeons would waive a surgery based solely on the percentage rate of POM, perhaps using other terms such as ”peri-nonoperative mortality.”

Conclusion

We have proposed a simple and practical formula for decision making regarding surgical vs palliative care in high-risk patients. By assigning a value that is composed of QOL and DOL in each pathway and including the risk of POM, a ratio of values provides a numerical estimation that can be used to show preference over a specific decision. An advantage of this formula, in addition to presenting an arithmetic value that is easier to understand, is that it can be used in shared decision making with patients. We emphasize that this model is only a preliminary concept at this time and has not been tested or validated for clinical use. Validation of such a model will require extensive work and testing within a large-scale population. We hope that this article will serve as a starting point for the development of other models, and that this formula will become more sophisticated with fewer limitations through larger multidisciplinary efforts in the future.

Corresponding author: Rabin Gerrah, MD, Good Samaritan Regional Medical Center, 3640 NW Samaritan Drive, Suite 100B, Corvallis, OR 97330; rgerrah@stanford.edu.

Disclosures: None reported.

A new study suggests that very high levels of high-density lipoprotein cholesterol (HDL-C) may be associated with higher mortality risk in patients with coronary artery disease (CAD).

Investigators studied close to 10,000 patients with CAD in two separate cohorts. After adjusting for an array of covariates, they found that individuals with HDL-C levels greater than 80 mg/dL had a 96% higher risk for all-cause mortality and a 71% higher risk for cardiovascular mortality than those with HDL-C levels between 40 and 60 mg/dL.

A U-shaped association was found, with higher risk for all-cause and cardiovascular mortality in patients with both very low and very high, compared with midrange, HDL-C values.

“Very high HDL levels are associated with increased risk of adverse outcomes, not lower risk, as previously thought. This is true not only in the general population, but also in people with known coronary artery disease,” senior author Arshed A. Quyyumi, MD, professor of medicine, division of cardiology, Emory University, Atlanta, told this news organization.

“Physicians have to be cognizant of the fact that, at levels of HDL-C above 80 mg/dL, they [should be] more aggressive with risk reduction and not believe that the patient is at ‘low risk’ because of high levels of ‘good’ cholesterol,” said Dr. Quyyumi, director of the Emory Clinical Cardiovascular Research Institute.

The study was published online in JAMA Cardiology.
 

Inverse association?

HDL-C levels have “historically been inversely associated with increased cardiovascular disease (CVD) risk; however, recent studies have questioned the efficacy of therapies designed to increase HDL-C levels,” the authors wrote. Moreover, genetic variants associated with HDL-C have not been found to be linked to CVD risk.

Whether “very high HDL-C levels in patients with coronary artery disease (CAD) are associated with mortality risk remains unknown,” they wrote. In this study, the researchers investigated not only the potential risk of elevated HDL-C levels in these patients, but also the association of known HDL-C genetic variants with this risk.

To do so, they analyzed data from a subset of patients with CAD in two independent study groups: the UK Biobank (UKB; n = 14,478; mean [standard deviation] age, 61.2 [5.8] years; 76.2% male; 93.8% White) and the Emory Cardiovascular Biobank (EmCAB; n = 5,467; mean age, 63.8 [12.3] years; 66.4% male; 73.2% White). Participants were followed prospectively for a median of 8.9 (interquartile range, 8.0-9.7) years and 6.7 (IQR, 4.0-10.8) years, respectively.

Additional data collected included medical and medication history and demographic characteristics, which were used as covariates, as well as genomic information.

Of the UKB cohort, 12.4% and 7.9% sustained all-cause or cardiovascular death, respectively, during the follow-up period, and 1.8% of participants had an HDL-C level above 80 mg/dL.

Among these participants with very high HDL-C levels, 16.9% and 8.6% had all-cause or cardiovascular death, respectively. Compared with the reference category (HDL-C level of 40-60 mg/dL), those with low HDL-C levels (≤ 30 mg/dL) had an expected higher risk for both all-cause and cardiovascular mortality, even after adjustment for covariates (hazard ratio, 1.33; 95% confidence interval, 1.07-1.64 and HR, 1.42; 95% CI, 1.09-1.85, respectively; P = .009).

“Importantly,” the authors stated, “compared with the reference category, individuals with very high HDL-C levels (>80 mg/dL) also had a higher risk of all-cause death (HR, 1.58 [1.16-2.14], P = .004).”

Although cardiovascular death rates were not significantly greater in unadjusted analyses, after adjustment, the highest HDL-C group had an increased risk for all-cause and cardiovascular death (HR, 1.96; 95% CI, 1.42-2.71; P < .001 and HR, 1.71; 95% CI, 1.09-2.68, respectively; P = .02).

Compared with females, males with HDL-C levels above 80 mg/dL had a higher risk for all-cause and cardiovascular death.

Red flag

Commenting for this news organization, Sadiya Sana Khan, MD, MSc, assistant professor of medicine (cardiology) and preventive medicine (epidemiology), Northwestern University, Chicago, said: “I think the most important point [of the study] is to identify people with very high HDL-C. This can serve as a reminder to discuss heart-healthy lifestyles and discussion of statin therapy if needed, based on LDL-C.”

In an accompanying editorial coauthored with Gregg Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, the pair wrote: “Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective.”

They advised clinicians to “use HDL-C levels as a surrogate marker, with very low and very high levels as a red flag to target for more intensive primary and secondary prevention, as the maxim for HDL-C as ‘good’ cholesterol only holds for HDL-C levels of 80 mg/dL or less.”

This study was supported in part by grants from the National Institutes of Health, the American Heart Association, and the Abraham J. & Phyllis Katz Foundation. Dr. Quyyumi and coauthors report no relevant financial relationships. Dr. Khan reports receiving grants from the American Heart Association and the National Institutes of Health outside the submitted work. Dr. Fonarow reports receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis outside the submitted work. No other disclosures were reported.

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

A new study suggests that very high levels of high-density lipoprotein cholesterol (HDL-C) may be associated with higher mortality risk in patients with coronary artery disease (CAD).

Investigators studied close to 10,000 patients with CAD in two separate cohorts. After adjusting for an array of covariates, they found that individuals with HDL-C levels greater than 80 mg/dL had a 96% higher risk for all-cause mortality and a 71% higher risk for cardiovascular mortality than those with HDL-C levels between 40 and 60 mg/dL.

A U-shaped association was found, with higher risk for all-cause and cardiovascular mortality in patients with both very low and very high, compared with midrange, HDL-C values.

“Very high HDL levels are associated with increased risk of adverse outcomes, not lower risk, as previously thought. This is true not only in the general population, but also in people with known coronary artery disease,” senior author Arshed A. Quyyumi, MD, professor of medicine, division of cardiology, Emory University, Atlanta, told this news organization.

“Physicians have to be cognizant of the fact that, at levels of HDL-C above 80 mg/dL, they [should be] more aggressive with risk reduction and not believe that the patient is at ‘low risk’ because of high levels of ‘good’ cholesterol,” said Dr. Quyyumi, director of the Emory Clinical Cardiovascular Research Institute.

The study was published online in JAMA Cardiology.
 

Inverse association?

HDL-C levels have “historically been inversely associated with increased cardiovascular disease (CVD) risk; however, recent studies have questioned the efficacy of therapies designed to increase HDL-C levels,” the authors wrote. Moreover, genetic variants associated with HDL-C have not been found to be linked to CVD risk.

Whether “very high HDL-C levels in patients with coronary artery disease (CAD) are associated with mortality risk remains unknown,” they wrote. In this study, the researchers investigated not only the potential risk of elevated HDL-C levels in these patients, but also the association of known HDL-C genetic variants with this risk.

To do so, they analyzed data from a subset of patients with CAD in two independent study groups: the UK Biobank (UKB; n = 14,478; mean [standard deviation] age, 61.2 [5.8] years; 76.2% male; 93.8% White) and the Emory Cardiovascular Biobank (EmCAB; n = 5,467; mean age, 63.8 [12.3] years; 66.4% male; 73.2% White). Participants were followed prospectively for a median of 8.9 (interquartile range, 8.0-9.7) years and 6.7 (IQR, 4.0-10.8) years, respectively.

Additional data collected included medical and medication history and demographic characteristics, which were used as covariates, as well as genomic information.

Of the UKB cohort, 12.4% and 7.9% sustained all-cause or cardiovascular death, respectively, during the follow-up period, and 1.8% of participants had an HDL-C level above 80 mg/dL.

Among these participants with very high HDL-C levels, 16.9% and 8.6% had all-cause or cardiovascular death, respectively. Compared with the reference category (HDL-C level of 40-60 mg/dL), those with low HDL-C levels (≤ 30 mg/dL) had an expected higher risk for both all-cause and cardiovascular mortality, even after adjustment for covariates (hazard ratio, 1.33; 95% confidence interval, 1.07-1.64 and HR, 1.42; 95% CI, 1.09-1.85, respectively; P = .009).

“Importantly,” the authors stated, “compared with the reference category, individuals with very high HDL-C levels (>80 mg/dL) also had a higher risk of all-cause death (HR, 1.58 [1.16-2.14], P = .004).”

Although cardiovascular death rates were not significantly greater in unadjusted analyses, after adjustment, the highest HDL-C group had an increased risk for all-cause and cardiovascular death (HR, 1.96; 95% CI, 1.42-2.71; P < .001 and HR, 1.71; 95% CI, 1.09-2.68, respectively; P = .02).

Compared with females, males with HDL-C levels above 80 mg/dL had a higher risk for all-cause and cardiovascular death.

Red flag

Commenting for this news organization, Sadiya Sana Khan, MD, MSc, assistant professor of medicine (cardiology) and preventive medicine (epidemiology), Northwestern University, Chicago, said: “I think the most important point [of the study] is to identify people with very high HDL-C. This can serve as a reminder to discuss heart-healthy lifestyles and discussion of statin therapy if needed, based on LDL-C.”

In an accompanying editorial coauthored with Gregg Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, the pair wrote: “Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective.”

They advised clinicians to “use HDL-C levels as a surrogate marker, with very low and very high levels as a red flag to target for more intensive primary and secondary prevention, as the maxim for HDL-C as ‘good’ cholesterol only holds for HDL-C levels of 80 mg/dL or less.”

This study was supported in part by grants from the National Institutes of Health, the American Heart Association, and the Abraham J. & Phyllis Katz Foundation. Dr. Quyyumi and coauthors report no relevant financial relationships. Dr. Khan reports receiving grants from the American Heart Association and the National Institutes of Health outside the submitted work. Dr. Fonarow reports receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis outside the submitted work. No other disclosures were reported.

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

A new study suggests that very high levels of high-density lipoprotein cholesterol (HDL-C) may be associated with higher mortality risk in patients with coronary artery disease (CAD).

Investigators studied close to 10,000 patients with CAD in two separate cohorts. After adjusting for an array of covariates, they found that individuals with HDL-C levels greater than 80 mg/dL had a 96% higher risk for all-cause mortality and a 71% higher risk for cardiovascular mortality than those with HDL-C levels between 40 and 60 mg/dL.

A U-shaped association was found, with higher risk for all-cause and cardiovascular mortality in patients with both very low and very high, compared with midrange, HDL-C values.

“Very high HDL levels are associated with increased risk of adverse outcomes, not lower risk, as previously thought. This is true not only in the general population, but also in people with known coronary artery disease,” senior author Arshed A. Quyyumi, MD, professor of medicine, division of cardiology, Emory University, Atlanta, told this news organization.

“Physicians have to be cognizant of the fact that, at levels of HDL-C above 80 mg/dL, they [should be] more aggressive with risk reduction and not believe that the patient is at ‘low risk’ because of high levels of ‘good’ cholesterol,” said Dr. Quyyumi, director of the Emory Clinical Cardiovascular Research Institute.

The study was published online in JAMA Cardiology.
 

Inverse association?

HDL-C levels have “historically been inversely associated with increased cardiovascular disease (CVD) risk; however, recent studies have questioned the efficacy of therapies designed to increase HDL-C levels,” the authors wrote. Moreover, genetic variants associated with HDL-C have not been found to be linked to CVD risk.

Whether “very high HDL-C levels in patients with coronary artery disease (CAD) are associated with mortality risk remains unknown,” they wrote. In this study, the researchers investigated not only the potential risk of elevated HDL-C levels in these patients, but also the association of known HDL-C genetic variants with this risk.

To do so, they analyzed data from a subset of patients with CAD in two independent study groups: the UK Biobank (UKB; n = 14,478; mean [standard deviation] age, 61.2 [5.8] years; 76.2% male; 93.8% White) and the Emory Cardiovascular Biobank (EmCAB; n = 5,467; mean age, 63.8 [12.3] years; 66.4% male; 73.2% White). Participants were followed prospectively for a median of 8.9 (interquartile range, 8.0-9.7) years and 6.7 (IQR, 4.0-10.8) years, respectively.

Additional data collected included medical and medication history and demographic characteristics, which were used as covariates, as well as genomic information.

Of the UKB cohort, 12.4% and 7.9% sustained all-cause or cardiovascular death, respectively, during the follow-up period, and 1.8% of participants had an HDL-C level above 80 mg/dL.

Among these participants with very high HDL-C levels, 16.9% and 8.6% had all-cause or cardiovascular death, respectively. Compared with the reference category (HDL-C level of 40-60 mg/dL), those with low HDL-C levels (≤ 30 mg/dL) had an expected higher risk for both all-cause and cardiovascular mortality, even after adjustment for covariates (hazard ratio, 1.33; 95% confidence interval, 1.07-1.64 and HR, 1.42; 95% CI, 1.09-1.85, respectively; P = .009).

“Importantly,” the authors stated, “compared with the reference category, individuals with very high HDL-C levels (>80 mg/dL) also had a higher risk of all-cause death (HR, 1.58 [1.16-2.14], P = .004).”

Although cardiovascular death rates were not significantly greater in unadjusted analyses, after adjustment, the highest HDL-C group had an increased risk for all-cause and cardiovascular death (HR, 1.96; 95% CI, 1.42-2.71; P < .001 and HR, 1.71; 95% CI, 1.09-2.68, respectively; P = .02).

Compared with females, males with HDL-C levels above 80 mg/dL had a higher risk for all-cause and cardiovascular death.

Red flag

Commenting for this news organization, Sadiya Sana Khan, MD, MSc, assistant professor of medicine (cardiology) and preventive medicine (epidemiology), Northwestern University, Chicago, said: “I think the most important point [of the study] is to identify people with very high HDL-C. This can serve as a reminder to discuss heart-healthy lifestyles and discussion of statin therapy if needed, based on LDL-C.”

In an accompanying editorial coauthored with Gregg Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, University of California, Los Angeles, the pair wrote: “Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective.”

They advised clinicians to “use HDL-C levels as a surrogate marker, with very low and very high levels as a red flag to target for more intensive primary and secondary prevention, as the maxim for HDL-C as ‘good’ cholesterol only holds for HDL-C levels of 80 mg/dL or less.”

This study was supported in part by grants from the National Institutes of Health, the American Heart Association, and the Abraham J. & Phyllis Katz Foundation. Dr. Quyyumi and coauthors report no relevant financial relationships. Dr. Khan reports receiving grants from the American Heart Association and the National Institutes of Health outside the submitted work. Dr. Fonarow reports receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis outside the submitted work. No other disclosures were reported.

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