MDedge Cardiology

Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.

Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.

The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).

Floaria Bicher/iStock/Getty Images Plus

In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.

The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).

This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.

The study was published in the Journal of the American College of Cardiology.
 

Evolving understanding

The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.

Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.

In general, the MIS-A– patients were sicker and had worse outcomes.

Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.

MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.

Immunologic differences

The immunologic profiles of these two distinct clinical phenotypes also differed.

In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.

In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.

“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”

The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.

The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.

MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.

They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.

Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.

The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”

Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.

“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.

“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.

“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.

This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.

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

Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.

Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.

The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).

Floaria Bicher/iStock/Getty Images Plus

In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.

The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).

This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.

The study was published in the Journal of the American College of Cardiology.
 

Evolving understanding

The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.

Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.

In general, the MIS-A– patients were sicker and had worse outcomes.

Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.

MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.

Immunologic differences

The immunologic profiles of these two distinct clinical phenotypes also differed.

In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.

In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.

“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”

The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.

The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.

MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.

They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.

Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.

The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”

Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.

“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.

“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.

“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.

This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.

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

Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.

Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.

The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).

Floaria Bicher/iStock/Getty Images Plus

In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.

The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).

This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.

The study was published in the Journal of the American College of Cardiology.
 

Evolving understanding

The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.

Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.

In general, the MIS-A– patients were sicker and had worse outcomes.

Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.

MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.

Immunologic differences

The immunologic profiles of these two distinct clinical phenotypes also differed.

In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.

In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.

“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”

The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.

The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.

MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.

They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.

Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.

The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”

Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.

“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.

“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.

“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.

This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.

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

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

Vishnu Kumar/Thinkstock

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

Vishnu Kumar/Thinkstock

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

Adults with hypertension who were vaccinated for COVID-19 with at least one booster were more than twice as likely as vaccinated and boosted individuals without hypertension to be hospitalized for severe COVID-19, according to data from more than 900 individuals.

“We were surprised to learn that many people who were hospitalized with COVID-19 had hypertension and no other risk factors,” said Susan Cheng, MD, MPH, director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, Los Angeles, and a senior author of the study. “This is concerning when you consider that almost half of American adults have high blood pressure.”

Vishnu Kumar/Thinkstock

COVID-19 vaccines demonstrated ability to reduce death and some of the most severe side effects from the infection in the early stages of the pandemic. Although the Omicron surge prompted recommendations for a third mRNA vaccine dose, “a proportion of individuals who received three mRNA vaccine doses still required hospitalization for COVID-19 during the Omicron surge,” and the characteristics associated with severe illness in vaccinated and boosted patients have not been explored, Joseph Ebinger, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues wrote.

Previous research has shown an association between high blood pressure an increased risk for developing severe COVID-19 compared to several other chronic health conditions, including kidney disease, type 2 diabetes, chronic obstructive pulmonary disease, and heart failure, the researchers noted.

In a study published in Hypertension, the researchers identified 912 adults who received at least three doses of mRNA COVID-19 vaccine and were later diagnosed with COVID-19 during the surge in infections from the Omicron variant between December 2021 and April 2022.

A total of 145 of the individuals were hospitalized (16%); of these, 125 (86%) had hypertension.

Patients with hypertension were the most likely to be hospitalized, with an odds ratio of 2.9. In addition to high blood pressure, factors including older age (OR, 1.3), chronic kidney disease (OR, 2.2), prior myocardial infarction or heart failure (OR, 2.2), and longer time since the last vaccination and COVID-19 infection were associated with increased risk of hospitalization in a multivariate analysis.

However, the increased risk of severe illness and hospitalization associated with high blood pressure persisted, with an OR of 2.6, in the absence of comorbid conditions such as type 2 diabetes, kidney disease, and heart failure, the researchers emphasized.

“Although the mechanism for hypertension-associated COVID-19 risk remains unclear, prior studies have identified delayed SARS-CoV-2 viral clearance and prolonged inflammatory response among hypertensive patients, which may contribute to greater disease severity,” they wrote.

The findings were limited by several factors, including the use of data from a single center and lack of information on which Omicron variants and subvariants were behind the infections, the researchers noted.

However, the results highlight the need for more research on how to reduce the risks of severe COVID-19 in vulnerable populations, and on the mechanism for a potential connection between high blood pressure and severe COVID-19, they said.

Given the high prevalence of hypertension worldwide, increased understanding of the hypertension-specific risks and identification of individual and population-level risk reduction strategies will be important to the transition of COVID-19 from pandemic to endemic, they concluded.
 

Omicron changes the game

“When the pandemic initially started, many conditions were seen to increase risk for more severe COVID illness, and hypertension was one of those factors – and then things changed,” lead author Dr. Ebinger said in an interview. “First, vaccines arrived on the scene and substantially reduced risk of severe COVID for everyone who received them. Second, Omicron arrived and, while more transmissible, this variant has been less likely to cause severe COVID. On the one hand, we have vaccines and boosters that we want to think of as ‘the great equalizer’ when it comes to preexisting conditions. On the other hand, we have a dominant set of SARS-CoV-2 subvariants that seem less virulent in most people.

“Taken together, we have been hoping and even assuming that we have been doing pretty well with minimizing risks. Unfortunately, our study results indicate this is not exactly the case,” he said.

“Although vaccines and boosters appear to have equalized or minimized the risks of severe COVID for some people, this has not happened for others – even in the setting of the milder Omicron variant. Of individuals who were fully vaccinated and boosted, having hypertension increased the odds of needing to be hospitalized after getting infected with Omicron by 2.6-fold, even when accounting for or in the absence of having any major chronic disease that might otherwise predispose to more severe COVID-19 illness,” Dr. Ebinger added.

“So, while the originally seen risks of having obesity or diabetes seem to have been minimized during this current era of pandemic, the risk of having hypertension has persisted. We found this both surprising and concerning, because hypertension is very common and present in over half of people over age 50.”

Surprisingly, “we found that a fair number of people, even after being fully vaccinated plus a having gotten a booster, will not only catch Omicron but get sick enough to need hospital care,” Dr. Ebinger emphasized. “Moreover, it is not just older adults with major comorbid conditions who are vulnerable. Our data show that this can happen to an adult of any age and especially if a person has only hypertension and otherwise no major chronic disease.”

The first takeaway message for clinicians at this time is to raise awareness, Dr. Ebinger stressed in the interview. “We need to raise understanding around the fact that receiving three doses of vaccine may not prevent severe COVID-19 illness in everyone, even when the circulating viral variant is presumed to be causing only mild disease in most people. Moreover, the people who are most at risk are not whom we might think they are. They are not the sickest of the sick. They include people who might not have major conditions such as heart disease or kidney disease, but they do have hypertension.”

Second, “we need more research to understand out why there is this link between hypertension and excess risk for the more severe forms of COVID-19, despite it arising from a supposedly milder variant,” said Dr. Ebinger.

“Third, we need to determine how to reduce these risks, whether through more tailored vaccine regimens or novel therapeutics or a combination approach,” he said.

Looking ahead, “the biological mechanism underpinning the association between hypertension and severe COVID-19 remains underexplored. Future work should focus on understanding the factors linking hypertension to severe COVID-19, as this may elucidate both information on how SARS-CoV-2 effects the body and potential targets for intervention,” Dr. Ebinger added.

The study was supported in part by Cedars-Sinai Medical Center, the Erika J. Glazer Family Foundation and the National Institutes of Health. The researchers had no financial conflicts to disclose.

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.

Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.

The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.

“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
 

SWIFT-DIRECT

SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.

Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).

With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).

“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.

“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.

There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).

Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
 

DIRECT-SAFE

DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.

Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).

Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.

“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.

“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.

To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.

Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.

Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.

SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

Wide variation in the cost of common cardiovascular (CV) tests and procedures, from stress tests to coronary interventions, was revealed in a cross-sectional analysis based on publicly available data from 20 top-ranked hospitals in the United States.

The analysis also suggested a low level of compliance with the 2021 Hospital Price Transparency Final Rule among the 20 centers.

“The variation we found in payer-negotiated prices for identical cardiovascular tests and procedures was stunning,” Rishi K. Wadhera, MD, MPP, MPhil, Beth Israel Deaconess Medical Center, Boston, told this news organization.

KatarzynaBialasiewicz/Thinkstock

Difficulties with data, interpretation

The researchers looked at payer and self-pay cash prices for noninvasive and invasive CV tests and procedures at the U.S. News & World Report 2021 top 20–ranked U.S. hospitals, based in part on Current Procedural Terminology codes.

Price differences among the hospitals were derived from median negotiated prices for each test and procedure at the centers across all payers. The interquartile ratio (IQR) of prices for each test or procedure across payers was used to evaluate within-hospital price variation.

“Only 80% of the hospitals reported prices for some cardiovascular tests and procedures,” Dr. Wadhera said. “For the most part, even among the hospitals that did report this information, it was extremely challenging to navigate and interpret the data provided.”

Further, the team found that only 7 of the 20 hospitals reported prices for all CV tests and procedures. Centers that did not post prices for some tests or procedures are named in the report’s Figure 1 and Figure 2.

The number of insurance plans listed for each test or procedure ranged from 1 to 432 in the analysis. Median prices ranged from $204 to $2,588 for an echocardiogram, $463 to $3,230 for a stress test, $2,821 to $9,382 for right heart catheterization, $2,868 to $9,203 for a coronary angiogram, $657 to $25,521 for a PCI, and $506 to $20,002 for pacemaker implantation, the report states.

A similar pattern was seen for self-pay cash prices.

Within-hospital variation also ranged broadly. For example, the widest IQR ranges were $3,143-$12,926 for a right heart catheterization, $4,011-$14,486 for a coronary angiogram, $11,325-$23,392 for a PCI, and $8,474-$22,694 for pacemaker implantation.

The report cites a number of limitations to the analysis, among those, the need to rely on the hospitals themselves for data quality and accuracy.
 

‘More needed besides transparency’

“As a means to better understand health care costs, many opined that full price transparency would leverage market dynamics and result in lower costs,” observed Clyde W. Yancy, MD, MSc, professor of medicine and chief of cardiology at Northwestern Medicine, Chicago. The findings “by an expert group of outcomes scientists make clear that more is needed besides price transparency to lower cost,” he said in an interview.

That said, he added, “there are sufficient variations and allowances made for data collection that it is preferable to hold the current findings circumspect at best. Importantly, the voice of the hospitals does not appear.”

Although “price variation among the top 20 hospitals is substantial,” he observed, “without a better assessment of root cause, actual charge capture, prevailing market dynamics – especially nursing and ancillary staff costs – and the general influence of inflation, it is too difficult to emerge with a precise interpretation.”

Across the 20 hospitals, “there are likely to be 20 different business models,” he added, with negotiated prices reflecting “at least regional, if not institutional, variations.”

“These are complex issues. The several-fold price differences in standard procedures are a concern and an area worth further study with the intention of lowering health care costs,” Dr. Yancy said. “But clearly our next efforts should not address lowering prices per se but understanding how prices are set [and] the connection with reimbursement and actual payments.”

Dr. Wadhera discloses receiving personal fees from Abbott and CVS Health unrelated to the current study; disclosures for the other authors are in the report. Dr. Yancy is deputy editor of JAMA Cardiology.

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

A U.S. study describes the immune response to COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurologic symptoms.

It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
 

Brain tissue autopsy

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.

As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
 

Neurologic symptoms’ molecular basis

Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.

These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.

Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
 

‘Brain fog’ explained?

The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.

“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”

The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.

This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.

A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.

A U.S. study describes the immune response to COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurologic symptoms.

It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
 

Brain tissue autopsy

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.

As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
 

Neurologic symptoms’ molecular basis

Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.

These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.

Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
 

‘Brain fog’ explained?

The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.

“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”

The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.

This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.

A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.

A U.S. study describes the immune response to COVID-19 infection that damages the brain’s blood vessels and may lead to short- and long-term neurologic symptoms.

It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
 

Brain tissue autopsy

“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”

In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.

As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
 

Neurologic symptoms’ molecular basis

Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.

These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.

“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”

Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.

Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
 

‘Brain fog’ explained?

The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.

“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”

The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.

This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.

A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.

U.S. children appear to be failing an important test – of their hearts, not minds.

New research from the Ann & Robert H. Lurie Children’s Hospital of Chicago shows that heart health is a concern for many long before adulthood because fewer than one-third of children aged 2-19 years scored highly on the American Heart Association’s checklist for ideal cardiovascular fitness.

“This study gives us a new baseline for children’s heart health in the United States,” said Amanda Perak, MD, pediatric cardiologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and a coauthor of the study.

Dr. Perak and colleagues published their findings in the journal Circulation.

The researchers identified 9888 children who completed the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey between 2013 and 2018. They analyzed the available data using the AHA’s Life’s Essential 8 – a 100-point assessment of eight predictors for measuring heart health, including sleep, nicotine exposure, and blood glucose.

Data for only three metrics were available for all children in the study: diet, physical activity, and body mass index. As children aged, more metrics were averaged to obtain the overall cardiovascular health score. For instance, cholesterol/lipid levels become available at age 6 years, and blood pressure can be measured starting at age 8 years.

Only 2.2% of children in the study had optimal heart health, according to the Life’s Essential 8 scoring system, which spans poor (0-49), moderate (50-79), and high (80-100). Fewer than one in three (29.1%) overall had high scores, and scores worsened with age.

In the 2- to 5-year age group, over half (56.5%) of the children had good heart health. However, only one-third (33.5%) of 6- to 11-year-olds scored highly. Meanwhile, only 14% of adolescents had good heart scores, Dr. Perak’s group found.

Heart health scores based on diet were lowest for every age group. In the youngest age group, the average cardiovascular health (CVH) score was about 61. In the 12- to 19-year age group, however, the average CVH score decreased to 28.5, the lowest measured score for any group in the study.

With such worrisome diet scores for the 12- to 19-year-old group, public health policies need to focus on changes, like removing sugar-sweetened beverage options from schools, according to Joseph Mahgerefteh, MD, director of preventive cardiology at the Mount Sinai Kravis Children’s Heart Center, New York. He added that parents and their children also have a role to play.

“Some of our teenagers forget they can drink water when they are thirsty, and it is not necessary to drink sugar-sweetened beverages for thirst,” Dr. Mahgerefteh, who was not involved in the study, said in an interview. “Fresh vegetable intake is so low to a degree that some of our patients refuse to have any type of vegetable in their diet.”

“As a physician community caring for these patients, we need to be much more aggressive with our counseling and referral of these patients,” added Barry Love, MD, director of the congenital cardiac catheterization program at the Mount Sinai Kravis Children’s Heart Center. “These youngsters will inevitably encounter the effect of these conditions – coronary artery disease and stroke – at a much earlier adult age.”

Dr. Perak, Dr. Mahgerefteh, and Dr. Love reported no relevant financial conflicts of interest.

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

U.S. children appear to be failing an important test – of their hearts, not minds.

New research from the Ann & Robert H. Lurie Children’s Hospital of Chicago shows that heart health is a concern for many long before adulthood because fewer than one-third of children aged 2-19 years scored highly on the American Heart Association’s checklist for ideal cardiovascular fitness.

“This study gives us a new baseline for children’s heart health in the United States,” said Amanda Perak, MD, pediatric cardiologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and a coauthor of the study.

Dr. Perak and colleagues published their findings in the journal Circulation.

The researchers identified 9888 children who completed the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey between 2013 and 2018. They analyzed the available data using the AHA’s Life’s Essential 8 – a 100-point assessment of eight predictors for measuring heart health, including sleep, nicotine exposure, and blood glucose.

Data for only three metrics were available for all children in the study: diet, physical activity, and body mass index. As children aged, more metrics were averaged to obtain the overall cardiovascular health score. For instance, cholesterol/lipid levels become available at age 6 years, and blood pressure can be measured starting at age 8 years.

Only 2.2% of children in the study had optimal heart health, according to the Life’s Essential 8 scoring system, which spans poor (0-49), moderate (50-79), and high (80-100). Fewer than one in three (29.1%) overall had high scores, and scores worsened with age.

In the 2- to 5-year age group, over half (56.5%) of the children had good heart health. However, only one-third (33.5%) of 6- to 11-year-olds scored highly. Meanwhile, only 14% of adolescents had good heart scores, Dr. Perak’s group found.

Heart health scores based on diet were lowest for every age group. In the youngest age group, the average cardiovascular health (CVH) score was about 61. In the 12- to 19-year age group, however, the average CVH score decreased to 28.5, the lowest measured score for any group in the study.

With such worrisome diet scores for the 12- to 19-year-old group, public health policies need to focus on changes, like removing sugar-sweetened beverage options from schools, according to Joseph Mahgerefteh, MD, director of preventive cardiology at the Mount Sinai Kravis Children’s Heart Center, New York. He added that parents and their children also have a role to play.

“Some of our teenagers forget they can drink water when they are thirsty, and it is not necessary to drink sugar-sweetened beverages for thirst,” Dr. Mahgerefteh, who was not involved in the study, said in an interview. “Fresh vegetable intake is so low to a degree that some of our patients refuse to have any type of vegetable in their diet.”

“As a physician community caring for these patients, we need to be much more aggressive with our counseling and referral of these patients,” added Barry Love, MD, director of the congenital cardiac catheterization program at the Mount Sinai Kravis Children’s Heart Center. “These youngsters will inevitably encounter the effect of these conditions – coronary artery disease and stroke – at a much earlier adult age.”

Dr. Perak, Dr. Mahgerefteh, and Dr. Love reported no relevant financial conflicts of interest.

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

U.S. children appear to be failing an important test – of their hearts, not minds.

New research from the Ann & Robert H. Lurie Children’s Hospital of Chicago shows that heart health is a concern for many long before adulthood because fewer than one-third of children aged 2-19 years scored highly on the American Heart Association’s checklist for ideal cardiovascular fitness.

“This study gives us a new baseline for children’s heart health in the United States,” said Amanda Perak, MD, pediatric cardiologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and a coauthor of the study.

Dr. Perak and colleagues published their findings in the journal Circulation.

The researchers identified 9888 children who completed the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey between 2013 and 2018. They analyzed the available data using the AHA’s Life’s Essential 8 – a 100-point assessment of eight predictors for measuring heart health, including sleep, nicotine exposure, and blood glucose.

Data for only three metrics were available for all children in the study: diet, physical activity, and body mass index. As children aged, more metrics were averaged to obtain the overall cardiovascular health score. For instance, cholesterol/lipid levels become available at age 6 years, and blood pressure can be measured starting at age 8 years.

Only 2.2% of children in the study had optimal heart health, according to the Life’s Essential 8 scoring system, which spans poor (0-49), moderate (50-79), and high (80-100). Fewer than one in three (29.1%) overall had high scores, and scores worsened with age.

In the 2- to 5-year age group, over half (56.5%) of the children had good heart health. However, only one-third (33.5%) of 6- to 11-year-olds scored highly. Meanwhile, only 14% of adolescents had good heart scores, Dr. Perak’s group found.

Heart health scores based on diet were lowest for every age group. In the youngest age group, the average cardiovascular health (CVH) score was about 61. In the 12- to 19-year age group, however, the average CVH score decreased to 28.5, the lowest measured score for any group in the study.

With such worrisome diet scores for the 12- to 19-year-old group, public health policies need to focus on changes, like removing sugar-sweetened beverage options from schools, according to Joseph Mahgerefteh, MD, director of preventive cardiology at the Mount Sinai Kravis Children’s Heart Center, New York. He added that parents and their children also have a role to play.

“Some of our teenagers forget they can drink water when they are thirsty, and it is not necessary to drink sugar-sweetened beverages for thirst,” Dr. Mahgerefteh, who was not involved in the study, said in an interview. “Fresh vegetable intake is so low to a degree that some of our patients refuse to have any type of vegetable in their diet.”

“As a physician community caring for these patients, we need to be much more aggressive with our counseling and referral of these patients,” added Barry Love, MD, director of the congenital cardiac catheterization program at the Mount Sinai Kravis Children’s Heart Center. “These youngsters will inevitably encounter the effect of these conditions – coronary artery disease and stroke – at a much earlier adult age.”

Dr. Perak, Dr. Mahgerefteh, and Dr. Love reported no relevant financial conflicts of interest.

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

Few people like to pay taxes, and physicians are no exception.

For the Medscape Physicians and Taxes Report 2022, physicians shared information about their tax debt as well as how they feel about the U.S. tax code, audits, and the prospects for the future.

Even though it may not always seem that way to physicians, their family tax bills – around $75,406 on average – are in line with the other top 10% of U.S. taxpayers, according to an examination of IRS data by the Tax Foundation. However, when it comes to local taxes, the Tax Foundation found that physicians pay more than average. (Forty-three states collect tax on individual incomes.)

The average physician’s family pays a 35% marginal tax rate, compared with the top marginal tax rate in the United States of 37%. (The marginal tax rate is the highest amount of tax charged on each additional dollar after the IRS bracket rates are applied to your income.)

According to Alexis Gallati, founder of Cerebral Tax Advisors, a Knoxville, Tenn.–based firm that caters to medical professionals, doctors also should pay attention to their effective tax rate, or the percentage of income they pay in taxes. It takes into account differing tax rates on ordinary income, capital gains, and other income sources, she says. “It gives a better 30,000-foot view of your tax situation.”

Some high-income families are required to pay the Alternative Minimum Tax (AMT), though in 2019 that applied to only one-tenth of U.S. households. The AMT is designed to make sure that high earners with many options for exemptions and deductions still contribute a minimum amount of tax. Only 13% of physicians surveyed said they paid the AMT, though 29% were unsure.
 

Filing taxes as painful as paying them

According to a 2021 Gallup poll, 50% of Americans think they pay too much tax. (About 44% think their tax bill is about right, and a kindhearted 4% think they pay too little.) Doctors are outliers on this one, with 75% saying they pay too much in taxes.

When asked what they would do to fix the tax system, the physicians in the Medscape survey had a wide array of proposed solutions, from “drop the corporate tax rate to nearly nothing to stimulate the economy” to “everyone should pay equitably. There are too many loopholes for the very wealthy.”

Some of the complaints were less about tax rates than the process of filing. One respondent said: “I would love for this system to not be our personal responsibility. Why should it be my duty to pay someone every year to do my taxes?”

About 48% of physicians prepare their own taxes (about the same percentage as the rest of the population), with most of those filing electronically, primarily because it saves time and the software is easy to use. Intuit TurboTax was the most popular online software, with 22% of respondents saying they currently used this product.

Of those who did pay someone to prepare their taxes, the complexity of their taxes cost them; the average respondent paid about three times the average rate for the service. In the long run, the cost might have been recouped.

Navjeet Chahal, managing partner and CEO of Chahal and Associates, a San Francisco–area firm specializing in working with physicians, points out that tax advisors don’t just fill out the forms; they proactively advise physicians about how they can limit their taxes. And indeed, most respondents feel that they got their money’s worth, with 70% saying their tax preparers charged a fair fee.

Though the physicians surveyed tended to think they pay too much tax, and several mentioned particular gripes with the system, the complexity of the tax code didn’t seem to be a big issue. While 82% of Americans polled in 2021 by Pew Research said they were bothered “a lot” or “some” by the complexity of the tax system, 68% of physicians agreed or slightly agreed that the U.S. tax system “makes sense.”
 

Gimme a break

Physicians are the beneficiaries of several types of tax breaks. Contributing to a pretax 401(k) account was the most common exemption, with 60% of physicians surveyed using this plan. Other tax breaks cited by respondents were: contributing to charity (54%), home mortgage interest (46%), and writing off business expenses (39%).

About one in five physicians has experienced an audit, but that risk has declined significantly in recent years, thanks to tighter IRS budgets. Overall, only about 1 in 167 U.S. taxpayers were audited in 2020, according to the IRS. Even for taxpayers reporting $5 million or more in income, the audit rate is only about 0.25%, the Government Accountability Office says.

The odds of a physician being summoned to a meeting with an auditor probably won’t increase for a few years, Mr. Gallati said. But the good news for doctors is bad news for lower-income Americans. “The IRS is woefully understaffed and underfunded, with the result that the agency is going for lower-hanging fruit and auditing more people in lower income brackets,” she said in an interview.

While one respondent described his experience with the IRS as “the audit from hell,” others thought it not so bad, with 72% saying the auditors treated them fairly. One respondent described the audit as “boring, short, and successful for me. The IRS owed me money.”

When it comes to taxes, physician respondents, on the whole, did not seem to be optimistic about the future. About 61% expect an increase in their tax rate because of Biden administration policies. One respondent veered into hyperbole with the comment: “I believe taxes will increase for physicians until they have no more money!”

Mr. Chahal doesn’t see it that way. He pointed out that recent attempts to raise taxes completely failed. “I personally don’t see that happening unless there’s a significant shift in the House and the Senate.”

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

Few people like to pay taxes, and physicians are no exception.

For the Medscape Physicians and Taxes Report 2022, physicians shared information about their tax debt as well as how they feel about the U.S. tax code, audits, and the prospects for the future.

Even though it may not always seem that way to physicians, their family tax bills – around $75,406 on average – are in line with the other top 10% of U.S. taxpayers, according to an examination of IRS data by the Tax Foundation. However, when it comes to local taxes, the Tax Foundation found that physicians pay more than average. (Forty-three states collect tax on individual incomes.)

The average physician’s family pays a 35% marginal tax rate, compared with the top marginal tax rate in the United States of 37%. (The marginal tax rate is the highest amount of tax charged on each additional dollar after the IRS bracket rates are applied to your income.)

According to Alexis Gallati, founder of Cerebral Tax Advisors, a Knoxville, Tenn.–based firm that caters to medical professionals, doctors also should pay attention to their effective tax rate, or the percentage of income they pay in taxes. It takes into account differing tax rates on ordinary income, capital gains, and other income sources, she says. “It gives a better 30,000-foot view of your tax situation.”

Some high-income families are required to pay the Alternative Minimum Tax (AMT), though in 2019 that applied to only one-tenth of U.S. households. The AMT is designed to make sure that high earners with many options for exemptions and deductions still contribute a minimum amount of tax. Only 13% of physicians surveyed said they paid the AMT, though 29% were unsure.
 

Filing taxes as painful as paying them

According to a 2021 Gallup poll, 50% of Americans think they pay too much tax. (About 44% think their tax bill is about right, and a kindhearted 4% think they pay too little.) Doctors are outliers on this one, with 75% saying they pay too much in taxes.

When asked what they would do to fix the tax system, the physicians in the Medscape survey had a wide array of proposed solutions, from “drop the corporate tax rate to nearly nothing to stimulate the economy” to “everyone should pay equitably. There are too many loopholes for the very wealthy.”

Some of the complaints were less about tax rates than the process of filing. One respondent said: “I would love for this system to not be our personal responsibility. Why should it be my duty to pay someone every year to do my taxes?”

About 48% of physicians prepare their own taxes (about the same percentage as the rest of the population), with most of those filing electronically, primarily because it saves time and the software is easy to use. Intuit TurboTax was the most popular online software, with 22% of respondents saying they currently used this product.

Of those who did pay someone to prepare their taxes, the complexity of their taxes cost them; the average respondent paid about three times the average rate for the service. In the long run, the cost might have been recouped.

Navjeet Chahal, managing partner and CEO of Chahal and Associates, a San Francisco–area firm specializing in working with physicians, points out that tax advisors don’t just fill out the forms; they proactively advise physicians about how they can limit their taxes. And indeed, most respondents feel that they got their money’s worth, with 70% saying their tax preparers charged a fair fee.

Though the physicians surveyed tended to think they pay too much tax, and several mentioned particular gripes with the system, the complexity of the tax code didn’t seem to be a big issue. While 82% of Americans polled in 2021 by Pew Research said they were bothered “a lot” or “some” by the complexity of the tax system, 68% of physicians agreed or slightly agreed that the U.S. tax system “makes sense.”
 

Gimme a break

Physicians are the beneficiaries of several types of tax breaks. Contributing to a pretax 401(k) account was the most common exemption, with 60% of physicians surveyed using this plan. Other tax breaks cited by respondents were: contributing to charity (54%), home mortgage interest (46%), and writing off business expenses (39%).

About one in five physicians has experienced an audit, but that risk has declined significantly in recent years, thanks to tighter IRS budgets. Overall, only about 1 in 167 U.S. taxpayers were audited in 2020, according to the IRS. Even for taxpayers reporting $5 million or more in income, the audit rate is only about 0.25%, the Government Accountability Office says.

The odds of a physician being summoned to a meeting with an auditor probably won’t increase for a few years, Mr. Gallati said. But the good news for doctors is bad news for lower-income Americans. “The IRS is woefully understaffed and underfunded, with the result that the agency is going for lower-hanging fruit and auditing more people in lower income brackets,” she said in an interview.

While one respondent described his experience with the IRS as “the audit from hell,” others thought it not so bad, with 72% saying the auditors treated them fairly. One respondent described the audit as “boring, short, and successful for me. The IRS owed me money.”

When it comes to taxes, physician respondents, on the whole, did not seem to be optimistic about the future. About 61% expect an increase in their tax rate because of Biden administration policies. One respondent veered into hyperbole with the comment: “I believe taxes will increase for physicians until they have no more money!”

Mr. Chahal doesn’t see it that way. He pointed out that recent attempts to raise taxes completely failed. “I personally don’t see that happening unless there’s a significant shift in the House and the Senate.”

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

Few people like to pay taxes, and physicians are no exception.

For the Medscape Physicians and Taxes Report 2022, physicians shared information about their tax debt as well as how they feel about the U.S. tax code, audits, and the prospects for the future.

Even though it may not always seem that way to physicians, their family tax bills – around $75,406 on average – are in line with the other top 10% of U.S. taxpayers, according to an examination of IRS data by the Tax Foundation. However, when it comes to local taxes, the Tax Foundation found that physicians pay more than average. (Forty-three states collect tax on individual incomes.)

The average physician’s family pays a 35% marginal tax rate, compared with the top marginal tax rate in the United States of 37%. (The marginal tax rate is the highest amount of tax charged on each additional dollar after the IRS bracket rates are applied to your income.)

According to Alexis Gallati, founder of Cerebral Tax Advisors, a Knoxville, Tenn.–based firm that caters to medical professionals, doctors also should pay attention to their effective tax rate, or the percentage of income they pay in taxes. It takes into account differing tax rates on ordinary income, capital gains, and other income sources, she says. “It gives a better 30,000-foot view of your tax situation.”

Some high-income families are required to pay the Alternative Minimum Tax (AMT), though in 2019 that applied to only one-tenth of U.S. households. The AMT is designed to make sure that high earners with many options for exemptions and deductions still contribute a minimum amount of tax. Only 13% of physicians surveyed said they paid the AMT, though 29% were unsure.
 

Filing taxes as painful as paying them

According to a 2021 Gallup poll, 50% of Americans think they pay too much tax. (About 44% think their tax bill is about right, and a kindhearted 4% think they pay too little.) Doctors are outliers on this one, with 75% saying they pay too much in taxes.

When asked what they would do to fix the tax system, the physicians in the Medscape survey had a wide array of proposed solutions, from “drop the corporate tax rate to nearly nothing to stimulate the economy” to “everyone should pay equitably. There are too many loopholes for the very wealthy.”

Some of the complaints were less about tax rates than the process of filing. One respondent said: “I would love for this system to not be our personal responsibility. Why should it be my duty to pay someone every year to do my taxes?”

About 48% of physicians prepare their own taxes (about the same percentage as the rest of the population), with most of those filing electronically, primarily because it saves time and the software is easy to use. Intuit TurboTax was the most popular online software, with 22% of respondents saying they currently used this product.

Of those who did pay someone to prepare their taxes, the complexity of their taxes cost them; the average respondent paid about three times the average rate for the service. In the long run, the cost might have been recouped.

Navjeet Chahal, managing partner and CEO of Chahal and Associates, a San Francisco–area firm specializing in working with physicians, points out that tax advisors don’t just fill out the forms; they proactively advise physicians about how they can limit their taxes. And indeed, most respondents feel that they got their money’s worth, with 70% saying their tax preparers charged a fair fee.

Though the physicians surveyed tended to think they pay too much tax, and several mentioned particular gripes with the system, the complexity of the tax code didn’t seem to be a big issue. While 82% of Americans polled in 2021 by Pew Research said they were bothered “a lot” or “some” by the complexity of the tax system, 68% of physicians agreed or slightly agreed that the U.S. tax system “makes sense.”
 

Gimme a break

Physicians are the beneficiaries of several types of tax breaks. Contributing to a pretax 401(k) account was the most common exemption, with 60% of physicians surveyed using this plan. Other tax breaks cited by respondents were: contributing to charity (54%), home mortgage interest (46%), and writing off business expenses (39%).

About one in five physicians has experienced an audit, but that risk has declined significantly in recent years, thanks to tighter IRS budgets. Overall, only about 1 in 167 U.S. taxpayers were audited in 2020, according to the IRS. Even for taxpayers reporting $5 million or more in income, the audit rate is only about 0.25%, the Government Accountability Office says.

The odds of a physician being summoned to a meeting with an auditor probably won’t increase for a few years, Mr. Gallati said. But the good news for doctors is bad news for lower-income Americans. “The IRS is woefully understaffed and underfunded, with the result that the agency is going for lower-hanging fruit and auditing more people in lower income brackets,” she said in an interview.

While one respondent described his experience with the IRS as “the audit from hell,” others thought it not so bad, with 72% saying the auditors treated them fairly. One respondent described the audit as “boring, short, and successful for me. The IRS owed me money.”

When it comes to taxes, physician respondents, on the whole, did not seem to be optimistic about the future. About 61% expect an increase in their tax rate because of Biden administration policies. One respondent veered into hyperbole with the comment: “I believe taxes will increase for physicians until they have no more money!”

Mr. Chahal doesn’t see it that way. He pointed out that recent attempts to raise taxes completely failed. “I personally don’t see that happening unless there’s a significant shift in the House and the Senate.”

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

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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