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Boosting hypertension screening, treatment would cut global mortality 7%
If 80% of individuals with hypertension were screened, 80% received treatment, and 80% then reached guideline-specified targets, up to 200 million cases of cardiovascular disease (CVD) and 130 million deaths could be averted by 2050, a modeling study suggests.
Achievement of the 80-80-80 target “could be one of the single most important global public health accomplishments of the coming decades,” according to the authors.
“We need to reprioritize hypertension care in our practices,” principal investigator David A. Watkins, MD, MPH, University of Washington, Seattle, told this news organization. “Only about one in five persons with hypertension around the world has their blood pressure well controlled. Oftentimes, clinicians are focused on addressing patients’ other health needs, many of which can be pressing in the short term, and we forget to talk about blood pressure, which has more than earned its reputation as ‘the silent killer.’ ”
The modeling study was published online in Nature Medicine, with lead author Sarah J. Pickersgill, MPH, also from the University of Washington.
Two interventions, three scenarios
Dr. Watkins and colleagues based their analysis on two approaches to blood pressure (BP) control shown to be beneficial: drug treatment to a systolic BP of either 130 mm Hg or 140 mm Hg or less, depending on local guidelines, and dietary sodium reduction, as recommended by the World Health Organization.
The team modeled the impacts of these interventions in 182 countries according to three scenarios:
- Business as usual (control): allowing hypertension to increase at historic rates of change and mean sodium intake to remain at current levels
- Progress: matching historically high-performing countries (for example, accelerating hypertension control by about 3% per year at intermediate levels of intervention coverage) while lowering mean sodium intake by 15% by 2030
- Aspirational: hypertension control achieved faster than historically high-performing countries (about 4% per year) and mean sodium intake decreased by 30% by 2027
The analysis suggests that in the progressive scenario, all countries could achieve 80-80-80 targets by 2050 and most countries by 2040; the aspirational scenario would have all countries meeting them by 2040. That would result in reductions in all-cause mortality of 4%-7% (76 million to 130 million deaths averted) with progressive and aspirational interventions, respectively, compared with the control scenario.
There would also be a slower rise in expected CVD from population growth and aging (110 million to 200 million cases averted). That is, the probability of dying from any CVD cause between the ages of 30 and 80 years would be reduced by 16% in the progressive scenario and 26% in the aspirational scenario.
Of note, about 83%-85% of the potential mortality reductions would result from scaling up hypertension treatment in the progressive and aspirational scenarios, respectively, with the remaining 15%-17% coming from sodium reduction, the researchers state.
Further, they propose, scaling up BP interventions could reduce CVD inequalities across countries, with low-income and lower-middle-income countries likely experiencing the largest reductions in disease rates and mortality.
Implementation barriers
“Health systems in many low- and middle-income countries have not traditionally been set up to succeed in chronic disease management in primary care,” Dr. Watkins noted. For interventions to be successful, he said, “several barriers need to be addressed, including: low population awareness of chronic diseases like hypertension and diabetes, which leads to low rates of screening and treatment; high out-of-pocket cost and low availability of medicines for chronic diseases; and need for adherence support and provider incentives for improving quality of chronic disease care in primary care settings.”
“Based on the analysis, achieving the 80-80-80 seems feasible, though actually getting there may be much more complicated. I wonder whether countries have the resources to implement the needed policies,” Rodrigo M. Carrillo-Larco, MD, researcher, department of epidemiology and biostatistics, School of Public Health, Imperial College London, told this news organization.
“It may be challenging, particularly after COVID-19, which revealed deficiencies in many health care systems, and care for hypertension may have been disturbed,” said Dr. Carrillo-Larco, who is not connected with the analysis.
That said, simplified BP screening approaches could help maximize the number of people screened overall, potentially identifying those with hypertension and raising awareness, he proposed. His team’s recent study showed that such approaches vary from country to country but are generally reliable and can be used effectively for population screening.
In addition, Dr. Carrillo-Larco said, any efforts by clinicians to improve adherence and help patients achieve BP control “would also have positive effects at the population level.”
The study was supported by a grant from the Bill & Melinda Gates Foundation, with additional funding by a grant to Dr. Watkins from Resolve to Save Lives. No conflicts of interest were declared.
A version of this article first appeared on Medscape.com.
If 80% of individuals with hypertension were screened, 80% received treatment, and 80% then reached guideline-specified targets, up to 200 million cases of cardiovascular disease (CVD) and 130 million deaths could be averted by 2050, a modeling study suggests.
Achievement of the 80-80-80 target “could be one of the single most important global public health accomplishments of the coming decades,” according to the authors.
“We need to reprioritize hypertension care in our practices,” principal investigator David A. Watkins, MD, MPH, University of Washington, Seattle, told this news organization. “Only about one in five persons with hypertension around the world has their blood pressure well controlled. Oftentimes, clinicians are focused on addressing patients’ other health needs, many of which can be pressing in the short term, and we forget to talk about blood pressure, which has more than earned its reputation as ‘the silent killer.’ ”
The modeling study was published online in Nature Medicine, with lead author Sarah J. Pickersgill, MPH, also from the University of Washington.
Two interventions, three scenarios
Dr. Watkins and colleagues based their analysis on two approaches to blood pressure (BP) control shown to be beneficial: drug treatment to a systolic BP of either 130 mm Hg or 140 mm Hg or less, depending on local guidelines, and dietary sodium reduction, as recommended by the World Health Organization.
The team modeled the impacts of these interventions in 182 countries according to three scenarios:
- Business as usual (control): allowing hypertension to increase at historic rates of change and mean sodium intake to remain at current levels
- Progress: matching historically high-performing countries (for example, accelerating hypertension control by about 3% per year at intermediate levels of intervention coverage) while lowering mean sodium intake by 15% by 2030
- Aspirational: hypertension control achieved faster than historically high-performing countries (about 4% per year) and mean sodium intake decreased by 30% by 2027
The analysis suggests that in the progressive scenario, all countries could achieve 80-80-80 targets by 2050 and most countries by 2040; the aspirational scenario would have all countries meeting them by 2040. That would result in reductions in all-cause mortality of 4%-7% (76 million to 130 million deaths averted) with progressive and aspirational interventions, respectively, compared with the control scenario.
There would also be a slower rise in expected CVD from population growth and aging (110 million to 200 million cases averted). That is, the probability of dying from any CVD cause between the ages of 30 and 80 years would be reduced by 16% in the progressive scenario and 26% in the aspirational scenario.
Of note, about 83%-85% of the potential mortality reductions would result from scaling up hypertension treatment in the progressive and aspirational scenarios, respectively, with the remaining 15%-17% coming from sodium reduction, the researchers state.
Further, they propose, scaling up BP interventions could reduce CVD inequalities across countries, with low-income and lower-middle-income countries likely experiencing the largest reductions in disease rates and mortality.
Implementation barriers
“Health systems in many low- and middle-income countries have not traditionally been set up to succeed in chronic disease management in primary care,” Dr. Watkins noted. For interventions to be successful, he said, “several barriers need to be addressed, including: low population awareness of chronic diseases like hypertension and diabetes, which leads to low rates of screening and treatment; high out-of-pocket cost and low availability of medicines for chronic diseases; and need for adherence support and provider incentives for improving quality of chronic disease care in primary care settings.”
“Based on the analysis, achieving the 80-80-80 seems feasible, though actually getting there may be much more complicated. I wonder whether countries have the resources to implement the needed policies,” Rodrigo M. Carrillo-Larco, MD, researcher, department of epidemiology and biostatistics, School of Public Health, Imperial College London, told this news organization.
“It may be challenging, particularly after COVID-19, which revealed deficiencies in many health care systems, and care for hypertension may have been disturbed,” said Dr. Carrillo-Larco, who is not connected with the analysis.
That said, simplified BP screening approaches could help maximize the number of people screened overall, potentially identifying those with hypertension and raising awareness, he proposed. His team’s recent study showed that such approaches vary from country to country but are generally reliable and can be used effectively for population screening.
In addition, Dr. Carrillo-Larco said, any efforts by clinicians to improve adherence and help patients achieve BP control “would also have positive effects at the population level.”
The study was supported by a grant from the Bill & Melinda Gates Foundation, with additional funding by a grant to Dr. Watkins from Resolve to Save Lives. No conflicts of interest were declared.
A version of this article first appeared on Medscape.com.
If 80% of individuals with hypertension were screened, 80% received treatment, and 80% then reached guideline-specified targets, up to 200 million cases of cardiovascular disease (CVD) and 130 million deaths could be averted by 2050, a modeling study suggests.
Achievement of the 80-80-80 target “could be one of the single most important global public health accomplishments of the coming decades,” according to the authors.
“We need to reprioritize hypertension care in our practices,” principal investigator David A. Watkins, MD, MPH, University of Washington, Seattle, told this news organization. “Only about one in five persons with hypertension around the world has their blood pressure well controlled. Oftentimes, clinicians are focused on addressing patients’ other health needs, many of which can be pressing in the short term, and we forget to talk about blood pressure, which has more than earned its reputation as ‘the silent killer.’ ”
The modeling study was published online in Nature Medicine, with lead author Sarah J. Pickersgill, MPH, also from the University of Washington.
Two interventions, three scenarios
Dr. Watkins and colleagues based their analysis on two approaches to blood pressure (BP) control shown to be beneficial: drug treatment to a systolic BP of either 130 mm Hg or 140 mm Hg or less, depending on local guidelines, and dietary sodium reduction, as recommended by the World Health Organization.
The team modeled the impacts of these interventions in 182 countries according to three scenarios:
- Business as usual (control): allowing hypertension to increase at historic rates of change and mean sodium intake to remain at current levels
- Progress: matching historically high-performing countries (for example, accelerating hypertension control by about 3% per year at intermediate levels of intervention coverage) while lowering mean sodium intake by 15% by 2030
- Aspirational: hypertension control achieved faster than historically high-performing countries (about 4% per year) and mean sodium intake decreased by 30% by 2027
The analysis suggests that in the progressive scenario, all countries could achieve 80-80-80 targets by 2050 and most countries by 2040; the aspirational scenario would have all countries meeting them by 2040. That would result in reductions in all-cause mortality of 4%-7% (76 million to 130 million deaths averted) with progressive and aspirational interventions, respectively, compared with the control scenario.
There would also be a slower rise in expected CVD from population growth and aging (110 million to 200 million cases averted). That is, the probability of dying from any CVD cause between the ages of 30 and 80 years would be reduced by 16% in the progressive scenario and 26% in the aspirational scenario.
Of note, about 83%-85% of the potential mortality reductions would result from scaling up hypertension treatment in the progressive and aspirational scenarios, respectively, with the remaining 15%-17% coming from sodium reduction, the researchers state.
Further, they propose, scaling up BP interventions could reduce CVD inequalities across countries, with low-income and lower-middle-income countries likely experiencing the largest reductions in disease rates and mortality.
Implementation barriers
“Health systems in many low- and middle-income countries have not traditionally been set up to succeed in chronic disease management in primary care,” Dr. Watkins noted. For interventions to be successful, he said, “several barriers need to be addressed, including: low population awareness of chronic diseases like hypertension and diabetes, which leads to low rates of screening and treatment; high out-of-pocket cost and low availability of medicines for chronic diseases; and need for adherence support and provider incentives for improving quality of chronic disease care in primary care settings.”
“Based on the analysis, achieving the 80-80-80 seems feasible, though actually getting there may be much more complicated. I wonder whether countries have the resources to implement the needed policies,” Rodrigo M. Carrillo-Larco, MD, researcher, department of epidemiology and biostatistics, School of Public Health, Imperial College London, told this news organization.
“It may be challenging, particularly after COVID-19, which revealed deficiencies in many health care systems, and care for hypertension may have been disturbed,” said Dr. Carrillo-Larco, who is not connected with the analysis.
That said, simplified BP screening approaches could help maximize the number of people screened overall, potentially identifying those with hypertension and raising awareness, he proposed. His team’s recent study showed that such approaches vary from country to country but are generally reliable and can be used effectively for population screening.
In addition, Dr. Carrillo-Larco said, any efforts by clinicians to improve adherence and help patients achieve BP control “would also have positive effects at the population level.”
The study was supported by a grant from the Bill & Melinda Gates Foundation, with additional funding by a grant to Dr. Watkins from Resolve to Save Lives. No conflicts of interest were declared.
A version of this article first appeared on Medscape.com.
The next blood pressure breakthrough: temporary tattoos
As scientists work on wearable technology that promises to revolutionize health care, researchers from the University of Texas at Austin and Texas A&M University, College Station, are reporting a big win in the pursuit of one highly popular target: a noninvasive solution for continuous blood pressure monitoring at home.
Not only that, but this development comes in the surprising form of a temporary tattoo. That’s right: Just like the kind that children like to wear.
the researchers report in their new study.
“With this new technology, we are going to have an opportunity to understand how our blood pressure fluctuates during the day. We will be able to quantify how stress is impacting us,” says Roozbeh Jafari, PhD, a professor of biomedical engineering, electrical engineering, and computer science at Texas A&M, College Station, and a coauthor of the study.
Revealing the whole picture, not just dots
At-home blood pressure monitors have been around for many years now. They work just like the blood pressure machines doctors use at their office: You place your arm inside a cuff, press a button, feel a squeeze on your arm, and get a reading.
While results from this method are accurate, they are also just a moment in time. Our blood pressure can vary greatly throughout the day – especially among people who have labile hypertension, where blood pressure changes from one extreme to the other. So, looking at point-in-time readings is a bit like focusing on a few dots inside of a pointillism painting – one might miss the bigger picture.
Doctors may also find continuous monitoring useful for getting rid of false readings from “white coat syndrome.” Basically, this means a person’s blood pressure rises due to the anxiety of being in a doctor’s office but is not true hypertension.
Bottom line: The ability to monitor a person’s blood pressure continuously for hours or even days can provide clearer, and more accurate, insights into a person’s health.
How do health monitoring tattoos work?
Electronic tattoos for health monitoring are not completely new. John A. Rogers, PhD, of Northwestern University, Chicago, first put forth the idea of monitoring through temporary tattoos 12 years ago. Some concepts, such as UV monitoring tattoos, had already been adopted by scientists and put on the market. But the existing models weren’t suitable for monitoring blood pressure, according to Deji Akinwande, PhD, a professor of electrical and computer engineering at the University of Texas at Austin and another coauthor of the study.
“[UV monitoring tattoos] are very thick,” he says. “They create too much movement when used to measure blood pressure because they slide around.”
So, the Texas-based research team worked to develop an option that was slimmer and more stable.
“The key ingredient within e-tattoos is graphene,” says Dr. Akinwande.
Graphene is carbon that’s similar to what’s inside your graphite pencil. The material is conductive, meaning it can conduct small electrical currents through the skin. For blood pressure monitoring, graphene promotes bioelectrical impedance analysis (BIA), which is like the technology used in smart scales that measure body fat.
With e-tattoos, the thin layers of graphene stick to the skin and do not slide around, getting rid of “artifacts,” or bad data. The graphene e-tattoos can be worn on the skin for about a week – or roughly as long as the temporary tattoos kids love.
Once the graphene captures the raw data, a machine learning algorithm interprets the information and provides results in units used for measuring blood pressure: millimeters of mercury (mmHg), commonly referred to as blood pressure “points.”
How accurate are the results? The tests measured blood pressure within 0.2 ± 5.8 mmHg (systolic), 0.2 ± 4.5 mmHg (diastolic), and 0.1 ± 5.3 mmHg (mean arterial pressure). In other words: If this were a basketball player shooting baskets, the great majority of shots taken would be swishes and occasionally a few would hit the rim. That means good accuracy.
When will e-tattoos be available?
The teams of Dr. Jafari and Dr. Akinwande are working on a second generation of their e-tattoo that they expect to be available in the next 5 years.
The upgrade they envision will be smaller and compatible with smartwatches and phones that use Bluetooth technology and near-field communication (NFC) to transfer data and give it power. With these updates, e-tattoos for continuous blood pressure monitoring will be ready for clinical trials and mainstream use soon after.
“Everyone can benefit from knowing their blood pressure recordings,” Dr. Akinwande says. “It is not just for people at risk for hypertension but for others to proactively monitor their health, for stress and other factors.”
A version of this article first appeared on WebMD.com.
As scientists work on wearable technology that promises to revolutionize health care, researchers from the University of Texas at Austin and Texas A&M University, College Station, are reporting a big win in the pursuit of one highly popular target: a noninvasive solution for continuous blood pressure monitoring at home.
Not only that, but this development comes in the surprising form of a temporary tattoo. That’s right: Just like the kind that children like to wear.
the researchers report in their new study.
“With this new technology, we are going to have an opportunity to understand how our blood pressure fluctuates during the day. We will be able to quantify how stress is impacting us,” says Roozbeh Jafari, PhD, a professor of biomedical engineering, electrical engineering, and computer science at Texas A&M, College Station, and a coauthor of the study.
Revealing the whole picture, not just dots
At-home blood pressure monitors have been around for many years now. They work just like the blood pressure machines doctors use at their office: You place your arm inside a cuff, press a button, feel a squeeze on your arm, and get a reading.
While results from this method are accurate, they are also just a moment in time. Our blood pressure can vary greatly throughout the day – especially among people who have labile hypertension, where blood pressure changes from one extreme to the other. So, looking at point-in-time readings is a bit like focusing on a few dots inside of a pointillism painting – one might miss the bigger picture.
Doctors may also find continuous monitoring useful for getting rid of false readings from “white coat syndrome.” Basically, this means a person’s blood pressure rises due to the anxiety of being in a doctor’s office but is not true hypertension.
Bottom line: The ability to monitor a person’s blood pressure continuously for hours or even days can provide clearer, and more accurate, insights into a person’s health.
How do health monitoring tattoos work?
Electronic tattoos for health monitoring are not completely new. John A. Rogers, PhD, of Northwestern University, Chicago, first put forth the idea of monitoring through temporary tattoos 12 years ago. Some concepts, such as UV monitoring tattoos, had already been adopted by scientists and put on the market. But the existing models weren’t suitable for monitoring blood pressure, according to Deji Akinwande, PhD, a professor of electrical and computer engineering at the University of Texas at Austin and another coauthor of the study.
“[UV monitoring tattoos] are very thick,” he says. “They create too much movement when used to measure blood pressure because they slide around.”
So, the Texas-based research team worked to develop an option that was slimmer and more stable.
“The key ingredient within e-tattoos is graphene,” says Dr. Akinwande.
Graphene is carbon that’s similar to what’s inside your graphite pencil. The material is conductive, meaning it can conduct small electrical currents through the skin. For blood pressure monitoring, graphene promotes bioelectrical impedance analysis (BIA), which is like the technology used in smart scales that measure body fat.
With e-tattoos, the thin layers of graphene stick to the skin and do not slide around, getting rid of “artifacts,” or bad data. The graphene e-tattoos can be worn on the skin for about a week – or roughly as long as the temporary tattoos kids love.
Once the graphene captures the raw data, a machine learning algorithm interprets the information and provides results in units used for measuring blood pressure: millimeters of mercury (mmHg), commonly referred to as blood pressure “points.”
How accurate are the results? The tests measured blood pressure within 0.2 ± 5.8 mmHg (systolic), 0.2 ± 4.5 mmHg (diastolic), and 0.1 ± 5.3 mmHg (mean arterial pressure). In other words: If this were a basketball player shooting baskets, the great majority of shots taken would be swishes and occasionally a few would hit the rim. That means good accuracy.
When will e-tattoos be available?
The teams of Dr. Jafari and Dr. Akinwande are working on a second generation of their e-tattoo that they expect to be available in the next 5 years.
The upgrade they envision will be smaller and compatible with smartwatches and phones that use Bluetooth technology and near-field communication (NFC) to transfer data and give it power. With these updates, e-tattoos for continuous blood pressure monitoring will be ready for clinical trials and mainstream use soon after.
“Everyone can benefit from knowing their blood pressure recordings,” Dr. Akinwande says. “It is not just for people at risk for hypertension but for others to proactively monitor their health, for stress and other factors.”
A version of this article first appeared on WebMD.com.
As scientists work on wearable technology that promises to revolutionize health care, researchers from the University of Texas at Austin and Texas A&M University, College Station, are reporting a big win in the pursuit of one highly popular target: a noninvasive solution for continuous blood pressure monitoring at home.
Not only that, but this development comes in the surprising form of a temporary tattoo. That’s right: Just like the kind that children like to wear.
the researchers report in their new study.
“With this new technology, we are going to have an opportunity to understand how our blood pressure fluctuates during the day. We will be able to quantify how stress is impacting us,” says Roozbeh Jafari, PhD, a professor of biomedical engineering, electrical engineering, and computer science at Texas A&M, College Station, and a coauthor of the study.
Revealing the whole picture, not just dots
At-home blood pressure monitors have been around for many years now. They work just like the blood pressure machines doctors use at their office: You place your arm inside a cuff, press a button, feel a squeeze on your arm, and get a reading.
While results from this method are accurate, they are also just a moment in time. Our blood pressure can vary greatly throughout the day – especially among people who have labile hypertension, where blood pressure changes from one extreme to the other. So, looking at point-in-time readings is a bit like focusing on a few dots inside of a pointillism painting – one might miss the bigger picture.
Doctors may also find continuous monitoring useful for getting rid of false readings from “white coat syndrome.” Basically, this means a person’s blood pressure rises due to the anxiety of being in a doctor’s office but is not true hypertension.
Bottom line: The ability to monitor a person’s blood pressure continuously for hours or even days can provide clearer, and more accurate, insights into a person’s health.
How do health monitoring tattoos work?
Electronic tattoos for health monitoring are not completely new. John A. Rogers, PhD, of Northwestern University, Chicago, first put forth the idea of monitoring through temporary tattoos 12 years ago. Some concepts, such as UV monitoring tattoos, had already been adopted by scientists and put on the market. But the existing models weren’t suitable for monitoring blood pressure, according to Deji Akinwande, PhD, a professor of electrical and computer engineering at the University of Texas at Austin and another coauthor of the study.
“[UV monitoring tattoos] are very thick,” he says. “They create too much movement when used to measure blood pressure because they slide around.”
So, the Texas-based research team worked to develop an option that was slimmer and more stable.
“The key ingredient within e-tattoos is graphene,” says Dr. Akinwande.
Graphene is carbon that’s similar to what’s inside your graphite pencil. The material is conductive, meaning it can conduct small electrical currents through the skin. For blood pressure monitoring, graphene promotes bioelectrical impedance analysis (BIA), which is like the technology used in smart scales that measure body fat.
With e-tattoos, the thin layers of graphene stick to the skin and do not slide around, getting rid of “artifacts,” or bad data. The graphene e-tattoos can be worn on the skin for about a week – or roughly as long as the temporary tattoos kids love.
Once the graphene captures the raw data, a machine learning algorithm interprets the information and provides results in units used for measuring blood pressure: millimeters of mercury (mmHg), commonly referred to as blood pressure “points.”
How accurate are the results? The tests measured blood pressure within 0.2 ± 5.8 mmHg (systolic), 0.2 ± 4.5 mmHg (diastolic), and 0.1 ± 5.3 mmHg (mean arterial pressure). In other words: If this were a basketball player shooting baskets, the great majority of shots taken would be swishes and occasionally a few would hit the rim. That means good accuracy.
When will e-tattoos be available?
The teams of Dr. Jafari and Dr. Akinwande are working on a second generation of their e-tattoo that they expect to be available in the next 5 years.
The upgrade they envision will be smaller and compatible with smartwatches and phones that use Bluetooth technology and near-field communication (NFC) to transfer data and give it power. With these updates, e-tattoos for continuous blood pressure monitoring will be ready for clinical trials and mainstream use soon after.
“Everyone can benefit from knowing their blood pressure recordings,” Dr. Akinwande says. “It is not just for people at risk for hypertension but for others to proactively monitor their health, for stress and other factors.”
A version of this article first appeared on WebMD.com.
Two distinct phenotypes of COVID-related myocarditis emerge
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+).
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+).
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+).
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.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Hypertension heightens risk for severe COVID-19, even in the fully vaxxed
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.”
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.”
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.”
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.
FROM HYPERTENSION
‘Case closed’: Bridging thrombolysis remains ‘gold standard’ in stroke thrombectomy
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.
FROM THE LANCET
‘Stunning variation’ in CV test, procedure costs revealed at top U.S. hospitals
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.
“For example, there was a 10-fold difference in the median price of an echocardiogram, and these differences were even larger for common procedures” such as percutaneous coronary intervention (PCI) and pacemaker implantation, he said. “It’s hard to argue that this variation reflects quality of care, given that we looked at a top group of highly ranked hospitals.”
“Even more striking was how the price of a cardiovascular test within the very same hospital could differ across commercial insurance companies,” he said. “For example, the price of a stress test varied 5-fold in one hospital, and in another hospital, more than 4-fold for a coronary angiogram.”
Dr. Wadhera is senior author on the study published online as a research letter in JAMA Internal Medicine, with lead author Andrew S. Oseran, MD, MBA, also from Beth Israel Deaconess Medical Center.
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.
“For example, there was a 10-fold difference in the median price of an echocardiogram, and these differences were even larger for common procedures” such as percutaneous coronary intervention (PCI) and pacemaker implantation, he said. “It’s hard to argue that this variation reflects quality of care, given that we looked at a top group of highly ranked hospitals.”
“Even more striking was how the price of a cardiovascular test within the very same hospital could differ across commercial insurance companies,” he said. “For example, the price of a stress test varied 5-fold in one hospital, and in another hospital, more than 4-fold for a coronary angiogram.”
Dr. Wadhera is senior author on the study published online as a research letter in JAMA Internal Medicine, with lead author Andrew S. Oseran, MD, MBA, also from Beth Israel Deaconess Medical Center.
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.
“For example, there was a 10-fold difference in the median price of an echocardiogram, and these differences were even larger for common procedures” such as percutaneous coronary intervention (PCI) and pacemaker implantation, he said. “It’s hard to argue that this variation reflects quality of care, given that we looked at a top group of highly ranked hospitals.”
“Even more striking was how the price of a cardiovascular test within the very same hospital could differ across commercial insurance companies,” he said. “For example, the price of a stress test varied 5-fold in one hospital, and in another hospital, more than 4-fold for a coronary angiogram.”
Dr. Wadhera is senior author on the study published online as a research letter in JAMA Internal Medicine, with lead author Andrew S. Oseran, MD, MBA, also from Beth Israel Deaconess Medical Center.
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.
Heart health poor for many U.S. children
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.
FROM CIRCULATION
Rosuvastatin again linked with risks to kidneys
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.
FROM THE JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Pig heart transplants and the ethical challenges that lie ahead
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.
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.”
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.
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.”
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.
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.”
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.
Overly tight sodium restriction may worsen HFpEF outcomes
Cutting out almost all salt when preparing meals was associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF), according to the results of a new study.
Results from a post hoc analysis of the TOPCAT trial show that those with a cooking salt score of zero were at significantly higher risk of the primary outcome of cardiovascular (CV) death, HF hospitalization, and aborted cardiac arrest than those whose score was above zero. Survival was similar in both groups.
“Some patients restrict dietary salt intake as least as possible according to their physicians’ words or their own understanding. However, the present study found that, in patients with heart failure with preserved ejection fraction, overstrict salt restriction could lead to poor prognosis – mainly heart failure hospitalization,” explained professor Chen Liu, MD, and Weihao Liang, MD, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China.
“Thus, when giving salt restriction advice to patients with heart failure with preserved ejection fraction, physicians should be careful instead of just saying “as least as possible,” they said in an email to this news organization.
The study was published in the journal Heart.
The authors note that HF guidelines recommend reduced salt intake, but there’s a lack of high-quality evidence to support those recommendations and no consensus on how low to go.
Previous studies have shown that reduced dietary sodium intake was associated with worse survival and higher readmission rate in patients with HF, whereas the SODIUM HF trial reported earlier this year that dietary sodium intake of less than 100 mmol (1,500 mg) per day did not improve 1-year clinical outcomes but moderately improved quality of life and New York Heart Association functional class.
“In daily clinical practice, we noticed that some physicians advised patients with heart failure to take salt as least as possible, but it could lead to hyponatremia and loss of appetite, which has been frequently reported to be associated with poor prognosis. Thus, we wanted to investigate the potential effect of overstrict salt restriction,” Dr. Liu and Dr. Liang explained.
The investigators examined data from 1,713 participants aged 50 and older with HFpEF (left ventricular ejection fraction 45% or greater) in the phase 3 TOPCAT trial, excluding those from Russia and Georgia. Patients self-reported how much salt they added to cooking staples, such as rice, pasta, potatoes, soup, meat, and vegetables, and were scored as 0 (none), 1 (⅛ teaspoon), 2 (¼ teaspoon), and 3 (½ teaspoon or more) points. Median follow-up was 2.9 years.
TOPCAT failed to show that spironolactone improved CV outcomes over placebo, but regional differences in data from Russia/Georgia and the Americas have raised concerns about its validity.
In the present analysis, almost half the participants (816) had a cooking salt score of 0, 56.4% were male, and 80.8% were White. They were more likely than participants with a salt score greater than zero to have a previous HF hospitalization, diabetes, poor renal function, and a lower ejection fraction (57% vs. 60%). Half were randomly assigned to spironolactone.
Compared with patients with a cooking salt score of 0, patients with a cooking salt score greater than 0 had significantly lower risks of the primary outcome (hazard ratio, 0.760; P = .002) and HF hospitalization (HR, 0.737; P = .003) but not all-cause (HR, 0.838) or CV (HR, 0.782) death.
The findings were consistent after full adjustment, with hazard ratios of 0.834 (P = .046), 0.791 (P = .024), 0.944, and 0.872, respectively.
Results of subgroup analyses suggested that patients aged 70 years or younger (HR, 0.644) and those of Black and other ethnicities (HR, 0.574) were at greater risk of the primary outcome from aggressive restriction of cooking salt.
“It was an interesting but unproved finding,” Dr. Liu and Dr. Liang observed. “One possible explanation is the difference in RAAS [renin-angiotensin-aldosterone system] physiology and its response to salt restriction among races, and the other is the difference in accustomed food, because the cooking salt score only accounted for sodium added during cooking but not sodium from ingredients.”
Spearman correlation analyses showed that the cooking salt score correlated significantly with systolic and diastolic blood pressure, serum sodium, and chloronium levels but not with plasma volume status, suggesting that low sodium intake did not have an intravascular volume contraction effect on patients with HFpEF.
The authors pointed out that the salt score was self-reported, hemodynamic parameters were seldom acquired in TOPCAT, and that reverse causation between low dietary sodium intake and worse HF might still exist, despite a propensity score-matching sensitivity analysis.
Reached for comment, Mary Norine Walsh, MD, the medical director of heart failure and cardiac transplantation, Ascension St. Vincent Heart Center, Indianapolis, said in an email that the authors appropriately excluded patients enrolled from Russia and Georgia because of concerns about the representativeness of patients with HFpEF in these two countries, which has been previously demonstrated.
“What limits the importance of the authors’ findings, which they acknowledge, is that the sodium intake for each patient was self-reported,” she said. “No confirmatory testing was done and recall bias could clearly have played a role.”
“Last, many patients with HFpEF have significant volume overload and dyspnea and appropriate sodium restriction is needed to help address symptoms and achieve a euvolemic state,” added Dr. Walsh, a past president of the American College of Cardiology.
Future trials are needed to determine an optimal salt restriction range for patients with heart failure, Dr. Liu and Dr. Liang suggested. “A randomized controlled trial may be hard to achieve because it is difficult to set a perfect control group. Therefore, an analysis using real-world data with a dose-response curve could be ideal.”
The study was funded by the National Natural Science Foundation of China, Guangdong Natural Science Foundation, and China Postdoctoral Science Foundation. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cutting out almost all salt when preparing meals was associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF), according to the results of a new study.
Results from a post hoc analysis of the TOPCAT trial show that those with a cooking salt score of zero were at significantly higher risk of the primary outcome of cardiovascular (CV) death, HF hospitalization, and aborted cardiac arrest than those whose score was above zero. Survival was similar in both groups.
“Some patients restrict dietary salt intake as least as possible according to their physicians’ words or their own understanding. However, the present study found that, in patients with heart failure with preserved ejection fraction, overstrict salt restriction could lead to poor prognosis – mainly heart failure hospitalization,” explained professor Chen Liu, MD, and Weihao Liang, MD, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China.
“Thus, when giving salt restriction advice to patients with heart failure with preserved ejection fraction, physicians should be careful instead of just saying “as least as possible,” they said in an email to this news organization.
The study was published in the journal Heart.
The authors note that HF guidelines recommend reduced salt intake, but there’s a lack of high-quality evidence to support those recommendations and no consensus on how low to go.
Previous studies have shown that reduced dietary sodium intake was associated with worse survival and higher readmission rate in patients with HF, whereas the SODIUM HF trial reported earlier this year that dietary sodium intake of less than 100 mmol (1,500 mg) per day did not improve 1-year clinical outcomes but moderately improved quality of life and New York Heart Association functional class.
“In daily clinical practice, we noticed that some physicians advised patients with heart failure to take salt as least as possible, but it could lead to hyponatremia and loss of appetite, which has been frequently reported to be associated with poor prognosis. Thus, we wanted to investigate the potential effect of overstrict salt restriction,” Dr. Liu and Dr. Liang explained.
The investigators examined data from 1,713 participants aged 50 and older with HFpEF (left ventricular ejection fraction 45% or greater) in the phase 3 TOPCAT trial, excluding those from Russia and Georgia. Patients self-reported how much salt they added to cooking staples, such as rice, pasta, potatoes, soup, meat, and vegetables, and were scored as 0 (none), 1 (⅛ teaspoon), 2 (¼ teaspoon), and 3 (½ teaspoon or more) points. Median follow-up was 2.9 years.
TOPCAT failed to show that spironolactone improved CV outcomes over placebo, but regional differences in data from Russia/Georgia and the Americas have raised concerns about its validity.
In the present analysis, almost half the participants (816) had a cooking salt score of 0, 56.4% were male, and 80.8% were White. They were more likely than participants with a salt score greater than zero to have a previous HF hospitalization, diabetes, poor renal function, and a lower ejection fraction (57% vs. 60%). Half were randomly assigned to spironolactone.
Compared with patients with a cooking salt score of 0, patients with a cooking salt score greater than 0 had significantly lower risks of the primary outcome (hazard ratio, 0.760; P = .002) and HF hospitalization (HR, 0.737; P = .003) but not all-cause (HR, 0.838) or CV (HR, 0.782) death.
The findings were consistent after full adjustment, with hazard ratios of 0.834 (P = .046), 0.791 (P = .024), 0.944, and 0.872, respectively.
Results of subgroup analyses suggested that patients aged 70 years or younger (HR, 0.644) and those of Black and other ethnicities (HR, 0.574) were at greater risk of the primary outcome from aggressive restriction of cooking salt.
“It was an interesting but unproved finding,” Dr. Liu and Dr. Liang observed. “One possible explanation is the difference in RAAS [renin-angiotensin-aldosterone system] physiology and its response to salt restriction among races, and the other is the difference in accustomed food, because the cooking salt score only accounted for sodium added during cooking but not sodium from ingredients.”
Spearman correlation analyses showed that the cooking salt score correlated significantly with systolic and diastolic blood pressure, serum sodium, and chloronium levels but not with plasma volume status, suggesting that low sodium intake did not have an intravascular volume contraction effect on patients with HFpEF.
The authors pointed out that the salt score was self-reported, hemodynamic parameters were seldom acquired in TOPCAT, and that reverse causation between low dietary sodium intake and worse HF might still exist, despite a propensity score-matching sensitivity analysis.
Reached for comment, Mary Norine Walsh, MD, the medical director of heart failure and cardiac transplantation, Ascension St. Vincent Heart Center, Indianapolis, said in an email that the authors appropriately excluded patients enrolled from Russia and Georgia because of concerns about the representativeness of patients with HFpEF in these two countries, which has been previously demonstrated.
“What limits the importance of the authors’ findings, which they acknowledge, is that the sodium intake for each patient was self-reported,” she said. “No confirmatory testing was done and recall bias could clearly have played a role.”
“Last, many patients with HFpEF have significant volume overload and dyspnea and appropriate sodium restriction is needed to help address symptoms and achieve a euvolemic state,” added Dr. Walsh, a past president of the American College of Cardiology.
Future trials are needed to determine an optimal salt restriction range for patients with heart failure, Dr. Liu and Dr. Liang suggested. “A randomized controlled trial may be hard to achieve because it is difficult to set a perfect control group. Therefore, an analysis using real-world data with a dose-response curve could be ideal.”
The study was funded by the National Natural Science Foundation of China, Guangdong Natural Science Foundation, and China Postdoctoral Science Foundation. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cutting out almost all salt when preparing meals was associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF), according to the results of a new study.
Results from a post hoc analysis of the TOPCAT trial show that those with a cooking salt score of zero were at significantly higher risk of the primary outcome of cardiovascular (CV) death, HF hospitalization, and aborted cardiac arrest than those whose score was above zero. Survival was similar in both groups.
“Some patients restrict dietary salt intake as least as possible according to their physicians’ words or their own understanding. However, the present study found that, in patients with heart failure with preserved ejection fraction, overstrict salt restriction could lead to poor prognosis – mainly heart failure hospitalization,” explained professor Chen Liu, MD, and Weihao Liang, MD, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China.
“Thus, when giving salt restriction advice to patients with heart failure with preserved ejection fraction, physicians should be careful instead of just saying “as least as possible,” they said in an email to this news organization.
The study was published in the journal Heart.
The authors note that HF guidelines recommend reduced salt intake, but there’s a lack of high-quality evidence to support those recommendations and no consensus on how low to go.
Previous studies have shown that reduced dietary sodium intake was associated with worse survival and higher readmission rate in patients with HF, whereas the SODIUM HF trial reported earlier this year that dietary sodium intake of less than 100 mmol (1,500 mg) per day did not improve 1-year clinical outcomes but moderately improved quality of life and New York Heart Association functional class.
“In daily clinical practice, we noticed that some physicians advised patients with heart failure to take salt as least as possible, but it could lead to hyponatremia and loss of appetite, which has been frequently reported to be associated with poor prognosis. Thus, we wanted to investigate the potential effect of overstrict salt restriction,” Dr. Liu and Dr. Liang explained.
The investigators examined data from 1,713 participants aged 50 and older with HFpEF (left ventricular ejection fraction 45% or greater) in the phase 3 TOPCAT trial, excluding those from Russia and Georgia. Patients self-reported how much salt they added to cooking staples, such as rice, pasta, potatoes, soup, meat, and vegetables, and were scored as 0 (none), 1 (⅛ teaspoon), 2 (¼ teaspoon), and 3 (½ teaspoon or more) points. Median follow-up was 2.9 years.
TOPCAT failed to show that spironolactone improved CV outcomes over placebo, but regional differences in data from Russia/Georgia and the Americas have raised concerns about its validity.
In the present analysis, almost half the participants (816) had a cooking salt score of 0, 56.4% were male, and 80.8% were White. They were more likely than participants with a salt score greater than zero to have a previous HF hospitalization, diabetes, poor renal function, and a lower ejection fraction (57% vs. 60%). Half were randomly assigned to spironolactone.
Compared with patients with a cooking salt score of 0, patients with a cooking salt score greater than 0 had significantly lower risks of the primary outcome (hazard ratio, 0.760; P = .002) and HF hospitalization (HR, 0.737; P = .003) but not all-cause (HR, 0.838) or CV (HR, 0.782) death.
The findings were consistent after full adjustment, with hazard ratios of 0.834 (P = .046), 0.791 (P = .024), 0.944, and 0.872, respectively.
Results of subgroup analyses suggested that patients aged 70 years or younger (HR, 0.644) and those of Black and other ethnicities (HR, 0.574) were at greater risk of the primary outcome from aggressive restriction of cooking salt.
“It was an interesting but unproved finding,” Dr. Liu and Dr. Liang observed. “One possible explanation is the difference in RAAS [renin-angiotensin-aldosterone system] physiology and its response to salt restriction among races, and the other is the difference in accustomed food, because the cooking salt score only accounted for sodium added during cooking but not sodium from ingredients.”
Spearman correlation analyses showed that the cooking salt score correlated significantly with systolic and diastolic blood pressure, serum sodium, and chloronium levels but not with plasma volume status, suggesting that low sodium intake did not have an intravascular volume contraction effect on patients with HFpEF.
The authors pointed out that the salt score was self-reported, hemodynamic parameters were seldom acquired in TOPCAT, and that reverse causation between low dietary sodium intake and worse HF might still exist, despite a propensity score-matching sensitivity analysis.
Reached for comment, Mary Norine Walsh, MD, the medical director of heart failure and cardiac transplantation, Ascension St. Vincent Heart Center, Indianapolis, said in an email that the authors appropriately excluded patients enrolled from Russia and Georgia because of concerns about the representativeness of patients with HFpEF in these two countries, which has been previously demonstrated.
“What limits the importance of the authors’ findings, which they acknowledge, is that the sodium intake for each patient was self-reported,” she said. “No confirmatory testing was done and recall bias could clearly have played a role.”
“Last, many patients with HFpEF have significant volume overload and dyspnea and appropriate sodium restriction is needed to help address symptoms and achieve a euvolemic state,” added Dr. Walsh, a past president of the American College of Cardiology.
Future trials are needed to determine an optimal salt restriction range for patients with heart failure, Dr. Liu and Dr. Liang suggested. “A randomized controlled trial may be hard to achieve because it is difficult to set a perfect control group. Therefore, an analysis using real-world data with a dose-response curve could be ideal.”
The study was funded by the National Natural Science Foundation of China, Guangdong Natural Science Foundation, and China Postdoctoral Science Foundation. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HEART