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Hypertension protocols curb racial bias in therapeutic inertia
Therapeutic inertia regarding intensification of blood pressure treatment has been shown to be more of an issue in Black patients, but this was not the case in the SPRINT trial, which involved a strict standardized approach to blood pressure management, a new analysis shows.
“Overall, we found that therapeutic inertia was similar in different races in the SPRINT trial. We did not see disparities that have been reported in previous observational studies,” lead author, Alexander Zheutlin, MD, University of Utah School of Medicine, Salt Lake City, told this news organization.
“These results show that a well-resourced approach in which a standardized approach to blood pressure measurement and treatment intensification is followed can overcome the racial disparity that is seen in therapeutic inertia and the treatment of blood pressure,” he added.
The study was published online in JAMA Network Open on Jan. 10.
The authors explain that hypertension remains a leading modifiable cause of racial disparities in cardiovascular disease. Despite similar treatment rates and increased availability of safe, effective, and affordable antihypertensive medications, blood pressure control rates among Black and Hispanic adults remain significantly lower than among White adults in the United States, and one of the factors contributing to this is thought to be therapeutic inertia – the phenomenon of clinicians not initiating or up-titrating clinically indicated therapy in the setting of unmet treatment goals.
The current analysis of the SPRINT trial was conducted to investigate whether racial and ethnic differences in therapeutic inertia in hypertension were present when blood pressure care was standardized and protocolized.
The landmark SPRINT trial compared intensive (<120 mm Hg) with standard (<140 mm Hg) systolic blood pressure treatment goals in adults 50 years and older at high risk for cardiovascular disease. The present analysis was restricted to participant visits with measured blood pressure above the target goal and included 4,141 patients in the standard group and 4,415 patients in the intensive group.
Results showed that the overall prevalence of therapeutic inertia – defined as no antihypertensive medication intensification at each study visit where the blood pressure was above target goal – was either similar or lower for Black and Hispanic participants than for White participants. This pattern was observed whether participants were randomized to the standard or intensive treatment group.
“These findings support the idea that a standardized approach to blood pressure management, as implemented in SPRINT, may help ensure equitable care is provided to all patients and could reduce the contribution of therapeutic inertia to disparities in uncontrolled blood pressure,” the authors say.
They point out that therapeutic inertia has been identified as a key clinician-level barrier to blood pressure control and is estimated to be present in more than 80% of clinic visits in community practice, whereas in the current analysis of the SPRINT trial, therapeutic inertia was present in 50% to 60% of participant visits with uncontrolled blood pressure.
“In SPRINT, blood pressure had to be measured at defined intervals with a specific method, and there were clear instructions on intensifying treatment if blood pressure was above a certain goal,” Dr. Zheutlin noted. “Our results show that within such strict confines, therapeutic inertia does not seem to be different between different racial groups. This suggests that we could make better gains in blood pressure control and more equitable treatment if we adopted a standardized approach to hypertension management.”
He added: “Many guidelines have been published on when to start treatment and the targets for blood pressure, but there is a lot of variation in how we turn these guidelines into protocols. We need to bring in more consistent protocols on blood pressure measurement and intensification and ensure they are followed. In practice, if the BP is 5 or 10 mm Hg above target, a clinician may defer a decision to intensify treatment and intensification never gets done. But if there was a strict protocol to follow, there would be less chance of this happening.”
Therapeutic inertia still high
In an accompanying commentary, Matthew Rivara, MD, Nisha Bansal, MD, and Bessie Young, MD, University of Washington, Seattle, say the current SPRINT analysis has broad implications for reducing racial and ethnic disparities in achievement of evidence-based treatment targets in the general population.
“In hypertension management, standardized protocols for medication adjustments may limit clinician practice heterogeneity to ultimately reduce differences in blood pressure control among racial and ethnic minority populations,” they write. But they add that such protocols must be implemented thoughtfully to incorporate individualized clinical assessment and clinician-patient shared decision-making.
Dr. Rivara et al. point out that the rates of therapeutic inertia in SPRINT, while lower than community-based estimates, were still very high. They suggest reasons for this could include clinician concerns about medication efficacy, adverse effects, and patient mistrust of medical professionals. Outside the clinical trial environment, additional considerations may include prescription drug and laboratory test costs, pharmacy access, and competing demands during busy clinic visits.
To address these challenges, they say that clinicians need education on current clinical practice guidelines, managing complications of intensified antihypertensive therapies, and shared decisionmaking, including culturally sensitive collaborative care. Similarly, care systems must support patients on how to address concerns about treatments.
Finally, further research is needed to better define the specific factors associated with therapeutic inertia to allow tailored interventions to overcome this inertia.
“In designing and performing such research, it is vital that investigators engage with racial and ethnic minority groups to better explore the intersection of race, ethnicity, therapeutic decision-making, trust, and shared decisionmaking,” they add.
The SPRINT trial was funded with federal funds from the National Institutes of Health. Dr. Zheutlin reported receiving grants from the NIH during the conduct of the study.
A version of this article first appeared on Medscape.com.
Therapeutic inertia regarding intensification of blood pressure treatment has been shown to be more of an issue in Black patients, but this was not the case in the SPRINT trial, which involved a strict standardized approach to blood pressure management, a new analysis shows.
“Overall, we found that therapeutic inertia was similar in different races in the SPRINT trial. We did not see disparities that have been reported in previous observational studies,” lead author, Alexander Zheutlin, MD, University of Utah School of Medicine, Salt Lake City, told this news organization.
“These results show that a well-resourced approach in which a standardized approach to blood pressure measurement and treatment intensification is followed can overcome the racial disparity that is seen in therapeutic inertia and the treatment of blood pressure,” he added.
The study was published online in JAMA Network Open on Jan. 10.
The authors explain that hypertension remains a leading modifiable cause of racial disparities in cardiovascular disease. Despite similar treatment rates and increased availability of safe, effective, and affordable antihypertensive medications, blood pressure control rates among Black and Hispanic adults remain significantly lower than among White adults in the United States, and one of the factors contributing to this is thought to be therapeutic inertia – the phenomenon of clinicians not initiating or up-titrating clinically indicated therapy in the setting of unmet treatment goals.
The current analysis of the SPRINT trial was conducted to investigate whether racial and ethnic differences in therapeutic inertia in hypertension were present when blood pressure care was standardized and protocolized.
The landmark SPRINT trial compared intensive (<120 mm Hg) with standard (<140 mm Hg) systolic blood pressure treatment goals in adults 50 years and older at high risk for cardiovascular disease. The present analysis was restricted to participant visits with measured blood pressure above the target goal and included 4,141 patients in the standard group and 4,415 patients in the intensive group.
Results showed that the overall prevalence of therapeutic inertia – defined as no antihypertensive medication intensification at each study visit where the blood pressure was above target goal – was either similar or lower for Black and Hispanic participants than for White participants. This pattern was observed whether participants were randomized to the standard or intensive treatment group.
“These findings support the idea that a standardized approach to blood pressure management, as implemented in SPRINT, may help ensure equitable care is provided to all patients and could reduce the contribution of therapeutic inertia to disparities in uncontrolled blood pressure,” the authors say.
They point out that therapeutic inertia has been identified as a key clinician-level barrier to blood pressure control and is estimated to be present in more than 80% of clinic visits in community practice, whereas in the current analysis of the SPRINT trial, therapeutic inertia was present in 50% to 60% of participant visits with uncontrolled blood pressure.
“In SPRINT, blood pressure had to be measured at defined intervals with a specific method, and there were clear instructions on intensifying treatment if blood pressure was above a certain goal,” Dr. Zheutlin noted. “Our results show that within such strict confines, therapeutic inertia does not seem to be different between different racial groups. This suggests that we could make better gains in blood pressure control and more equitable treatment if we adopted a standardized approach to hypertension management.”
He added: “Many guidelines have been published on when to start treatment and the targets for blood pressure, but there is a lot of variation in how we turn these guidelines into protocols. We need to bring in more consistent protocols on blood pressure measurement and intensification and ensure they are followed. In practice, if the BP is 5 or 10 mm Hg above target, a clinician may defer a decision to intensify treatment and intensification never gets done. But if there was a strict protocol to follow, there would be less chance of this happening.”
Therapeutic inertia still high
In an accompanying commentary, Matthew Rivara, MD, Nisha Bansal, MD, and Bessie Young, MD, University of Washington, Seattle, say the current SPRINT analysis has broad implications for reducing racial and ethnic disparities in achievement of evidence-based treatment targets in the general population.
“In hypertension management, standardized protocols for medication adjustments may limit clinician practice heterogeneity to ultimately reduce differences in blood pressure control among racial and ethnic minority populations,” they write. But they add that such protocols must be implemented thoughtfully to incorporate individualized clinical assessment and clinician-patient shared decision-making.
Dr. Rivara et al. point out that the rates of therapeutic inertia in SPRINT, while lower than community-based estimates, were still very high. They suggest reasons for this could include clinician concerns about medication efficacy, adverse effects, and patient mistrust of medical professionals. Outside the clinical trial environment, additional considerations may include prescription drug and laboratory test costs, pharmacy access, and competing demands during busy clinic visits.
To address these challenges, they say that clinicians need education on current clinical practice guidelines, managing complications of intensified antihypertensive therapies, and shared decisionmaking, including culturally sensitive collaborative care. Similarly, care systems must support patients on how to address concerns about treatments.
Finally, further research is needed to better define the specific factors associated with therapeutic inertia to allow tailored interventions to overcome this inertia.
“In designing and performing such research, it is vital that investigators engage with racial and ethnic minority groups to better explore the intersection of race, ethnicity, therapeutic decision-making, trust, and shared decisionmaking,” they add.
The SPRINT trial was funded with federal funds from the National Institutes of Health. Dr. Zheutlin reported receiving grants from the NIH during the conduct of the study.
A version of this article first appeared on Medscape.com.
Therapeutic inertia regarding intensification of blood pressure treatment has been shown to be more of an issue in Black patients, but this was not the case in the SPRINT trial, which involved a strict standardized approach to blood pressure management, a new analysis shows.
“Overall, we found that therapeutic inertia was similar in different races in the SPRINT trial. We did not see disparities that have been reported in previous observational studies,” lead author, Alexander Zheutlin, MD, University of Utah School of Medicine, Salt Lake City, told this news organization.
“These results show that a well-resourced approach in which a standardized approach to blood pressure measurement and treatment intensification is followed can overcome the racial disparity that is seen in therapeutic inertia and the treatment of blood pressure,” he added.
The study was published online in JAMA Network Open on Jan. 10.
The authors explain that hypertension remains a leading modifiable cause of racial disparities in cardiovascular disease. Despite similar treatment rates and increased availability of safe, effective, and affordable antihypertensive medications, blood pressure control rates among Black and Hispanic adults remain significantly lower than among White adults in the United States, and one of the factors contributing to this is thought to be therapeutic inertia – the phenomenon of clinicians not initiating or up-titrating clinically indicated therapy in the setting of unmet treatment goals.
The current analysis of the SPRINT trial was conducted to investigate whether racial and ethnic differences in therapeutic inertia in hypertension were present when blood pressure care was standardized and protocolized.
The landmark SPRINT trial compared intensive (<120 mm Hg) with standard (<140 mm Hg) systolic blood pressure treatment goals in adults 50 years and older at high risk for cardiovascular disease. The present analysis was restricted to participant visits with measured blood pressure above the target goal and included 4,141 patients in the standard group and 4,415 patients in the intensive group.
Results showed that the overall prevalence of therapeutic inertia – defined as no antihypertensive medication intensification at each study visit where the blood pressure was above target goal – was either similar or lower for Black and Hispanic participants than for White participants. This pattern was observed whether participants were randomized to the standard or intensive treatment group.
“These findings support the idea that a standardized approach to blood pressure management, as implemented in SPRINT, may help ensure equitable care is provided to all patients and could reduce the contribution of therapeutic inertia to disparities in uncontrolled blood pressure,” the authors say.
They point out that therapeutic inertia has been identified as a key clinician-level barrier to blood pressure control and is estimated to be present in more than 80% of clinic visits in community practice, whereas in the current analysis of the SPRINT trial, therapeutic inertia was present in 50% to 60% of participant visits with uncontrolled blood pressure.
“In SPRINT, blood pressure had to be measured at defined intervals with a specific method, and there were clear instructions on intensifying treatment if blood pressure was above a certain goal,” Dr. Zheutlin noted. “Our results show that within such strict confines, therapeutic inertia does not seem to be different between different racial groups. This suggests that we could make better gains in blood pressure control and more equitable treatment if we adopted a standardized approach to hypertension management.”
He added: “Many guidelines have been published on when to start treatment and the targets for blood pressure, but there is a lot of variation in how we turn these guidelines into protocols. We need to bring in more consistent protocols on blood pressure measurement and intensification and ensure they are followed. In practice, if the BP is 5 or 10 mm Hg above target, a clinician may defer a decision to intensify treatment and intensification never gets done. But if there was a strict protocol to follow, there would be less chance of this happening.”
Therapeutic inertia still high
In an accompanying commentary, Matthew Rivara, MD, Nisha Bansal, MD, and Bessie Young, MD, University of Washington, Seattle, say the current SPRINT analysis has broad implications for reducing racial and ethnic disparities in achievement of evidence-based treatment targets in the general population.
“In hypertension management, standardized protocols for medication adjustments may limit clinician practice heterogeneity to ultimately reduce differences in blood pressure control among racial and ethnic minority populations,” they write. But they add that such protocols must be implemented thoughtfully to incorporate individualized clinical assessment and clinician-patient shared decision-making.
Dr. Rivara et al. point out that the rates of therapeutic inertia in SPRINT, while lower than community-based estimates, were still very high. They suggest reasons for this could include clinician concerns about medication efficacy, adverse effects, and patient mistrust of medical professionals. Outside the clinical trial environment, additional considerations may include prescription drug and laboratory test costs, pharmacy access, and competing demands during busy clinic visits.
To address these challenges, they say that clinicians need education on current clinical practice guidelines, managing complications of intensified antihypertensive therapies, and shared decisionmaking, including culturally sensitive collaborative care. Similarly, care systems must support patients on how to address concerns about treatments.
Finally, further research is needed to better define the specific factors associated with therapeutic inertia to allow tailored interventions to overcome this inertia.
“In designing and performing such research, it is vital that investigators engage with racial and ethnic minority groups to better explore the intersection of race, ethnicity, therapeutic decision-making, trust, and shared decisionmaking,” they add.
The SPRINT trial was funded with federal funds from the National Institutes of Health. Dr. Zheutlin reported receiving grants from the NIH during the conduct of the study.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Cardiac inflammation can be present after mild COVID infection
Myocardial inflammation is present in a small proportion of patients who have recovered from relatively mild cases of COVID-19 infection, a new study shows.
“Our findings suggest that even in patients who have had relatively mild cases of COVID-19, some will have inflammatory changes to the heart, and these changes can be present without any cardiac symptoms,” senior author, Paaladinesh Thavendiranathan, MD, University of Toronto, told this news organization.
“While our data suggest that this inflammation improves over time, and the outcomes seem positive, we don’t know if there will be any long-term consequences,” he added.
Noting that even a short period of inflammation in the heart may be associated with symptoms or arrhythmias in the longer term, Dr. Thavendiranathan said: “I would recommend that it is best to avoid getting the infection if there is any chance of heart inflammation.”
The study was published online in JAMA Cardiology on Jan. 12.
The authors explain that among patients hospitalized with COVID, early studies suggested that approximately one in four experience cardiovascular injury, defined as an elevation in troponin levels, which was associated with a 5- to 10-fold increase in the risk for death. But there is limited information on cardiac injury in patients who do not require hospitalization.
Although a broad range of abnormal myocardial tissue has been reported in several cardiac MRI studies of patients recovered from COVID infection, there is little understanding of persistent changes in myocardial metabolism in recovered patients, which is a potential concern, given that COVID-19 is associated with systemic inflammation during the acute illness, they say.
For the current study, the researchers examined myocardial inflammation measured using two different methods – cardiac MRI and fluorodeoxyglucose–positron emission tomography (FDG-PET) – in individuals who had recovered from COVID-19 infection and looked at how this related to changes in inflammatory blood markers.
Lead author Kate Hanneman, MD, also from the University of Toronto, explained that FDG-PET imaging is more sensitive than MRI in detecting active inflammation. “Inflammatory cells have a higher uptake of glucose, and FDG-PET imaging is used to look for metabolically active inflammatory tissue that takes up glucose. It gives complementary information to MRI. Cardiac MRI shows structural or functional changes, such as scarring or edema, whereas FDG-PET imaging directly measures metabolic activity related to inflammatory cells.”
The study involved 47 individuals, 51% female, with a mean age of 43 years, who had recently recovered from COVID-19 infection. Of these, the majority had had relatively mild COVID disease, with 85% not requiring hospitalization.
Cardiac imaging was performed a mean of 67 days after the diagnosis of COVID-19. At the time of imaging, 19 participants (40%) reported at least one cardiac symptom, including palpitations, chest pain, and shortness of breath.
Results showed that eight patients (17%) had focal FDG uptake on PET consistent with myocardial inflammation. Compared with those without FDG uptake, patients with focal FDG uptake had higher regional T2, T1, and extracellular volume (colocalizing with focal FDG uptake), higher prevalence of late gadolinium enhancement indicating fibrosis, lower left ventricular ejection fraction, worse global longitudinal and circumferential strain, and higher systemic inflammatory blood markers, including interleukin (IL)-6, IL- 8, an high-sensitivity C-reactive protein.
Of the 47 patients in the study, 13 had received at least one dose of a COVID-19 vaccine. There was no significant difference in the proportion of patients who were PET-positive among those who had received a COVID-19 vaccine and those who had not.
There was also no difference in inflammation in patients who had been hospitalized with COVID-19 and those who had managed their infection at home.
Among patients with focal FDG uptake, PET, MRI, and inflammatory blood markers improved at follow-up imaging performed a mean of 52 days after the first imaging. The authors say this suggests that these abnormalities were not related to pre-existing cardiovascular disease.
Of the eight patients with positive FDG-PET results, two did not show any MRI abnormalities. These two patients also had elevated inflammatory biomarkers. “PET is a more sensitive method of measuring cardiac inflammation, and our results show that these changes may not always translate into functional changes seen on MRI,” Dr. Thavendiranathan noted.
The only cardiac risk factor that was more common in participants with FDG uptake was hypertension. Although cardiac symptoms were nearly twice as common in participants with focal FDG uptake, this difference was not statistically significant.
“Given the growing number of survivors with similar symptoms, these interesting findings warrant further investigation,” the authors say.
Noting that FDG uptake correlated with elevations in systemic inflammatory biomarkers, the researchers suggest that “a more intense systemic inflammatory process may be contributing to cardiac inflammation and the consequential alteration to regional and global myocardial function in PET-positive participants.”
On repeat imaging 2 months later, all eight patients who showed FDG uptake showed improvement or resolution of inflammation without any treatment, although two patients still had some signs of inflammation. Blood biomarkers also improved on follow-up.
“This is encouraging information, but we need longer-term data to see if there are any long-term repercussions of this inflammation,” Dr. Hanneman said.
“Overall, the study findings suggest an imaging phenotype that is expected to have good prognosis. However, longer-term follow-up studies are required to understand the need for ongoing cardiac surveillance, relationship to cardiac symptoms, guidance for safe return to exercise and sports participation, and long-term cardiovascular disease risk,” the researchers state.
This study was funded by grants from the Joint Department of Medical Imaging Academic Incentive Fund, Peter Munk Cardiac Center Innovation Committee, and Ted Rogers Center for Heart Research. Dr. Hanneman reports personal fees from Sanofi Genzyme, Amicus, and Medscape outside the submitted work.
A version of this article first appeared on Medscape.com.
Myocardial inflammation is present in a small proportion of patients who have recovered from relatively mild cases of COVID-19 infection, a new study shows.
“Our findings suggest that even in patients who have had relatively mild cases of COVID-19, some will have inflammatory changes to the heart, and these changes can be present without any cardiac symptoms,” senior author, Paaladinesh Thavendiranathan, MD, University of Toronto, told this news organization.
“While our data suggest that this inflammation improves over time, and the outcomes seem positive, we don’t know if there will be any long-term consequences,” he added.
Noting that even a short period of inflammation in the heart may be associated with symptoms or arrhythmias in the longer term, Dr. Thavendiranathan said: “I would recommend that it is best to avoid getting the infection if there is any chance of heart inflammation.”
The study was published online in JAMA Cardiology on Jan. 12.
The authors explain that among patients hospitalized with COVID, early studies suggested that approximately one in four experience cardiovascular injury, defined as an elevation in troponin levels, which was associated with a 5- to 10-fold increase in the risk for death. But there is limited information on cardiac injury in patients who do not require hospitalization.
Although a broad range of abnormal myocardial tissue has been reported in several cardiac MRI studies of patients recovered from COVID infection, there is little understanding of persistent changes in myocardial metabolism in recovered patients, which is a potential concern, given that COVID-19 is associated with systemic inflammation during the acute illness, they say.
For the current study, the researchers examined myocardial inflammation measured using two different methods – cardiac MRI and fluorodeoxyglucose–positron emission tomography (FDG-PET) – in individuals who had recovered from COVID-19 infection and looked at how this related to changes in inflammatory blood markers.
Lead author Kate Hanneman, MD, also from the University of Toronto, explained that FDG-PET imaging is more sensitive than MRI in detecting active inflammation. “Inflammatory cells have a higher uptake of glucose, and FDG-PET imaging is used to look for metabolically active inflammatory tissue that takes up glucose. It gives complementary information to MRI. Cardiac MRI shows structural or functional changes, such as scarring or edema, whereas FDG-PET imaging directly measures metabolic activity related to inflammatory cells.”
The study involved 47 individuals, 51% female, with a mean age of 43 years, who had recently recovered from COVID-19 infection. Of these, the majority had had relatively mild COVID disease, with 85% not requiring hospitalization.
Cardiac imaging was performed a mean of 67 days after the diagnosis of COVID-19. At the time of imaging, 19 participants (40%) reported at least one cardiac symptom, including palpitations, chest pain, and shortness of breath.
Results showed that eight patients (17%) had focal FDG uptake on PET consistent with myocardial inflammation. Compared with those without FDG uptake, patients with focal FDG uptake had higher regional T2, T1, and extracellular volume (colocalizing with focal FDG uptake), higher prevalence of late gadolinium enhancement indicating fibrosis, lower left ventricular ejection fraction, worse global longitudinal and circumferential strain, and higher systemic inflammatory blood markers, including interleukin (IL)-6, IL- 8, an high-sensitivity C-reactive protein.
Of the 47 patients in the study, 13 had received at least one dose of a COVID-19 vaccine. There was no significant difference in the proportion of patients who were PET-positive among those who had received a COVID-19 vaccine and those who had not.
There was also no difference in inflammation in patients who had been hospitalized with COVID-19 and those who had managed their infection at home.
Among patients with focal FDG uptake, PET, MRI, and inflammatory blood markers improved at follow-up imaging performed a mean of 52 days after the first imaging. The authors say this suggests that these abnormalities were not related to pre-existing cardiovascular disease.
Of the eight patients with positive FDG-PET results, two did not show any MRI abnormalities. These two patients also had elevated inflammatory biomarkers. “PET is a more sensitive method of measuring cardiac inflammation, and our results show that these changes may not always translate into functional changes seen on MRI,” Dr. Thavendiranathan noted.
The only cardiac risk factor that was more common in participants with FDG uptake was hypertension. Although cardiac symptoms were nearly twice as common in participants with focal FDG uptake, this difference was not statistically significant.
“Given the growing number of survivors with similar symptoms, these interesting findings warrant further investigation,” the authors say.
Noting that FDG uptake correlated with elevations in systemic inflammatory biomarkers, the researchers suggest that “a more intense systemic inflammatory process may be contributing to cardiac inflammation and the consequential alteration to regional and global myocardial function in PET-positive participants.”
On repeat imaging 2 months later, all eight patients who showed FDG uptake showed improvement or resolution of inflammation without any treatment, although two patients still had some signs of inflammation. Blood biomarkers also improved on follow-up.
“This is encouraging information, but we need longer-term data to see if there are any long-term repercussions of this inflammation,” Dr. Hanneman said.
“Overall, the study findings suggest an imaging phenotype that is expected to have good prognosis. However, longer-term follow-up studies are required to understand the need for ongoing cardiac surveillance, relationship to cardiac symptoms, guidance for safe return to exercise and sports participation, and long-term cardiovascular disease risk,” the researchers state.
This study was funded by grants from the Joint Department of Medical Imaging Academic Incentive Fund, Peter Munk Cardiac Center Innovation Committee, and Ted Rogers Center for Heart Research. Dr. Hanneman reports personal fees from Sanofi Genzyme, Amicus, and Medscape outside the submitted work.
A version of this article first appeared on Medscape.com.
Myocardial inflammation is present in a small proportion of patients who have recovered from relatively mild cases of COVID-19 infection, a new study shows.
“Our findings suggest that even in patients who have had relatively mild cases of COVID-19, some will have inflammatory changes to the heart, and these changes can be present without any cardiac symptoms,” senior author, Paaladinesh Thavendiranathan, MD, University of Toronto, told this news organization.
“While our data suggest that this inflammation improves over time, and the outcomes seem positive, we don’t know if there will be any long-term consequences,” he added.
Noting that even a short period of inflammation in the heart may be associated with symptoms or arrhythmias in the longer term, Dr. Thavendiranathan said: “I would recommend that it is best to avoid getting the infection if there is any chance of heart inflammation.”
The study was published online in JAMA Cardiology on Jan. 12.
The authors explain that among patients hospitalized with COVID, early studies suggested that approximately one in four experience cardiovascular injury, defined as an elevation in troponin levels, which was associated with a 5- to 10-fold increase in the risk for death. But there is limited information on cardiac injury in patients who do not require hospitalization.
Although a broad range of abnormal myocardial tissue has been reported in several cardiac MRI studies of patients recovered from COVID infection, there is little understanding of persistent changes in myocardial metabolism in recovered patients, which is a potential concern, given that COVID-19 is associated with systemic inflammation during the acute illness, they say.
For the current study, the researchers examined myocardial inflammation measured using two different methods – cardiac MRI and fluorodeoxyglucose–positron emission tomography (FDG-PET) – in individuals who had recovered from COVID-19 infection and looked at how this related to changes in inflammatory blood markers.
Lead author Kate Hanneman, MD, also from the University of Toronto, explained that FDG-PET imaging is more sensitive than MRI in detecting active inflammation. “Inflammatory cells have a higher uptake of glucose, and FDG-PET imaging is used to look for metabolically active inflammatory tissue that takes up glucose. It gives complementary information to MRI. Cardiac MRI shows structural or functional changes, such as scarring or edema, whereas FDG-PET imaging directly measures metabolic activity related to inflammatory cells.”
The study involved 47 individuals, 51% female, with a mean age of 43 years, who had recently recovered from COVID-19 infection. Of these, the majority had had relatively mild COVID disease, with 85% not requiring hospitalization.
Cardiac imaging was performed a mean of 67 days after the diagnosis of COVID-19. At the time of imaging, 19 participants (40%) reported at least one cardiac symptom, including palpitations, chest pain, and shortness of breath.
Results showed that eight patients (17%) had focal FDG uptake on PET consistent with myocardial inflammation. Compared with those without FDG uptake, patients with focal FDG uptake had higher regional T2, T1, and extracellular volume (colocalizing with focal FDG uptake), higher prevalence of late gadolinium enhancement indicating fibrosis, lower left ventricular ejection fraction, worse global longitudinal and circumferential strain, and higher systemic inflammatory blood markers, including interleukin (IL)-6, IL- 8, an high-sensitivity C-reactive protein.
Of the 47 patients in the study, 13 had received at least one dose of a COVID-19 vaccine. There was no significant difference in the proportion of patients who were PET-positive among those who had received a COVID-19 vaccine and those who had not.
There was also no difference in inflammation in patients who had been hospitalized with COVID-19 and those who had managed their infection at home.
Among patients with focal FDG uptake, PET, MRI, and inflammatory blood markers improved at follow-up imaging performed a mean of 52 days after the first imaging. The authors say this suggests that these abnormalities were not related to pre-existing cardiovascular disease.
Of the eight patients with positive FDG-PET results, two did not show any MRI abnormalities. These two patients also had elevated inflammatory biomarkers. “PET is a more sensitive method of measuring cardiac inflammation, and our results show that these changes may not always translate into functional changes seen on MRI,” Dr. Thavendiranathan noted.
The only cardiac risk factor that was more common in participants with FDG uptake was hypertension. Although cardiac symptoms were nearly twice as common in participants with focal FDG uptake, this difference was not statistically significant.
“Given the growing number of survivors with similar symptoms, these interesting findings warrant further investigation,” the authors say.
Noting that FDG uptake correlated with elevations in systemic inflammatory biomarkers, the researchers suggest that “a more intense systemic inflammatory process may be contributing to cardiac inflammation and the consequential alteration to regional and global myocardial function in PET-positive participants.”
On repeat imaging 2 months later, all eight patients who showed FDG uptake showed improvement or resolution of inflammation without any treatment, although two patients still had some signs of inflammation. Blood biomarkers also improved on follow-up.
“This is encouraging information, but we need longer-term data to see if there are any long-term repercussions of this inflammation,” Dr. Hanneman said.
“Overall, the study findings suggest an imaging phenotype that is expected to have good prognosis. However, longer-term follow-up studies are required to understand the need for ongoing cardiac surveillance, relationship to cardiac symptoms, guidance for safe return to exercise and sports participation, and long-term cardiovascular disease risk,” the researchers state.
This study was funded by grants from the Joint Department of Medical Imaging Academic Incentive Fund, Peter Munk Cardiac Center Innovation Committee, and Ted Rogers Center for Heart Research. Dr. Hanneman reports personal fees from Sanofi Genzyme, Amicus, and Medscape outside the submitted work.
A version of this article first appeared on Medscape.com.
What does a pig-to-human heart transplant mean for medicine?
Scientific achievements usually raise big new questions, and the remarkable surgery that took place on Jan. 7, when Maryland resident David Bennett was transplanted with a genetically modified heart from a pig, has been no different.
The 57-year-old with end-stage heart failure had been repeatedly turned down for a standard transplant and was judged a poor candidate for a ventricular assist device. Now his new heart is beating soundly and apparently accepted by his immune system as Mr. Bennett, his physicians at the University of Maryland where the procedure took place, and indeed the world set out on a journey with far more unknowns than knowns.
“I think even just a couple of years ago, people felt that xenotransplantation for the heart and other organs was still a long way off. And it seems like it’s started to move very quickly,” Larry A. Allen, MD, University of Colorado, Aurora, said in an interview.
Demand for donor hearts far outstrips supply, and despite advances in the development of ventricular assist pumps and artificial hearts, “there are still significant limitations to them in terms of clotting, stroke, and infection. We’ve seen the use of those devices plateau,” Dr. Allen said. “So, the concept of a nonhuman source of organs is exciting and very much in need, if people can get it to work.”
“I really credit the surgeons at the University of Maryland for courageous clinical work and a brilliant scientific innovation,” Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, said in an interview. “But it’s always in the implementation that we have to hold our breath.” Heart xenotransplantation is an old idea that “has never before been successful,” he said. And standard heart transplantation has set a high bar, with a 1-year survival of about 90% and low 1-year risk for rejection. Whether the new procedure can meet that standard is unknown, as is its potential for complications, such as chronic rejection or cancers due to long-term immunosuppression. Those are “major questions requiring more time and careful follow-up.”
‘Still a nascent technology’
“This is an exciting and courageous step forward in heart transplantation, and kudos to the team at the University of Maryland,” said Mandeep R. Mehra, MD, Brigham and Woman’s Hospital, Boston. But “there are many challenges here.”
The procedure’s 10 gene modifications were reportedly aimed at preventing hyperacute rejection of the heart and its excessive growth after transplantation, and making the organ less immunogenic, Dr. Mehra said in an interview. But even if those goals are met, could the same changes potentially impede the heart’s adaptation to human physiology, such as during ambulation or stress?
That kind of adaptation may become important. For example, Dr. Mehra observed, normally a pig heart “provides flow in a four-footed configuration, and pig temperature is inherently higher than humans by several degrees, so it will be functioning in a relatively hypothermic environment.”
Transplantation remains the gold standard for patients with advanced heart failure despite modern medical and device therapy, Dr. Allen agreed. But “if we can raise pig hearts that provide the organ, and it can be implanted with a surgery that’s been done for 50 years, and rejection can be managed with gene editing and tailored immunosuppression, then it’s not hard to think about this very rapidly replacing a lot of what we do in the advanced heart failure and transplantation world.”
Certainly, it would be a major advance if the gene editing technique successfully improves the heart’s immunologic compatibility, Dr. Yancy noted. But do we have enough genomic knowledge to select gene deletions and insertions in the safest way for a successful outcome? “We have to appreciate that this is still a nascent technology, and we should be careful that there might be consequences that we haven’t anticipated.”
For example, he said, the xenotransplantation and gene-modifying techniques should be explored in a range of patients, including older and younger people, women and men, and people of different ethnicities and races.
“There may be some differences based on ancestry, based on gender, based on aging, that will influence the way in which these engineered donor hearts are experienced clinically,” Dr. Yancy said.
The xenotransplantation technique’s potential impact on health equity should also be considered, as it “almost assuredly will be a very expensive technology that will be utilized in a very select population,” he noted. “We need to have a really wide lens to think about all of the potential ramifications.”
‘This field needs to evolve’
Dr. Mehra also flagged the procedure’s potential cost should it become mainstream. Perhaps that would promote dialogue on how to primarily use it “after legitimately exhausting all available options, such as total artificial heart support.”
It might also teach the field to take greater advantage of the many donated hearts discarded as suboptimal. “The general usage rate for offered organs is around a third,” despite opportunities to expand use of those that are “less than perfect,” Dr. Mehra said. “I think that the field will grow with the community focusing on reduced discards of current available heart organs, and not necessarily grow because of the availability of ‘xeno-organs.’ ”
“This field needs to evolve because we’re actively transplanting patients today. But in my mind, the real future is to have such a sufficient understanding of the biology of left ventricular dysfunction that transplantation is a rare event,” Dr. Yancy proposed.
“I’m not certain that heart transplantation per se is the endgame. I think the avoidance of transplantation is the real endgame,” he said. “This may be controversial, but my vision of the future is not one where we have a supply of animals that we can use for transplantation. My vision of the future is that heart transplantation becomes obsolete.”
A version of this article first appeared on Medscape.com.
Scientific achievements usually raise big new questions, and the remarkable surgery that took place on Jan. 7, when Maryland resident David Bennett was transplanted with a genetically modified heart from a pig, has been no different.
The 57-year-old with end-stage heart failure had been repeatedly turned down for a standard transplant and was judged a poor candidate for a ventricular assist device. Now his new heart is beating soundly and apparently accepted by his immune system as Mr. Bennett, his physicians at the University of Maryland where the procedure took place, and indeed the world set out on a journey with far more unknowns than knowns.
“I think even just a couple of years ago, people felt that xenotransplantation for the heart and other organs was still a long way off. And it seems like it’s started to move very quickly,” Larry A. Allen, MD, University of Colorado, Aurora, said in an interview.
Demand for donor hearts far outstrips supply, and despite advances in the development of ventricular assist pumps and artificial hearts, “there are still significant limitations to them in terms of clotting, stroke, and infection. We’ve seen the use of those devices plateau,” Dr. Allen said. “So, the concept of a nonhuman source of organs is exciting and very much in need, if people can get it to work.”
“I really credit the surgeons at the University of Maryland for courageous clinical work and a brilliant scientific innovation,” Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, said in an interview. “But it’s always in the implementation that we have to hold our breath.” Heart xenotransplantation is an old idea that “has never before been successful,” he said. And standard heart transplantation has set a high bar, with a 1-year survival of about 90% and low 1-year risk for rejection. Whether the new procedure can meet that standard is unknown, as is its potential for complications, such as chronic rejection or cancers due to long-term immunosuppression. Those are “major questions requiring more time and careful follow-up.”
‘Still a nascent technology’
“This is an exciting and courageous step forward in heart transplantation, and kudos to the team at the University of Maryland,” said Mandeep R. Mehra, MD, Brigham and Woman’s Hospital, Boston. But “there are many challenges here.”
The procedure’s 10 gene modifications were reportedly aimed at preventing hyperacute rejection of the heart and its excessive growth after transplantation, and making the organ less immunogenic, Dr. Mehra said in an interview. But even if those goals are met, could the same changes potentially impede the heart’s adaptation to human physiology, such as during ambulation or stress?
That kind of adaptation may become important. For example, Dr. Mehra observed, normally a pig heart “provides flow in a four-footed configuration, and pig temperature is inherently higher than humans by several degrees, so it will be functioning in a relatively hypothermic environment.”
Transplantation remains the gold standard for patients with advanced heart failure despite modern medical and device therapy, Dr. Allen agreed. But “if we can raise pig hearts that provide the organ, and it can be implanted with a surgery that’s been done for 50 years, and rejection can be managed with gene editing and tailored immunosuppression, then it’s not hard to think about this very rapidly replacing a lot of what we do in the advanced heart failure and transplantation world.”
Certainly, it would be a major advance if the gene editing technique successfully improves the heart’s immunologic compatibility, Dr. Yancy noted. But do we have enough genomic knowledge to select gene deletions and insertions in the safest way for a successful outcome? “We have to appreciate that this is still a nascent technology, and we should be careful that there might be consequences that we haven’t anticipated.”
For example, he said, the xenotransplantation and gene-modifying techniques should be explored in a range of patients, including older and younger people, women and men, and people of different ethnicities and races.
“There may be some differences based on ancestry, based on gender, based on aging, that will influence the way in which these engineered donor hearts are experienced clinically,” Dr. Yancy said.
The xenotransplantation technique’s potential impact on health equity should also be considered, as it “almost assuredly will be a very expensive technology that will be utilized in a very select population,” he noted. “We need to have a really wide lens to think about all of the potential ramifications.”
‘This field needs to evolve’
Dr. Mehra also flagged the procedure’s potential cost should it become mainstream. Perhaps that would promote dialogue on how to primarily use it “after legitimately exhausting all available options, such as total artificial heart support.”
It might also teach the field to take greater advantage of the many donated hearts discarded as suboptimal. “The general usage rate for offered organs is around a third,” despite opportunities to expand use of those that are “less than perfect,” Dr. Mehra said. “I think that the field will grow with the community focusing on reduced discards of current available heart organs, and not necessarily grow because of the availability of ‘xeno-organs.’ ”
“This field needs to evolve because we’re actively transplanting patients today. But in my mind, the real future is to have such a sufficient understanding of the biology of left ventricular dysfunction that transplantation is a rare event,” Dr. Yancy proposed.
“I’m not certain that heart transplantation per se is the endgame. I think the avoidance of transplantation is the real endgame,” he said. “This may be controversial, but my vision of the future is not one where we have a supply of animals that we can use for transplantation. My vision of the future is that heart transplantation becomes obsolete.”
A version of this article first appeared on Medscape.com.
Scientific achievements usually raise big new questions, and the remarkable surgery that took place on Jan. 7, when Maryland resident David Bennett was transplanted with a genetically modified heart from a pig, has been no different.
The 57-year-old with end-stage heart failure had been repeatedly turned down for a standard transplant and was judged a poor candidate for a ventricular assist device. Now his new heart is beating soundly and apparently accepted by his immune system as Mr. Bennett, his physicians at the University of Maryland where the procedure took place, and indeed the world set out on a journey with far more unknowns than knowns.
“I think even just a couple of years ago, people felt that xenotransplantation for the heart and other organs was still a long way off. And it seems like it’s started to move very quickly,” Larry A. Allen, MD, University of Colorado, Aurora, said in an interview.
Demand for donor hearts far outstrips supply, and despite advances in the development of ventricular assist pumps and artificial hearts, “there are still significant limitations to them in terms of clotting, stroke, and infection. We’ve seen the use of those devices plateau,” Dr. Allen said. “So, the concept of a nonhuman source of organs is exciting and very much in need, if people can get it to work.”
“I really credit the surgeons at the University of Maryland for courageous clinical work and a brilliant scientific innovation,” Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, said in an interview. “But it’s always in the implementation that we have to hold our breath.” Heart xenotransplantation is an old idea that “has never before been successful,” he said. And standard heart transplantation has set a high bar, with a 1-year survival of about 90% and low 1-year risk for rejection. Whether the new procedure can meet that standard is unknown, as is its potential for complications, such as chronic rejection or cancers due to long-term immunosuppression. Those are “major questions requiring more time and careful follow-up.”
‘Still a nascent technology’
“This is an exciting and courageous step forward in heart transplantation, and kudos to the team at the University of Maryland,” said Mandeep R. Mehra, MD, Brigham and Woman’s Hospital, Boston. But “there are many challenges here.”
The procedure’s 10 gene modifications were reportedly aimed at preventing hyperacute rejection of the heart and its excessive growth after transplantation, and making the organ less immunogenic, Dr. Mehra said in an interview. But even if those goals are met, could the same changes potentially impede the heart’s adaptation to human physiology, such as during ambulation or stress?
That kind of adaptation may become important. For example, Dr. Mehra observed, normally a pig heart “provides flow in a four-footed configuration, and pig temperature is inherently higher than humans by several degrees, so it will be functioning in a relatively hypothermic environment.”
Transplantation remains the gold standard for patients with advanced heart failure despite modern medical and device therapy, Dr. Allen agreed. But “if we can raise pig hearts that provide the organ, and it can be implanted with a surgery that’s been done for 50 years, and rejection can be managed with gene editing and tailored immunosuppression, then it’s not hard to think about this very rapidly replacing a lot of what we do in the advanced heart failure and transplantation world.”
Certainly, it would be a major advance if the gene editing technique successfully improves the heart’s immunologic compatibility, Dr. Yancy noted. But do we have enough genomic knowledge to select gene deletions and insertions in the safest way for a successful outcome? “We have to appreciate that this is still a nascent technology, and we should be careful that there might be consequences that we haven’t anticipated.”
For example, he said, the xenotransplantation and gene-modifying techniques should be explored in a range of patients, including older and younger people, women and men, and people of different ethnicities and races.
“There may be some differences based on ancestry, based on gender, based on aging, that will influence the way in which these engineered donor hearts are experienced clinically,” Dr. Yancy said.
The xenotransplantation technique’s potential impact on health equity should also be considered, as it “almost assuredly will be a very expensive technology that will be utilized in a very select population,” he noted. “We need to have a really wide lens to think about all of the potential ramifications.”
‘This field needs to evolve’
Dr. Mehra also flagged the procedure’s potential cost should it become mainstream. Perhaps that would promote dialogue on how to primarily use it “after legitimately exhausting all available options, such as total artificial heart support.”
It might also teach the field to take greater advantage of the many donated hearts discarded as suboptimal. “The general usage rate for offered organs is around a third,” despite opportunities to expand use of those that are “less than perfect,” Dr. Mehra said. “I think that the field will grow with the community focusing on reduced discards of current available heart organs, and not necessarily grow because of the availability of ‘xeno-organs.’ ”
“This field needs to evolve because we’re actively transplanting patients today. But in my mind, the real future is to have such a sufficient understanding of the biology of left ventricular dysfunction that transplantation is a rare event,” Dr. Yancy proposed.
“I’m not certain that heart transplantation per se is the endgame. I think the avoidance of transplantation is the real endgame,” he said. “This may be controversial, but my vision of the future is not one where we have a supply of animals that we can use for transplantation. My vision of the future is that heart transplantation becomes obsolete.”
A version of this article first appeared on Medscape.com.
Pig heart successfully transplanted to man
A genetically modified pig heart has been successfully transplanted into a 57-year-old man who had no other treatment options but is “doing well” 3 days after the procedure, officials at the University of Maryland Medical Center (UMMC), Baltimore, announced Jan. 10.
“This organ transplant demonstrated for the first time that a genetically modified animal heart can function like a human heart without immediate rejection by the body,” they said.
Three genes associated with antibody-mediated rejection had been knocked out in the pig supplying the transplanted heart, and six human genes associated with immune acceptance of the organ had been inserted into the pig’s genome, notes a UMMC press release.
“Lastly, one additional gene in the pig was knocked out to prevent excessive growth of the pig heart tissue, which totaled 10 unique gene edits made in the donor pig,” the release states.
The patient, Maryland resident David Bennett, had required mechanical circulatory support to stay alive but was rejected for standard heart transplantation at UMMC and other centers. He was ineligible for an implanted ventricular assist device due to ventricular arrhythmias.
Mr. Bennett “is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits,” the announcement says.
“We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future,” notes a quote from Bartley P. Griffith, MD, the UMMC surgeon who performed the procedure.
The pig supplying the heart was provided to the center by Revivicor (Blacksburg, Virginia), a regenerative medicine company. An experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Massachusetts) was also used, in addition to standard immunosuppressants.
A version of this article first appeared on Medscape.com.
A genetically modified pig heart has been successfully transplanted into a 57-year-old man who had no other treatment options but is “doing well” 3 days after the procedure, officials at the University of Maryland Medical Center (UMMC), Baltimore, announced Jan. 10.
“This organ transplant demonstrated for the first time that a genetically modified animal heart can function like a human heart without immediate rejection by the body,” they said.
Three genes associated with antibody-mediated rejection had been knocked out in the pig supplying the transplanted heart, and six human genes associated with immune acceptance of the organ had been inserted into the pig’s genome, notes a UMMC press release.
“Lastly, one additional gene in the pig was knocked out to prevent excessive growth of the pig heart tissue, which totaled 10 unique gene edits made in the donor pig,” the release states.
The patient, Maryland resident David Bennett, had required mechanical circulatory support to stay alive but was rejected for standard heart transplantation at UMMC and other centers. He was ineligible for an implanted ventricular assist device due to ventricular arrhythmias.
Mr. Bennett “is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits,” the announcement says.
“We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future,” notes a quote from Bartley P. Griffith, MD, the UMMC surgeon who performed the procedure.
The pig supplying the heart was provided to the center by Revivicor (Blacksburg, Virginia), a regenerative medicine company. An experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Massachusetts) was also used, in addition to standard immunosuppressants.
A version of this article first appeared on Medscape.com.
A genetically modified pig heart has been successfully transplanted into a 57-year-old man who had no other treatment options but is “doing well” 3 days after the procedure, officials at the University of Maryland Medical Center (UMMC), Baltimore, announced Jan. 10.
“This organ transplant demonstrated for the first time that a genetically modified animal heart can function like a human heart without immediate rejection by the body,” they said.
Three genes associated with antibody-mediated rejection had been knocked out in the pig supplying the transplanted heart, and six human genes associated with immune acceptance of the organ had been inserted into the pig’s genome, notes a UMMC press release.
“Lastly, one additional gene in the pig was knocked out to prevent excessive growth of the pig heart tissue, which totaled 10 unique gene edits made in the donor pig,” the release states.
The patient, Maryland resident David Bennett, had required mechanical circulatory support to stay alive but was rejected for standard heart transplantation at UMMC and other centers. He was ineligible for an implanted ventricular assist device due to ventricular arrhythmias.
Mr. Bennett “is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits,” the announcement says.
“We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future,” notes a quote from Bartley P. Griffith, MD, the UMMC surgeon who performed the procedure.
The pig supplying the heart was provided to the center by Revivicor (Blacksburg, Virginia), a regenerative medicine company. An experimental antirejection medication (Kiniksa Pharmaceuticals; Lexington, Massachusetts) was also used, in addition to standard immunosuppressants.
A version of this article first appeared on Medscape.com.
COVID-vaccine myocarditis: Rare, mild, and usually in young men
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
The risk of myocarditis after immunization with mRNA-based vaccines against SARS-CoV-2 raised concerns when it came to light in early 2021. But as report after report showed such cases to be rare and usually mild and self-limited, focus has turned to the “how and why.”
The mechanism linking the BNT162b2 (Pfizer-BioNTech) and especially mRNA-1273 (Moderna) vaccines to the occurrence of myocarditis is unclear for now, but one potential driver may be tied to a peculiarity that became apparent early: It occurs overwhelmingly in younger males, from 16 to perhaps 40 or 50 years of age. Excess risk has not been consistently seen among women, girls, and older men.
That observation has led to speculation that higher testosterone levels in adolescent boys and young men may somehow promote the adverse vaccine effect, whereas greater levels of estrogen among girls and women in the same age range may be cardioprotective.
Unlikely, brief, and ‘benign’
“Most of the myocarditis is benign, by which I mean that maybe the patients are admitted due to chest pain, but without reduction in ventricular function,” Enrico Ammirati, MD, PhD, a myocarditis expert at De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, said in an interview.
In a Nov. 14 address on this topic at the annual scientific sessions of the American Heart Association, Dror Mevorach, MD, described the typical case presentation as “mild” and one that clears in fairly short order based on resolution of “clinical symptoms, inflammatory markers and troponin decline, EKG normalization, echo normalization, and a relatively short length of hospital stay.”
Dr. Mevorach, of Hadassah Hebrew University Medical Center, Jerusalem, subsequently published the findings in a report in the New England Journal of Medicine that described 136 confirmed myocarditis cases among more than 5 million people in Israel immunized with the Pfizer-BioNTech vaccine. Myocarditis was considered “mild” in 129 cases, or 95%.
And the risk is tiny, compared with myocarditis from infection by SARS-CoV-2, not to mention the possibility of nasty clinical COVID-19 complications such as pneumonia and pulmonary embolism, Dr. Mevorach observed.
Many other reports agree that the incidence is minimal, especially given the rewards of vaccination. In a separate NEJM publication in September 2021 – from Noam Barda, MD, Clalit (Israel) Research Institute, and colleagues on 1.7 million people in that country, about half unvaccinated and half given the Pfizer-BioNTech vaccine – there were an estimated 2.7 cases of myocarditis per 100,000 vaccinated persons. There were also 11 cases of myocarditis per 100,000 persons who were positive for SARS-CoV-2 infection.
And in a recent case series of vaccinated people aged 16 or older, the myocarditis rate after a first or second Pfizer-BioNTech or Moderna injection was estimated at 1 or fewer per 100,000. The corresponding estimate was 4 such cases per 100,000 after a positive SARS-CoV-2 test among the same population, notes a report published Dec.14, 2021, in Nature Medicine.
In general, “the risk of any kind of cardiac injury is vastly lower with a vaccine than it is with the actual viral infection,” Leslie T. Cooper Jr., MD, a myocarditis expert and clinical trialist at the Mayo Clinic, Jacksonville, Fla., said in an interview. With the mRNA-based vaccines, “we do not have any conceivable danger signal that would outweigh the benefit of vaccination.”
Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”
Modulation of immune responses
Details about the immune processes underlying mRNA-vaccine myocarditis, hormone modulated or not, have been elusive. The complication doesn’t resemble serum sickness, nor does it seem to be a reaction to infection by other cardiotropic viruses, such as coxsackie virus B, a cause of viral myocarditis, Dr. Bozkurt said. The latter had been a compelling possibility because such hypersensitivity to smallpox vaccination is well recognized.
“We don’t know the mechanism, that’s the short answer. But there are many hypotheses,” she said. One candidate widely proposed in the literature: autoantibodies driven by molecular mimicry between the SARS-CoV-2 spike protein targeted by the mRNA vaccines and a structurally similar myocardial protein, possibly alpha-myosin, noted Dr. Bozkurt and colleagues in a recent publication.
But elevations in specific “antiheart antibodies” have not been documented in recipients of the two mRNA-based vaccines, said Dr. Cooper. “So, I would say that – although molecular mimicry is a well-established mechanism of, for example, rheumatic carditis after a streptococcal A infection – that has not been demonstrated yet for COVID-19 mRNA vaccination–related myocarditis.”
“We probably won’t know, ever, with a huge level of certainty, the exact mechanisms,” Dr. Cooper added. There is no animal model for vaccine-induced myocarditis, and “We’re still talking very, very small numbers of patients. The vast majority of them recover,” and so don’t generally provide mechanistic clues.
Prospects for younger children
Vaccination against SARS-CoV-2 has now been authorized by the Centers for Disease Control and Prevention for kids as young as 5-11 years, using the Pfizer-BioNTech vaccine. Experience so far suggests the immunization is safe in that age group with negligible risk of myocarditis or other complications. But with prospects of possible authorization in children younger than 5, should myocarditis be a concern for them?
Probably not, if the complication is driven primarily by sex hormones, Dr. Cooper proposed. “One would predict that before puberty you would have a lower – much, much lower – rate of myocarditis in males than you would in the 16- to 19-year-old range, and that it would be roughly equal to females.” Dr. Ammirati and Dr. Bozkurt largely agreed.
It remains to be seen whether the vaccine-related myocarditis risk applies to children younger than 12, “but I doubt it. I think it’s going to be puberty-related,” Dr. Bozkurt said. Still, “I don’t want to hypothesize without data.”
A version of this article first appeared on Medscape.com.
A high-risk medical device didn’t meet federal standards. The government paid millions for more
In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.
But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.
Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.
Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.
If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.
“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”
The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.
The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.
CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.
The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.
CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.
A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”
In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.
In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.
The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.
In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.
Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.
Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.
“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.
Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.
Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.
Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.
“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.
This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.
In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.
But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.
Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.
Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.
If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.
“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”
The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.
The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.
CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.
The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.
CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.
A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”
In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.
In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.
The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.
In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.
Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.
Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.
“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.
Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.
Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.
Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.
“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.
This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.
In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.
But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.
Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.
Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.
If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.
“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”
The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.
The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.
CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.
The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.
CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.
A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”
In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.
In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.
The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.
In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.
Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.
Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.
“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.
Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.
Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.
Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.
“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.
This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.
SGLT2 inhibitors improve cardiovascular outcomes across groups
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show “remarkable consistency of class benefit” for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.
The findings, from a meta-analysis of 10 major randomized clinical trials, were published online Jan. 5, 2021, in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at Southern Illinois University, Springfield, and colleagues.
“Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients,” Dr. Bhattarai and colleagues wrote.
The cardiovascular outcomes of SGLT2 inhibitor therapy, they noted, “can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled.”
However, they also noted that SGLT inhibitors did not reduce the risk of acute MIn overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.
Ten trials, consistent cardiovascular benefits
Dr. Bhattarai and colleagues searched the literature through Jan. 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled, randomized clinical trials in which participants had atherosclerotic cardiovascular disease or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.
The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors, compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2-inhibitor group, with a number needed to treat of 5.7 (P < .001).
Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal MI, or nonfatal stroke. Those events occurred in 9.82% versus 10.22%(OR, 0.90; P = .03).
Hospitalizations and ED visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs. 6.81%; OR, 0.67; P < .001), as was cardiovascular death (4.65% vs. 5.14%; OR, 0.87; P = .009). The reduction in heart failure is likely caused by a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors said.
On the other hand, no reductions were seen in acute MI, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors, compared with 4.70% of the placebo group, a nonsignificant difference with an OR of 0.95 (P = 0.22). This is likely because of the fact that SGLT2 inhibitors don’t have known antianginal properties or vasodilatory effects, they don’t reduce myocardial oxygen consumption, and they don’t prevent cardiac muscle remodeling, they noted.
All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% versus 7.86% (odds ratio, 0.87; P = .004).
Benefits seen across age, sex, and race/ethnicity subgroups
While no differences in benefit were found between men and women when compared with placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [OR, 0.75; P < .001] vs. 5.34% [OR, 0.78; P = .002]).
By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [OR, 0.79; P < 0.001] vs. 10.47% [OR, 0.78; P < .001]).
And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White, compared with those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (OR, 0.82; P < .001) and 8.75% (OR, 0.66; P = .06), respectively.
“Owing to the short-term trial durations, future long-term prospective studies and postmarketing surveillance studies are warranted to discover the rate of cardiovascular outcomes,” Dr. Bhattarai and colleagues concluded.
The authors have no disclosures.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Cardiac device interrogation after death ‘richly informative’
Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.
Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.
Their study results were published online in JACC: Clinical Electrophysiology.
Cause of death revealed in half of cases
They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.
Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.
Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.
CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.
In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.
In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.
“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.
And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.
Still, postmortem CIED interrogation remains uncommon, the study team notes.
They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.
“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.
The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.
Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.
Their study results were published online in JACC: Clinical Electrophysiology.
Cause of death revealed in half of cases
They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.
Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.
Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.
CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.
In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.
In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.
“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.
And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.
Still, postmortem CIED interrogation remains uncommon, the study team notes.
They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.
“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.
The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Interrogating the cardiac implantable electronic device (CIED) after death can yield important information about critical device malfunction, premortem abnormalities, and the mechanism and timing of death, a new study suggests.
Postmortem CIED interrogation is “richly informative” in assisting both cardiac and forensic investigations and “should be considered for select patients with CIEDs undergoing autopsy,” say Elizabeth Paratz, MBBS, department of cardiology, Baker Heart and Diabetes Institute, Prahran, Australia, and colleagues.
Their study results were published online in JACC: Clinical Electrophysiology.
Cause of death revealed in half of cases
They reviewed CIED interrogations in 260 deceased individuals undergoing medicolegal investigation of sudden death (162 patients) or unexplained death (98 patients) by the Victorian Institute of Forensic Medicine between 2005 and 2020.
Roughly two-thirds were male (68.8%) and their median age was 72.8 years; 202 patients had pacemakers, 56 had defibrillators, and 2 had loop recorders. The cause of death was cardiac in 79.6% of cases.
Postmortem CIED interrogation was successful in 98.5% cases and directly informed cause of death in 131 cases (50.4%), with fatal ventricular arrhythmias identified in 121 patients.
CIED interrogation assisted in determining the cause of death in 63.6% of cases of sudden death and 28.6% of nonsudden death cases.
In 20 cases (7.7%), CIED interrogation uncovered potential device malfunction. Issues included failure to appropriately treat ventricular arrhythmias in 13 cases; lead issues in 3 cases, including 2 cases resulting in failure to treat ventricular arrhythmias; as well as battery depletion in 6 cases.
In 72 patients (27.7%), the device recorded abnormalities in the 30 days before death. These abnormalities included nonsustained ventricular tachycardia in 26 cases, rapid atrial fibrillation in 17, elective replacement indicator or end-of-life status in 22, intrathoracic impedance alarms or lead issues in 3 each, and therapy delivered in 1 instance.
“In several cases, the absence of an arrhythmia carried medicolegal implications: For example, in eight fatal motor vehicle accident cases, only one patient had a ventricular arrhythmia documented on their CIED,” Dr. Paratz and colleagues report.
And in six cases in which the patient was found dead after a prolonged period, CIED interrogation determined time of death. And in one case, CIED interrogation was the primary means of identifying the patient.
Still, postmortem CIED interrogation remains uncommon, the study team notes.
They point to a 2007 survey of Chicago morticians that found roughly 370 CIEDs were explanted per year prior to cremation, but only 4% of morticians had ever returned a CIED to the manufacturer for analysis.
“Encouraging postmortem interrogation of CIEDs may assist in postmarketing surveillance for critical faults, as well as in providing an electrophysiological appraisal of terminal rhythms and device responses in a variety of physiological scenarios,” the researchers say.
The study had no commercial funding. Dr. Paratz is supported by a National Health and Medical Research Council/National Heart Foundation cofunded Postgraduate Scholarship, Royal Australasian College of Physicians JJ Billings Scholarship, and PSA Insurance Cardiovascular Scholarship. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JACC: CLINICAL ELECTROPHYSIOLOGY
Small myocarditis risk now seen for adenovirus-based COVID-19 vaccine
The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.
The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.
The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.
“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.
“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.
To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.
As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.
Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.
“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”
The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.
“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.
It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.
“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”
James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.
“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
Large-scale data
The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.
The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.
There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).
In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.
Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.
“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.
“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
Analyses by sex and age
A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.
“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.
Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).
“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.
The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.
Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).
“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”
Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.
“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”
Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.
The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.
The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.
“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.
“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.
To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.
As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.
Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.
“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”
The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.
“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.
It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.
“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”
James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.
“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
Large-scale data
The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.
The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.
There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).
In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.
Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.
“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.
“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
Analyses by sex and age
A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.
“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.
Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).
“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.
The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.
Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).
“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”
Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.
“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”
Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
The first large population study to investigate the association between different COVID-19 vaccines types and cardiac effects and adverse events shows a small increase in the risk for acute myocarditis with both the mRNA-based vaccines and – in what may a first in the literature – an adenovirus-vector vaccine.
The excess risk was seen following the first dose of the ChAdOc1 (AstraZeneca/Oxford), the adenovirus-based vaccine, and the mRNA-based BNT162b2 (Pfizer/BioNTech). It was observed after first and second doses of the mRNA-1273 (Moderna) vaccine.
The incidence rate ratios for myocarditis 1-7 days after the first AstraZeneca, Pfizer, and Moderna injections were 1.76, 1.45, and 8.38, respectively, and 23.1 after the second dose of the Moderna vaccine.
“There’s a bit more uncertainty and worry about mRNA vaccines because it’s quite a new vector for vaccination and, therefore, there’s been more focus on the potential side effects,” said Nicholas Mills, MD.
“But it doesn’t surprise me the signal is present for all types of vaccines because they’re designed to generate a systemic immune response and that is, unfortunately, where you can cause small risks for immune-mediated illnesses like myocarditis,” Dr. Mills, from the University of Edinburgh, told this news organization. Dr. Mills is a coauthor on the study, published Dec. 14 in Nature Medicine.
To put the risks in context, the group estimated between 1 and 10 additional myocarditis hospitalizations or deaths per 1 million people vaccinated, but 40 excess myocarditis events per million following a positive SARS-CoV-2 test result.
As reported, rates of excess myocarditis events associated with a first dose were 2 per million injections of the AstraZeneca vaccine, 1 per million for the Pfizer vaccine, and 6 per million with the Moderna vaccine.
Following a second dose, there were 10 additional myocarditis events per million people receiving the Moderna vaccine and none among recipients of the AstraZeneca or Pfizer vaccines.
“It was particularly seen within the first 7 days of the first dose, which is very consistent with what we see in people who have viral myocarditis,” Dr. Mills said. “So it looks like a real signal but it’s very small.”
The results are in line with previous studies of the Pfizer vaccine in Israel and studies of the Moderna vaccine in the United States, Biykem Bozkurt, MD, PhD, professor of medicine at Baylor College of Medicine, Houston, told this news organization.
“What this paper does is confirm that cardiovascular complications – and they are only looking at a small component of those cardiovascular complications – are markedly higher with the COVID-19 infection than with the vaccines,” she said.
It also adds a new twist to the search for the mechanisms of myocarditis, which has focused on the immunogenicity of the RNA in the Pfizer and Moderna vaccines but also hypothesized that molecular mimicry between the SARS-CoV-2 spike glycoprotein and cell antigens, antibody production against cardiac proteins, and testosterone may play a role.
“But now it doesn’t look like the risk is solely confined to the mRNA vaccine platform because it’s also happening with the adenovirus,” Dr. Bozkurt said. “The mechanisms require future experimental and clinical research and we’ll need more granular data with cohorts that are closely followed up as well as subclinical follow-up.”
James de Lemos, MD, professor of medicine at the University of Texas Southwestern Medical Center, Dallas, and cochair of the American Heart Association’s COVID-19 CVD Registry, said he was also not surprised by a myocarditis signal with AstraZeneca’s adenovirus vaccine.
“Looking at relative risks has biological implications, but the clinical and public health implications are that the absolute risk with the adenovirus is trivial. And you see that with their estimations of absolute risk where it’s literally sort of a needle in the haystack of 1 or 2 per million,” he said in an interview.
Large-scale data
The investigators examined the rates of hospital admission or death from myocarditis, pericarditis, and cardiac arrhythmia in the 28 days following SARS-CoV-2 vaccination or infection by linking the English National Immunisation Database of COVID-19 vaccination with a national patient-level health care database of 38.6 million people, aged 16 years or older, vaccinated from Dec.1, 2020, to Aug. 24, 2021.
The number of people admitted to the hospital or who died during the study period was 1,615 for myocarditis, 1,574 for pericarditis, and 385,508 for cardiac arrhythmia.
There was no evidence of an increased risk for pericarditis or cardiac arrhythmia following vaccination, except for arrhythmia in the 28 days following a second dose of the Moderna vaccine (IRR, 1.46).
In contrast, the risk was increased for pericarditis (IRR, 2.79) and cardiac arrhythmia (IRR, 5.35) in the 28 days following a positive SARS-CoV-2 test result.
Although the scale of the analysis allows for more precise estimates than what’s been possible in smaller data sets, there is the challenge of diagnosing COVID-19 from billing codes and the potential for ascertainment bias, noted Dr. de Lemos.
“Having said that, I think it’s a really important study, because it’s the first study to put the incidence in context in the same general population the risks of myocarditis with various vaccines and with COVID-19,” he said.
“That’s really important and provides a lot of reassurance for those who are trying to balance the risks and benefits of vaccination.”
Analyses by sex and age
A subgroup analysis by age showed increased risks for myocarditis with the mRNA vaccines only in those younger than 40, whereas no association was found with the Oxford adenovirus vaccine.
“We’re not seeing any signal here that would make us change the recommendation for vaccination in children as a consequence of this risk,” Dr. Mills said during a press briefing.
Dr. Bozkurt pointed out, however, that the estimated excess in myocarditis events following a second dose of the Moderna vaccine in these younger adults reportedly exceeded that for SARS-CoV-2 infection (15 per million vs. 10 per million).
“For that age group, it’s concerning and needs further clarification. This hasn’t been seen before,” she said.
The average age was 39 years for those receiving two doses of the Moderna vaccine and 55 for recipients of the Pfizer and Oxford vaccines. The Moderna vaccine wasn’t rolled out until April 2021 in the United Kingdom, the authors noted, so the number of patients who received this vaccine is lower.
Although reports have suggested young males are at greater risk for myocarditis after vaccination, an analysis by sex found that women had an increased risk for myocarditis after a first dose of the AstraZeneca (IRR, 1.40) and Pfizer (IRR, 1.54) vaccines and following a positive COVID-19 test result (IRR, 11.00).
“Women being at increased risk is rather a new message,” Dr. Bozkurt said. “But the incidence rate ratios are being compared against the unvaccinated, so when you see the increase in women, it doesn’t mean it’s increased against men. It would be helpful for sex-specific incidence rate ratios to be reported for younger age subgroups, such as ages 16-20 and 20-30, to determine whether there’s an increased risk for males compared to females at younger ages.”
Age and sex differences are huge questions, but “I think we’ll learn a lot about myocarditis in general from what is going to be an explosion of research into the vaccine-associated causes,” Dr. de Lemos said.
“That will help us understand myocarditis more broadly and prepare us for the next generation of vaccines, which inevitably will be mRNA based.”
Dr. Mills reported having no relevant disclosures. Dr. Bozkurt reported consulting for Bayer and scPharmaceuticals and serving on a clinical-events committee for a trial supported by Abbott Pharmaceuticals and on a data and safety monitoring board for a trial supported by Liva Nova Pharmaceuticals. Dr. De Lemos reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
New data on rare myocarditis after COVID-19 vaccination
Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.
“This study supports what we’ve been seeing. People identified and treated early and appropriately for the rare complication of COVID-19 vaccine-related myocarditis typically experienced only mild cases and short recovery times,” American Heart Association President Donald M. Lloyd-Jones, MD, said in a podcast.
“Overwhelmingly, the data continue to indicate [that] the benefits of COVID-19 vaccine far outweigh any very rare risks of adverse events from the vaccine, including myocarditis,” Dr. Lloyd-Jones added.
The study was published online Dec. 6 in Circulation.
Using data from 26 pediatric medical centers across the United States and Canada, the researchers reviewed the medical records of 139 patients younger than 21 with suspected myocarditis within 1 month of receiving a COVID-19 vaccination.
They made the following key observations:
- Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
- Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
- Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
- Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
- Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
- Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
- Median time spent in the hospital was 2 days.
- A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
- More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
- Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
- 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.
“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.
“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.
Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”
The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.
“This study supports what we’ve been seeing. People identified and treated early and appropriately for the rare complication of COVID-19 vaccine-related myocarditis typically experienced only mild cases and short recovery times,” American Heart Association President Donald M. Lloyd-Jones, MD, said in a podcast.
“Overwhelmingly, the data continue to indicate [that] the benefits of COVID-19 vaccine far outweigh any very rare risks of adverse events from the vaccine, including myocarditis,” Dr. Lloyd-Jones added.
The study was published online Dec. 6 in Circulation.
Using data from 26 pediatric medical centers across the United States and Canada, the researchers reviewed the medical records of 139 patients younger than 21 with suspected myocarditis within 1 month of receiving a COVID-19 vaccination.
They made the following key observations:
- Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
- Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
- Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
- Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
- Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
- Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
- Median time spent in the hospital was 2 days.
- A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
- More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
- Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
- 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.
“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.
“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.
Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”
The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.
Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.
“This study supports what we’ve been seeing. People identified and treated early and appropriately for the rare complication of COVID-19 vaccine-related myocarditis typically experienced only mild cases and short recovery times,” American Heart Association President Donald M. Lloyd-Jones, MD, said in a podcast.
“Overwhelmingly, the data continue to indicate [that] the benefits of COVID-19 vaccine far outweigh any very rare risks of adverse events from the vaccine, including myocarditis,” Dr. Lloyd-Jones added.
The study was published online Dec. 6 in Circulation.
Using data from 26 pediatric medical centers across the United States and Canada, the researchers reviewed the medical records of 139 patients younger than 21 with suspected myocarditis within 1 month of receiving a COVID-19 vaccination.
They made the following key observations:
- Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
- Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
- Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
- Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
- Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
- Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
- Median time spent in the hospital was 2 days.
- A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
- More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
- Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
- 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.
“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.
“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.
Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”
The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.
A version of this article first appeared on Medscape.com.