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‘Molecular map’ of CLL yields fresh genetic insights
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
FROM NATURE GENETICS
Paxlovid reduces risk of COVID death by 79% in older adults
The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.
The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.
“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.
“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”
, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.
Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.
The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.
Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.
Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.
Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.
Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.
For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.
The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.
The study didn’t receive any financial or in-kind support, the authors said.
A version of this article first appeared on WebMD.com.
The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.
The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.
“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.
“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”
, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.
Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.
The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.
Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.
Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.
Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.
Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.
For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.
The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.
The study didn’t receive any financial or in-kind support, the authors said.
A version of this article first appeared on WebMD.com.
The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.
The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.
“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.
“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”
, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.
Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.
The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.
Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.
Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.
Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.
Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.
For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.
The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.
The study didn’t receive any financial or in-kind support, the authors said.
A version of this article first appeared on WebMD.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Vaccine hope now for leading cause of U.S. infant hospitalizations: RSV
Respiratory syncytial virus (RSV) is the leading cause of U.S. infant hospitalizations overall and across population subgroups, new data published in the Journal of Infectious Diseases confirm.
Acute bronchiolitis caused by RSV accounted for 9.6% (95% confidence interval, 9.4%-9.9%) and 9.3% (95% CI, 9.0%-9.6%) of total infant hospitalizations from January 2009 to September 2015 and October 2015 to December 2019, respectively.
Journal issue includes 14 RSV studies
The latest issue of the journal includes a special section with results from 14 studies related to the widespread, easy-to-catch virus, highlighting the urgency of finding a solution for all infants.
In one study, authors led by Mina Suh, MPH, with EpidStrategies, a division of ToxStrategies in Rockville, Md., reported that, in children under the age of 5 years in the United States, RSV caused 58,000 annual hospitalizations and from 100 to 500 annual deaths from 2009 to 2019 (the latest year data were available).
Globally, in 2015, among infants younger than 6 months, an estimated 1.4 million hospital admissions and 27,300 in-hospital deaths were attributed to RSV lower respiratory tract infection (LRTI).
The researchers used the largest publicly available, all-payer database in the United States – the National (Nationwide) Inpatient Sample – to describe the leading causes of infant hospitalizations.
The authors noted that, because clinicians don’t routinely perform lab tests for RSV, the true health care burden is likely higher and its public health impact greater than these numbers show.
Immunization candidates advance
There are no preventative options currently available to substantially cut RSV infections in all infants, though immunization candidates are advancing, showing safety and efficacy in clinical trials.
Palivizumab is currently the only available option in the United States to prevent RSV and is recommended only for a small group of infants with particular forms of heart or lung disease and those born prematurely at 29 weeks’ gestational age. Further, palivizumab has to be given monthly throughout the RSV season.
Another of the studies in the journal supplement concluded that a universal immunization strategy with one of the candidates, nirsevimab (Sanofi, AstraZeneca), an investigational long-acting monoclonal antibody, could substantially reduce the health burden and economic burden for U.S. infants in their first RSV season.
The researchers, led by Alexia Kieffer, MSc, MPH, with Sanofi, used static decision-analytic modeling for the estimates. Modeled RSV-related outcomes included primary care and ED visits, hospitalizations, including ICU admission and mechanical ventilations, and RSV-related deaths.
“The results of this model suggested that the use of nirsevimab in all infants could reduce health events by 55% and the overall costs to the payer by 49%,” the authors of the study wrote.
According to the study, universal immunization of all infants with nirsevimab is expected to reduce 290,174 RSV-related medically attended LRTI (MALRTI), 24,986 hospitalizations, and cut $612 million in costs to the health care system.
The authors wrote: “While this reduction would be driven by term infants, who account for most of the RSV-MALRTI burden; all infants, including palivizumab-eligible and preterm infants who suffer from significantly higher rates of disease, would benefit from this immunization strategy.”
Excitement for another option
Jörn-Hendrik Weitkamp, MD, professor of pediatrics and director for patient-oriented research at Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn., said in an interview there is much excitement in the field for nirsevimab as it has significant advantages over palivizumab.
RSV “is a huge burden to the children, the families, the hospitals, and the medical system,” he said.
Ideally there would be a vaccine to offer the best protection, he noted.
“People have spent their lives, their careers trying to develop a vaccine for RSV,” he said, but that has been elusive for more than 60 years. Therefore, passive immunization is the best of the current options, he says, and nirsevimab “seems to be very effective.”
What’s not clear, Dr. Weitkamp said, is how much nirsevimab will cost as it is not yet approved by the Food and Drug Administration. However, it has the great advantage of being given only once before the season starts instead of monthly (as required for palivizumab) through the season, “which is painful, inconvenient, and traumatizing. We limit that one to the children at highest risk.”
Rolling out an infant nirsevimab program would likely vary by geographic region, Ms. Kieffer and colleagues said, to help ensure infants are protected during the peak of their region’s RSV season.
The journal’s RSV supplement was supported by Sanofi and AstraZeneca. The studies by Ms. Suh and colleagues and Ms. Kieffer and colleagues were supported by AstraZeneca and Sanofi. Ms. Suh and several coauthors are employees of EpidStrategies. One coauthor is an employee of Sanofi and may hold shares and/or stock options in the company. Ms. Kieffer and several coauthors are employees of Sanofi and may hold shares and/or stock options in the company. Dr. Weitkamp reported no relevant financial relationships.
Respiratory syncytial virus (RSV) is the leading cause of U.S. infant hospitalizations overall and across population subgroups, new data published in the Journal of Infectious Diseases confirm.
Acute bronchiolitis caused by RSV accounted for 9.6% (95% confidence interval, 9.4%-9.9%) and 9.3% (95% CI, 9.0%-9.6%) of total infant hospitalizations from January 2009 to September 2015 and October 2015 to December 2019, respectively.
Journal issue includes 14 RSV studies
The latest issue of the journal includes a special section with results from 14 studies related to the widespread, easy-to-catch virus, highlighting the urgency of finding a solution for all infants.
In one study, authors led by Mina Suh, MPH, with EpidStrategies, a division of ToxStrategies in Rockville, Md., reported that, in children under the age of 5 years in the United States, RSV caused 58,000 annual hospitalizations and from 100 to 500 annual deaths from 2009 to 2019 (the latest year data were available).
Globally, in 2015, among infants younger than 6 months, an estimated 1.4 million hospital admissions and 27,300 in-hospital deaths were attributed to RSV lower respiratory tract infection (LRTI).
The researchers used the largest publicly available, all-payer database in the United States – the National (Nationwide) Inpatient Sample – to describe the leading causes of infant hospitalizations.
The authors noted that, because clinicians don’t routinely perform lab tests for RSV, the true health care burden is likely higher and its public health impact greater than these numbers show.
Immunization candidates advance
There are no preventative options currently available to substantially cut RSV infections in all infants, though immunization candidates are advancing, showing safety and efficacy in clinical trials.
Palivizumab is currently the only available option in the United States to prevent RSV and is recommended only for a small group of infants with particular forms of heart or lung disease and those born prematurely at 29 weeks’ gestational age. Further, palivizumab has to be given monthly throughout the RSV season.
Another of the studies in the journal supplement concluded that a universal immunization strategy with one of the candidates, nirsevimab (Sanofi, AstraZeneca), an investigational long-acting monoclonal antibody, could substantially reduce the health burden and economic burden for U.S. infants in their first RSV season.
The researchers, led by Alexia Kieffer, MSc, MPH, with Sanofi, used static decision-analytic modeling for the estimates. Modeled RSV-related outcomes included primary care and ED visits, hospitalizations, including ICU admission and mechanical ventilations, and RSV-related deaths.
“The results of this model suggested that the use of nirsevimab in all infants could reduce health events by 55% and the overall costs to the payer by 49%,” the authors of the study wrote.
According to the study, universal immunization of all infants with nirsevimab is expected to reduce 290,174 RSV-related medically attended LRTI (MALRTI), 24,986 hospitalizations, and cut $612 million in costs to the health care system.
The authors wrote: “While this reduction would be driven by term infants, who account for most of the RSV-MALRTI burden; all infants, including palivizumab-eligible and preterm infants who suffer from significantly higher rates of disease, would benefit from this immunization strategy.”
Excitement for another option
Jörn-Hendrik Weitkamp, MD, professor of pediatrics and director for patient-oriented research at Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn., said in an interview there is much excitement in the field for nirsevimab as it has significant advantages over palivizumab.
RSV “is a huge burden to the children, the families, the hospitals, and the medical system,” he said.
Ideally there would be a vaccine to offer the best protection, he noted.
“People have spent their lives, their careers trying to develop a vaccine for RSV,” he said, but that has been elusive for more than 60 years. Therefore, passive immunization is the best of the current options, he says, and nirsevimab “seems to be very effective.”
What’s not clear, Dr. Weitkamp said, is how much nirsevimab will cost as it is not yet approved by the Food and Drug Administration. However, it has the great advantage of being given only once before the season starts instead of monthly (as required for palivizumab) through the season, “which is painful, inconvenient, and traumatizing. We limit that one to the children at highest risk.”
Rolling out an infant nirsevimab program would likely vary by geographic region, Ms. Kieffer and colleagues said, to help ensure infants are protected during the peak of their region’s RSV season.
The journal’s RSV supplement was supported by Sanofi and AstraZeneca. The studies by Ms. Suh and colleagues and Ms. Kieffer and colleagues were supported by AstraZeneca and Sanofi. Ms. Suh and several coauthors are employees of EpidStrategies. One coauthor is an employee of Sanofi and may hold shares and/or stock options in the company. Ms. Kieffer and several coauthors are employees of Sanofi and may hold shares and/or stock options in the company. Dr. Weitkamp reported no relevant financial relationships.
Respiratory syncytial virus (RSV) is the leading cause of U.S. infant hospitalizations overall and across population subgroups, new data published in the Journal of Infectious Diseases confirm.
Acute bronchiolitis caused by RSV accounted for 9.6% (95% confidence interval, 9.4%-9.9%) and 9.3% (95% CI, 9.0%-9.6%) of total infant hospitalizations from January 2009 to September 2015 and October 2015 to December 2019, respectively.
Journal issue includes 14 RSV studies
The latest issue of the journal includes a special section with results from 14 studies related to the widespread, easy-to-catch virus, highlighting the urgency of finding a solution for all infants.
In one study, authors led by Mina Suh, MPH, with EpidStrategies, a division of ToxStrategies in Rockville, Md., reported that, in children under the age of 5 years in the United States, RSV caused 58,000 annual hospitalizations and from 100 to 500 annual deaths from 2009 to 2019 (the latest year data were available).
Globally, in 2015, among infants younger than 6 months, an estimated 1.4 million hospital admissions and 27,300 in-hospital deaths were attributed to RSV lower respiratory tract infection (LRTI).
The researchers used the largest publicly available, all-payer database in the United States – the National (Nationwide) Inpatient Sample – to describe the leading causes of infant hospitalizations.
The authors noted that, because clinicians don’t routinely perform lab tests for RSV, the true health care burden is likely higher and its public health impact greater than these numbers show.
Immunization candidates advance
There are no preventative options currently available to substantially cut RSV infections in all infants, though immunization candidates are advancing, showing safety and efficacy in clinical trials.
Palivizumab is currently the only available option in the United States to prevent RSV and is recommended only for a small group of infants with particular forms of heart or lung disease and those born prematurely at 29 weeks’ gestational age. Further, palivizumab has to be given monthly throughout the RSV season.
Another of the studies in the journal supplement concluded that a universal immunization strategy with one of the candidates, nirsevimab (Sanofi, AstraZeneca), an investigational long-acting monoclonal antibody, could substantially reduce the health burden and economic burden for U.S. infants in their first RSV season.
The researchers, led by Alexia Kieffer, MSc, MPH, with Sanofi, used static decision-analytic modeling for the estimates. Modeled RSV-related outcomes included primary care and ED visits, hospitalizations, including ICU admission and mechanical ventilations, and RSV-related deaths.
“The results of this model suggested that the use of nirsevimab in all infants could reduce health events by 55% and the overall costs to the payer by 49%,” the authors of the study wrote.
According to the study, universal immunization of all infants with nirsevimab is expected to reduce 290,174 RSV-related medically attended LRTI (MALRTI), 24,986 hospitalizations, and cut $612 million in costs to the health care system.
The authors wrote: “While this reduction would be driven by term infants, who account for most of the RSV-MALRTI burden; all infants, including palivizumab-eligible and preterm infants who suffer from significantly higher rates of disease, would benefit from this immunization strategy.”
Excitement for another option
Jörn-Hendrik Weitkamp, MD, professor of pediatrics and director for patient-oriented research at Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tenn., said in an interview there is much excitement in the field for nirsevimab as it has significant advantages over palivizumab.
RSV “is a huge burden to the children, the families, the hospitals, and the medical system,” he said.
Ideally there would be a vaccine to offer the best protection, he noted.
“People have spent their lives, their careers trying to develop a vaccine for RSV,” he said, but that has been elusive for more than 60 years. Therefore, passive immunization is the best of the current options, he says, and nirsevimab “seems to be very effective.”
What’s not clear, Dr. Weitkamp said, is how much nirsevimab will cost as it is not yet approved by the Food and Drug Administration. However, it has the great advantage of being given only once before the season starts instead of monthly (as required for palivizumab) through the season, “which is painful, inconvenient, and traumatizing. We limit that one to the children at highest risk.”
Rolling out an infant nirsevimab program would likely vary by geographic region, Ms. Kieffer and colleagues said, to help ensure infants are protected during the peak of their region’s RSV season.
The journal’s RSV supplement was supported by Sanofi and AstraZeneca. The studies by Ms. Suh and colleagues and Ms. Kieffer and colleagues were supported by AstraZeneca and Sanofi. Ms. Suh and several coauthors are employees of EpidStrategies. One coauthor is an employee of Sanofi and may hold shares and/or stock options in the company. Ms. Kieffer and several coauthors are employees of Sanofi and may hold shares and/or stock options in the company. Dr. Weitkamp reported no relevant financial relationships.
FROM THE JOURNAL OF INFECTIOUS DISEASES
Skip chemoRT in low-risk nasopharyngeal cancer?
and with lower toxicity, compared with a combination of radiation and concurrent chemoradiotherapy, a team of investigators in China suggest.
In a randomized phase 3 trial, there was no significant difference in 3-year failure-free survival (FFS) rates for patients with low-risk stage 2/T3N0 nasopharyngeal carcinoma (NPC) who received intensity-modulated radiation therapy (IMRT) alone, compared with patients who received a combination of IMRT and concurrent cisplatin-based chemoradiotherapy.
The trial met its primary endpoint of non-inferiority for IMRT alone with 3-year FFS rates of 90.5% for 169 patients randomized to IMRT alone, and 91.9% for the combined therapy (P for noninferiority < .001).
“The trial results were different from studies on stage 2 NPC conducted in the two-dimensional conventional radiotherapy era that showed concurrent cisplatin chemotherapy provided radio sensitization to enhance locoregional control and overall survival,” investigators Ling-Long Tang, MD and colleagues from Sun Yat-Sen University in Guanzhou, China, reported in JAMA.
“It is possible that IMRT may have maximized locoregional control in many patients with low-risk NPC, which is generally radiosensitive, as supported by more than 90% locoregional relapse-free survival rates in almost all contemporary series for stage 2 disease,” they wrote.
In addition to meeting the primary noninferiority endpoint, there were no significant differences in secondary efficacy endpoints of overall survival, locoregional relapse, or metastasis.
The safety analysis, however, showed that patients in IMRT-alone group had significantly fewer grade 3 or 4 adverse events (17% vs. 46%, 95% with a significant 95% confidence interval for the difference), and patients who received only IMRT had significantly better quality-of-life scores during radiotherapy across multiple domains.
“I expect that as a result of this study, most patients with stage 2 [Epstein-Barr virus]–associated NPC will be treated with IMRT alone,” said Lori Wirth, MD, a head and neck cancer specialist at Massachusetts General Hospital Cancer Center in Boston.
“This noninferiority study showed that IMRT alone (without concurrent cisplatin) does not lead to greater locoregional relapse or distant metastatic disease. Not only that, but also the study confirmed what we would expect that IMRT alone without concurrent cisplatin is better tolerated with less acute toxicity and improved quality of life compared to chemoRT,” she said in a comment.
“One question that remains is related to long-term toxicity: ‘Will the IMRT-alone patients also experience less lifelong toxicity from treatment?’ If yes, that would be great,” she said.
The open-label, phase 3 trial was conducted at five Chinese hospitals with a total of 341 patients randomly assigned to IMRT alone or with concurrent chemoradiotherapy consisting of IMRT with cisplatin 100 mg/m2 every 3 weeks for three cycles.
As noted before, the primary endpoint was 3-year FFS, defined as time from randomization to any disease relapse or death. The predetermined noninferiority margin was 10%.
Secondary endpoints included overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for physical function, symptom control, or health-related quality of life.
The study was supported by grants from the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Key-Area Research and Development Program of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovatio, and the Sun Yat-Sen University Clinical Research 5010 Program. The authors and Dr. Wirth reported no relevant conflicts of interest.
and with lower toxicity, compared with a combination of radiation and concurrent chemoradiotherapy, a team of investigators in China suggest.
In a randomized phase 3 trial, there was no significant difference in 3-year failure-free survival (FFS) rates for patients with low-risk stage 2/T3N0 nasopharyngeal carcinoma (NPC) who received intensity-modulated radiation therapy (IMRT) alone, compared with patients who received a combination of IMRT and concurrent cisplatin-based chemoradiotherapy.
The trial met its primary endpoint of non-inferiority for IMRT alone with 3-year FFS rates of 90.5% for 169 patients randomized to IMRT alone, and 91.9% for the combined therapy (P for noninferiority < .001).
“The trial results were different from studies on stage 2 NPC conducted in the two-dimensional conventional radiotherapy era that showed concurrent cisplatin chemotherapy provided radio sensitization to enhance locoregional control and overall survival,” investigators Ling-Long Tang, MD and colleagues from Sun Yat-Sen University in Guanzhou, China, reported in JAMA.
“It is possible that IMRT may have maximized locoregional control in many patients with low-risk NPC, which is generally radiosensitive, as supported by more than 90% locoregional relapse-free survival rates in almost all contemporary series for stage 2 disease,” they wrote.
In addition to meeting the primary noninferiority endpoint, there were no significant differences in secondary efficacy endpoints of overall survival, locoregional relapse, or metastasis.
The safety analysis, however, showed that patients in IMRT-alone group had significantly fewer grade 3 or 4 adverse events (17% vs. 46%, 95% with a significant 95% confidence interval for the difference), and patients who received only IMRT had significantly better quality-of-life scores during radiotherapy across multiple domains.
“I expect that as a result of this study, most patients with stage 2 [Epstein-Barr virus]–associated NPC will be treated with IMRT alone,” said Lori Wirth, MD, a head and neck cancer specialist at Massachusetts General Hospital Cancer Center in Boston.
“This noninferiority study showed that IMRT alone (without concurrent cisplatin) does not lead to greater locoregional relapse or distant metastatic disease. Not only that, but also the study confirmed what we would expect that IMRT alone without concurrent cisplatin is better tolerated with less acute toxicity and improved quality of life compared to chemoRT,” she said in a comment.
“One question that remains is related to long-term toxicity: ‘Will the IMRT-alone patients also experience less lifelong toxicity from treatment?’ If yes, that would be great,” she said.
The open-label, phase 3 trial was conducted at five Chinese hospitals with a total of 341 patients randomly assigned to IMRT alone or with concurrent chemoradiotherapy consisting of IMRT with cisplatin 100 mg/m2 every 3 weeks for three cycles.
As noted before, the primary endpoint was 3-year FFS, defined as time from randomization to any disease relapse or death. The predetermined noninferiority margin was 10%.
Secondary endpoints included overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for physical function, symptom control, or health-related quality of life.
The study was supported by grants from the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Key-Area Research and Development Program of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovatio, and the Sun Yat-Sen University Clinical Research 5010 Program. The authors and Dr. Wirth reported no relevant conflicts of interest.
and with lower toxicity, compared with a combination of radiation and concurrent chemoradiotherapy, a team of investigators in China suggest.
In a randomized phase 3 trial, there was no significant difference in 3-year failure-free survival (FFS) rates for patients with low-risk stage 2/T3N0 nasopharyngeal carcinoma (NPC) who received intensity-modulated radiation therapy (IMRT) alone, compared with patients who received a combination of IMRT and concurrent cisplatin-based chemoradiotherapy.
The trial met its primary endpoint of non-inferiority for IMRT alone with 3-year FFS rates of 90.5% for 169 patients randomized to IMRT alone, and 91.9% for the combined therapy (P for noninferiority < .001).
“The trial results were different from studies on stage 2 NPC conducted in the two-dimensional conventional radiotherapy era that showed concurrent cisplatin chemotherapy provided radio sensitization to enhance locoregional control and overall survival,” investigators Ling-Long Tang, MD and colleagues from Sun Yat-Sen University in Guanzhou, China, reported in JAMA.
“It is possible that IMRT may have maximized locoregional control in many patients with low-risk NPC, which is generally radiosensitive, as supported by more than 90% locoregional relapse-free survival rates in almost all contemporary series for stage 2 disease,” they wrote.
In addition to meeting the primary noninferiority endpoint, there were no significant differences in secondary efficacy endpoints of overall survival, locoregional relapse, or metastasis.
The safety analysis, however, showed that patients in IMRT-alone group had significantly fewer grade 3 or 4 adverse events (17% vs. 46%, 95% with a significant 95% confidence interval for the difference), and patients who received only IMRT had significantly better quality-of-life scores during radiotherapy across multiple domains.
“I expect that as a result of this study, most patients with stage 2 [Epstein-Barr virus]–associated NPC will be treated with IMRT alone,” said Lori Wirth, MD, a head and neck cancer specialist at Massachusetts General Hospital Cancer Center in Boston.
“This noninferiority study showed that IMRT alone (without concurrent cisplatin) does not lead to greater locoregional relapse or distant metastatic disease. Not only that, but also the study confirmed what we would expect that IMRT alone without concurrent cisplatin is better tolerated with less acute toxicity and improved quality of life compared to chemoRT,” she said in a comment.
“One question that remains is related to long-term toxicity: ‘Will the IMRT-alone patients also experience less lifelong toxicity from treatment?’ If yes, that would be great,” she said.
The open-label, phase 3 trial was conducted at five Chinese hospitals with a total of 341 patients randomly assigned to IMRT alone or with concurrent chemoradiotherapy consisting of IMRT with cisplatin 100 mg/m2 every 3 weeks for three cycles.
As noted before, the primary endpoint was 3-year FFS, defined as time from randomization to any disease relapse or death. The predetermined noninferiority margin was 10%.
Secondary endpoints included overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for physical function, symptom control, or health-related quality of life.
The study was supported by grants from the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Key-Area Research and Development Program of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovatio, and the Sun Yat-Sen University Clinical Research 5010 Program. The authors and Dr. Wirth reported no relevant conflicts of interest.
FROM JAMA
TikTok’s impact on adolescent mental health
For younger generations, TikTok is a go-to site for those who like short and catchy video clips. As a social media platform that allows concise video sharing, TikTok has over 1 billion monthly global users. Because of its platform size, a plethora of resources, and influence on media discourse, TikTok is the place for content creators to share visual media. Its cursory, condensed content delivery with videos capped at 1-minute focuses on high-yield information and rapid identification of fundamental points that are both engaging and entertaining.
Currently, on TikTok, 40 billion views are associated with the hashtag #mentalhealth. Content creators and regular users are employing this platform to share their own experiences, opinions, and strategies to overcome their struggles. While it is understandable for creators to share their personal stories that may be abusive, traumatic, or violent, they may not be prepared for their video to “go viral.”
Like any other social media platform, hateful speech such as racism, sexism, or xenophobia can accumulate on TikTok, which may cause more self-harm than self-help. Oversharing about personal strategies may lead to misconceived advice for TikTok viewers, while watching these TikTok videos can have negative mental health effects, even though there are no malicious intentions behind the creators who post these videos.
Hence, public health should pay more attention to the potential health-related implications this platform can create, as the quality of the information and the qualifications of the creators are mostly unrevealed. The concerns include undisclosed conflicts of interest, unchecked spread of misinformation, difficulty identifying source credibility, and excessive false information that viewers must filter through.1,2
Individual TikTok users may follow accounts and interpret these content creators as therapists and the content they see as therapy. They may also believe that a close relationship with the content creator exists when it does not. Specifically, these relationships may be defined as parasocial relationships, which are one-sided relationships where one person (the TikTok viewer) extends emotional energy, interest, and time, and the other party (the content creator) is completely unaware of the other’s existence.3 Additionally, Americans who are uninsured/underinsured may turn to this diluted version of therapy to compensate for the one-on-one or group therapy they need.
While TikTok may seem like a dangerous platform to browse through or post on, its growing influence cannot be underestimated. With 41% of TikTok users between the ages of 16 and 24, this is an ideal platform to disseminate public health information pertaining to this age group (for example, safe sex practices, substance abuse, and mental health issues).4 Because younger generations have incorporated social media into their daily lives, the medical community can harness TikTok’s potential to disseminate accurate information to potential patients for targeted medical education.
For example, Jake Goodman, MD, MBA, and Melissa Shepard, MD, each have more than a million TikTok followers and are notable psychiatrists who post a variety of content ranging from recognizing signs of depression to reducing stigma around mental health. Similarly, Justin Puder, PhD, is a licensed psychologist who advocates for ways to overcome mental health issues. By creating diverse content with appealing strategies, spreading accurate medical knowledge, and answering common medical questions for the public, these ‘mental health influencers’ educate potential patients to create patient-centered interactions.
While there are many pros and cons to social media platforms, it is undeniable that these platforms – such as TikTok – are here to stay. It is crucial for members of the medical community to recognize the outlets that younger generations use to express themselves and to exploit these media channels therapeutically.
Ms. Wong is a fourth-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Dr. Chua is a psychiatrist with the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia, and assistant professor of clinical psychiatry at the University of Pennsylvania, also in Philadelphia.
References
1. Gottlieb M and Dyer S. Information and Disinformation: Social Media in the COVID-19 Crisis. Acad Emerg Med. 2020 Jul;27(7):640-1. doi: 10.1111/acem.14036.
2. De Veirman M et al. Front Psychol. 2019;10:2685. doi: 10.3389/fpsyg.2019.02685.
3. Bennett N-K et al. “Parasocial Relationships: The Nature of Celebrity Fascinations.” National Register of Health Service Psychologists. https://www.findapsychologist.org/parasocial-relationships-the-nature-of-celebrity-fascinations/.
4. Eghtesadi M and Florea A. Can J Public Health. 2020 Jun;111(3):389-91. doi: 10.17269/s41997-020-00343-0.
For younger generations, TikTok is a go-to site for those who like short and catchy video clips. As a social media platform that allows concise video sharing, TikTok has over 1 billion monthly global users. Because of its platform size, a plethora of resources, and influence on media discourse, TikTok is the place for content creators to share visual media. Its cursory, condensed content delivery with videos capped at 1-minute focuses on high-yield information and rapid identification of fundamental points that are both engaging and entertaining.
Currently, on TikTok, 40 billion views are associated with the hashtag #mentalhealth. Content creators and regular users are employing this platform to share their own experiences, opinions, and strategies to overcome their struggles. While it is understandable for creators to share their personal stories that may be abusive, traumatic, or violent, they may not be prepared for their video to “go viral.”
Like any other social media platform, hateful speech such as racism, sexism, or xenophobia can accumulate on TikTok, which may cause more self-harm than self-help. Oversharing about personal strategies may lead to misconceived advice for TikTok viewers, while watching these TikTok videos can have negative mental health effects, even though there are no malicious intentions behind the creators who post these videos.
Hence, public health should pay more attention to the potential health-related implications this platform can create, as the quality of the information and the qualifications of the creators are mostly unrevealed. The concerns include undisclosed conflicts of interest, unchecked spread of misinformation, difficulty identifying source credibility, and excessive false information that viewers must filter through.1,2
Individual TikTok users may follow accounts and interpret these content creators as therapists and the content they see as therapy. They may also believe that a close relationship with the content creator exists when it does not. Specifically, these relationships may be defined as parasocial relationships, which are one-sided relationships where one person (the TikTok viewer) extends emotional energy, interest, and time, and the other party (the content creator) is completely unaware of the other’s existence.3 Additionally, Americans who are uninsured/underinsured may turn to this diluted version of therapy to compensate for the one-on-one or group therapy they need.
While TikTok may seem like a dangerous platform to browse through or post on, its growing influence cannot be underestimated. With 41% of TikTok users between the ages of 16 and 24, this is an ideal platform to disseminate public health information pertaining to this age group (for example, safe sex practices, substance abuse, and mental health issues).4 Because younger generations have incorporated social media into their daily lives, the medical community can harness TikTok’s potential to disseminate accurate information to potential patients for targeted medical education.
For example, Jake Goodman, MD, MBA, and Melissa Shepard, MD, each have more than a million TikTok followers and are notable psychiatrists who post a variety of content ranging from recognizing signs of depression to reducing stigma around mental health. Similarly, Justin Puder, PhD, is a licensed psychologist who advocates for ways to overcome mental health issues. By creating diverse content with appealing strategies, spreading accurate medical knowledge, and answering common medical questions for the public, these ‘mental health influencers’ educate potential patients to create patient-centered interactions.
While there are many pros and cons to social media platforms, it is undeniable that these platforms – such as TikTok – are here to stay. It is crucial for members of the medical community to recognize the outlets that younger generations use to express themselves and to exploit these media channels therapeutically.
Ms. Wong is a fourth-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Dr. Chua is a psychiatrist with the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia, and assistant professor of clinical psychiatry at the University of Pennsylvania, also in Philadelphia.
References
1. Gottlieb M and Dyer S. Information and Disinformation: Social Media in the COVID-19 Crisis. Acad Emerg Med. 2020 Jul;27(7):640-1. doi: 10.1111/acem.14036.
2. De Veirman M et al. Front Psychol. 2019;10:2685. doi: 10.3389/fpsyg.2019.02685.
3. Bennett N-K et al. “Parasocial Relationships: The Nature of Celebrity Fascinations.” National Register of Health Service Psychologists. https://www.findapsychologist.org/parasocial-relationships-the-nature-of-celebrity-fascinations/.
4. Eghtesadi M and Florea A. Can J Public Health. 2020 Jun;111(3):389-91. doi: 10.17269/s41997-020-00343-0.
For younger generations, TikTok is a go-to site for those who like short and catchy video clips. As a social media platform that allows concise video sharing, TikTok has over 1 billion monthly global users. Because of its platform size, a plethora of resources, and influence on media discourse, TikTok is the place for content creators to share visual media. Its cursory, condensed content delivery with videos capped at 1-minute focuses on high-yield information and rapid identification of fundamental points that are both engaging and entertaining.
Currently, on TikTok, 40 billion views are associated with the hashtag #mentalhealth. Content creators and regular users are employing this platform to share their own experiences, opinions, and strategies to overcome their struggles. While it is understandable for creators to share their personal stories that may be abusive, traumatic, or violent, they may not be prepared for their video to “go viral.”
Like any other social media platform, hateful speech such as racism, sexism, or xenophobia can accumulate on TikTok, which may cause more self-harm than self-help. Oversharing about personal strategies may lead to misconceived advice for TikTok viewers, while watching these TikTok videos can have negative mental health effects, even though there are no malicious intentions behind the creators who post these videos.
Hence, public health should pay more attention to the potential health-related implications this platform can create, as the quality of the information and the qualifications of the creators are mostly unrevealed. The concerns include undisclosed conflicts of interest, unchecked spread of misinformation, difficulty identifying source credibility, and excessive false information that viewers must filter through.1,2
Individual TikTok users may follow accounts and interpret these content creators as therapists and the content they see as therapy. They may also believe that a close relationship with the content creator exists when it does not. Specifically, these relationships may be defined as parasocial relationships, which are one-sided relationships where one person (the TikTok viewer) extends emotional energy, interest, and time, and the other party (the content creator) is completely unaware of the other’s existence.3 Additionally, Americans who are uninsured/underinsured may turn to this diluted version of therapy to compensate for the one-on-one or group therapy they need.
While TikTok may seem like a dangerous platform to browse through or post on, its growing influence cannot be underestimated. With 41% of TikTok users between the ages of 16 and 24, this is an ideal platform to disseminate public health information pertaining to this age group (for example, safe sex practices, substance abuse, and mental health issues).4 Because younger generations have incorporated social media into their daily lives, the medical community can harness TikTok’s potential to disseminate accurate information to potential patients for targeted medical education.
For example, Jake Goodman, MD, MBA, and Melissa Shepard, MD, each have more than a million TikTok followers and are notable psychiatrists who post a variety of content ranging from recognizing signs of depression to reducing stigma around mental health. Similarly, Justin Puder, PhD, is a licensed psychologist who advocates for ways to overcome mental health issues. By creating diverse content with appealing strategies, spreading accurate medical knowledge, and answering common medical questions for the public, these ‘mental health influencers’ educate potential patients to create patient-centered interactions.
While there are many pros and cons to social media platforms, it is undeniable that these platforms – such as TikTok – are here to stay. It is crucial for members of the medical community to recognize the outlets that younger generations use to express themselves and to exploit these media channels therapeutically.
Ms. Wong is a fourth-year medical student at the New York Institute of Technology College of Osteopathic Medicine in Old Westbury, N.Y. Dr. Chua is a psychiatrist with the department of child and adolescent psychiatry and behavioral sciences at Children’s Hospital of Philadelphia, and assistant professor of clinical psychiatry at the University of Pennsylvania, also in Philadelphia.
References
1. Gottlieb M and Dyer S. Information and Disinformation: Social Media in the COVID-19 Crisis. Acad Emerg Med. 2020 Jul;27(7):640-1. doi: 10.1111/acem.14036.
2. De Veirman M et al. Front Psychol. 2019;10:2685. doi: 10.3389/fpsyg.2019.02685.
3. Bennett N-K et al. “Parasocial Relationships: The Nature of Celebrity Fascinations.” National Register of Health Service Psychologists. https://www.findapsychologist.org/parasocial-relationships-the-nature-of-celebrity-fascinations/.
4. Eghtesadi M and Florea A. Can J Public Health. 2020 Jun;111(3):389-91. doi: 10.17269/s41997-020-00343-0.
ACC fills gaps on guidance for nonstatin therapies for LDL-C lowering
To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).
Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.
These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.
The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.
The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.
The writing group focused on three key areas regarding the use of nonstatin therapies where recent scientific evidence is still under review and clinical trials are still underway:
- In what patient populations should newer nonstatin therapies be considered?
- In what situations should newer nonstatin therapies be considered?
- If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?
The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.
“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.
“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.
He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”
“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.
The document has been endorsed by the National Lipid Association.
This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).
Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.
These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.
The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.
The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.
The writing group focused on three key areas regarding the use of nonstatin therapies where recent scientific evidence is still under review and clinical trials are still underway:
- In what patient populations should newer nonstatin therapies be considered?
- In what situations should newer nonstatin therapies be considered?
- If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?
The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.
“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.
“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.
He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”
“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.
The document has been endorsed by the National Lipid Association.
This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).
Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.
These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.
The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.
The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.
The writing group focused on three key areas regarding the use of nonstatin therapies where recent scientific evidence is still under review and clinical trials are still underway:
- In what patient populations should newer nonstatin therapies be considered?
- In what situations should newer nonstatin therapies be considered?
- If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?
The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.
“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.
“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.
He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”
“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.
The document has been endorsed by the National Lipid Association.
This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
No benefit of routine stress test POST-PCI in high-risk patients
New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).
At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.
“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.
The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.
“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”
Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
‘Compelling new evidence’
In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”
Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.
“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”
Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events.
“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.
“So, I think it’s a good study – well conducted, good numbers – that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
High-risk characteristics
Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”
But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”
The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.
High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.
Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.
At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.
Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).
Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.
POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer outside the submitted work. Dr. Wilson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).
At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.
“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.
The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.
“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”
Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
‘Compelling new evidence’
In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”
Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.
“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”
Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events.
“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.
“So, I think it’s a good study – well conducted, good numbers – that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
High-risk characteristics
Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”
But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”
The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.
High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.
Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.
At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.
Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).
Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.
POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer outside the submitted work. Dr. Wilson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).
At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.
“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.
The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.
“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”
Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
‘Compelling new evidence’
In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”
Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.
“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”
Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events.
“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.
“So, I think it’s a good study – well conducted, good numbers – that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
High-risk characteristics
Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”
But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”
The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.
High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.
Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.
At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.
Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).
Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.
POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer outside the submitted work. Dr. Wilson reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
Rivaroxaban outmatched by VKAs for AFib in rheumatic heart disease
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Contrary to expectations, vitamin K antagonists (VKAs) reduced the risk for ischemic stroke and death, compared with the factor Xa inhibitor rivaroxaban, (Xarelto, Janssen) in patients with rheumatic heart disease and atrial fibrillation (AFib), in the INVICTUS trial.
Patients receiving a VKA, typically warfarin, had a 25% lower risk for the primary outcome – a composite of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes outcome – than receiving rivaroxaban (hazard ratio, 1.25; 95% confidence interval, 1.10-1.41).
This difference was driven primarily by a significant reduction in the risk for death in the VKA group, and without a significant increase in major bleeding, reported Ganesan Karthikeyan, MD, from the All India Institute of Medical Sciences in New Delhi.
“VKA should remain the standard of care for patients with rheumatic heart disease and atrial fibrillation,” he concluded in a hotline session at the annual congress of the European Society of Cardiology.
The study, simultaneously published in the New England Journal of Medicine, is the first randomized controlled trial to assess anticoagulant therapy in patients with rheumatic heart disease and AFib.
“Who could have possibly guessed these results? Certainly not me,” said invited discussant Renato D. Lopes, MD, MHS, PhD, Duke Clinical Research Institute, Durham, N.C. “To me, this is one more classical example of why we need to do randomized trials, since they are the only reliable way to determine treatment effects and drive clinical practice.”
Evidence gap
Rheumatic heart disease affects over 40 million people, mainly living in low- and low- to middle-income countries. About 20% of symptomatic patients have AF and an elevated stroke risk, but previous AFib trials excluded these patients, Dr. Karthikeyan noted.
INVICTUS was led by the Population Health Research Institute in Hamilton, Ont., and enrolled 4,565 patients from 24 countries in Africa, Asia, and Latin America who had rheumatic heart disease, AFib or atrial flutter, and an increased stroke risk caused by any of the following: CHA2DS2VASc score of 2 or more, moderate to severe mitral stenosis (valve area ≤ 2.0 cm2), left atrial spontaneous echo contrast, or left atrial thrombus.
Participants were randomly assigned to receive rivaroxaban, 20 mg once daily (15 mg/d if creatinine clearance was 15-49 mL/min), or a VKA titrated to an international normalized ratio (INR) of 2.0-3.0.
Warfarin was used in 79%-85% of patients assigned to VKA, with the percentage varying between visits. The INR was in therapeutic range in 33.2% of patients at baseline, 65.1% at 3 years, and 64.1% at 4 years.
During an average follow-up of 3.1 years, the primary outcome occurred in 446 patients in the VKA group (6.49% per year) and 560 patients in the rivaroxaban group (8.21% per year). The restricted mean survival time for the primary outcome was 1,675 vs. 1,599 days, respectively (difference, –76 days; 95% CI, –121 to –31 days; P for superiority < .001).
The rate of stroke or systemic embolism was similar between the VKA and rivaroxaban groups (75 vs. 94 events), although ischemic strokes were significantly lower with VKA (48 vs. 74 events).
No easy explanation
Deaths were significantly lower with VKA than rivaroxaban, at 442 versus 552 (restricted mean survival time for death, 1,608 vs. 1,587 days; difference, −72 days; 95% CI, –117 to –28 days).
“This reduction is not easily explained,” Dr. Karthikeyan acknowledged. “We cannot explain this reduction by the reduction in stroke that we saw because the number of deaths that are prevented by VKA are far larger than the number of strokes that are prevented. Moreover, the number of deaths were mainly heart failure or sudden deaths.”
Numbers of patients with major bleeding were also similar in the VKA and rivaroxaban groups (56 vs. 40 patients; P = .18), although numbers with fatal bleeding were lower with rivaroxaban (15 vs. 4, respectively).
By design, there were more physician interactions for monthly monitoring of INR in the VKA group, “but we do not believe such a large reduction can be explained entirely by increased health care contact,” he said. Moreover, there was no significant between-group difference in heart failure medications or hospitalizations or the need for valve replacement.
Almost a quarter (23%) of patients in the rivaroxaban group permanently discontinued the study drug versus just 6% in the VKA group.
Importantly, the mortality benefit emerged much later than in other trials and coincided with the time when the INR became therapeutic at about 3 years, Dr. Karthikeyan said. But it is unknown whether this is because of the INR or an unrelated effect.
More physician contact
Following the presentation, session cochair C. Michael Gibson, MD, Baim Institute for Clinical Research, Harvard Medical School, Boston, questioned the 23% discontinuation rate for rivaroxaban. “Is this really a superiority of warfarin or is this superiority of having someone come in and see their physician for a lot of checks on their INR?”
In response, Dr. Karthikeyan said that permanent discontinuation rates were about 20%-25% in shorter-duration direct oral anticoagulant trials, such as RELY, ROCKET-AF, and ARISTOLE, and exceeded 30% in ENGAGE-AF with 2.8 years’ follow-up.
“So, this is not new,” he said, adding that 31.4% of rivaroxaban patients did so for valve replacement surgery and subsequently received nonstudy VKA.
Dr. Lopes said it is important to keep in mind that INVICTUS enrolled a “very different population” that was younger (mean age, 50.5 years), was much more often female (72.3%), and had fewer comorbidities than patients with AFib who did not have rheumatic heart disease in the pivotal trials.
“It will be interesting to see the treatment effect according to mitral stenosis severity, since we had about 30% with mild mitral stenosis and additionally 18% of patients without mitral stenosis,” he added.
Co–principal investigator Stuart J. Connolly, MD, from the Population Health Research Institute, said physician contacts may be a factor but that the mortality difference was clear, highly significant, and sufficiently powered.
“What’s amazing is that what we’re seeing here is something that hasn’t been previously described with VKA or warfarin, which is that it reduces mortality,” he said in an interview.
Rivaroxaban has never been shown to reduce mortality in any particular condition, and a meta-analysis of other novel oral anticoagulants shows only a small reduction in mortality, caused almost completely by less intracranial hemorrhage than warfarin, he added. “So, we don’t think this is a problem with rivaroxaban. In some ways, rivaroxaban is an innocent bystander to a trial of warfarin in patients with rheumatic heart disease and atrial fibrillation.”
Dr. Connolly said more work is needed to explain the findings and analyses are planned to see which patients are at highest risk for death as well as looking at the relationship between INR control and outcomes.
“We need to do more research on what it is about VKA that could explain this,” he said. “Is it affecting the myocardium in some way, is it preventing fibrosis, is there some off target effect, not on the anticoagulation system, that could explain this?”
Athena Poppas, MD, chief of cardiology at Brown University, Providence, R.I., and past president of the American College of Cardiology, said “INVICTUS is an incredibly important study that needed to be done.”
“The results – though disappointing and surprising in some ways – I don’t think we can explain them away and change what we are doing right now,” she said in an interview.
Although warfarin is a cheap drug, Dr. Poppas said, it would be tremendously helpful to have an alternative treatment for these patients. Mechanistic studies are needed to understand the observed mortality advantage and low bleeding rates but that trials of other novel anticoagulants are also needed.
“But I’m not sure that will happen,” she added. “It’s unlikely to be industry sponsored, so it would be a very expensive lift with a low likelihood of success.”
In an editorial accompanying the paper, Gregory Y.H. Lip, MD, University of Liverpool (England), pointed out that observational data show similar or even higher risks for major bleeding with rivaroxaban than with warfarin. “To improve outcomes in these patients, we therefore need to look beyond anticoagulation alone or beyond a type of anticoagulation drug per se. Indeed, a one-size-fits-all approach may not be appropriate.”
The study was funded by an unrestricted grant from Bayer. Dr. Karthikeyan and Dr. Poppas reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
COVID-19 vaccine safe in patients with heart failure
Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.
Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.
Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
Major risk is not receiving vaccine
These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.
Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.
The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.
However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”
The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.
The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.
“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).
“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.
Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.
“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.
“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.
“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”
95% of patients with HF in Denmark double vaccinated
The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.
Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.
The rates of vaccination in this study were much higher than those for patients with HF in the United States.
In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,
In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”
“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”
The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.
Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.
The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.
During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).
The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.
The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.
A version of this article first appeared on Medscape.com.
Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.
Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.
Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
Major risk is not receiving vaccine
These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.
Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.
The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.
However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”
The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.
The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.
“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).
“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.
Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.
“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.
“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.
“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”
95% of patients with HF in Denmark double vaccinated
The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.
Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.
The rates of vaccination in this study were much higher than those for patients with HF in the United States.
In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,
In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”
“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”
The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.
Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.
The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.
During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).
The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.
The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.
A version of this article first appeared on Medscape.com.
Patients with heart failure (HF) who received two doses of COVID mRNA vaccines were not more likely to have worsening disease, venous thromboembolism, or myocarditis within 90 days than similar unvaccinated patients, in a case-control study in Denmark.
Moreover, in the 90 days after receiving the second shot, vaccinated patients were less likely to die of any cause, compared with unvaccinated patients during a similar 90-day period.
Caroline Sindet-Pedersen, PhD, Herlev and Gentofte Hospital, Hellerup, Denmark, and colleagues presented these findings at the annual congress of the European Society of Cardiology.
Major risk is not receiving vaccine
These results “confirm that the major risk for patients with HF is not receiving vaccination for COVID-19,” Marco Metra, MD, who was not involved with this research, said in an interview.
Dr. Metra was coauthor of an ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic, published online ahead of print November 2021 in the European Heart Journal.
The guidance explains that patients with HF are at increased risk for hospitalization, need for mechanical ventilation, and death because of COVID-19, and that vaccination reduces the risk for serious illness from COVID-19, Dr. Sindet-Pedersen and colleagues explained in a press release from the ESC.
However, “concerns remain,” they added, “about the safety of the SARS-CoV-2 mRNA vaccines in heart failure patients, due to a perceived increased risk of cardiovascular side effects.”
The study findings suggest that “there should be no concern about cardiovascular side effects from mRNA vaccines in heart failure patients,” Dr. Sindet-Pedersen and colleagues summarized.
The results also “point to a beneficial effect of vaccination on mortality” and “indicate that patients with HF should be prioritized for COVID-19 vaccinations and boosters,” they added.
“There are ongoing concerns about the safety of COVID-19 vaccination in fragile patients and patients with heart failure,” said Dr. Metra, professor of cardiology and director of the Institute of Cardiology of the Civil Hospital and University of Brescia (Italy).
“These concerns are not based on evidence but just on reports of rare side effects (namely, myocarditis and pericarditis) in vaccinated people,” he added.
Dr. Metra also coauthored a position paper on COVID-19 vaccination in patients with HF from the Heart Failure Association of the ESC, which was published online October 2021 in the European Journal of Heart Failure.
“The current study,” he summarized, “shows a lower risk of mortality among patients vaccinated, compared with those not vaccinated.
“It has limitations,” he cautioned, “as it is not a prospective randomized study, but [rather] an observational one with comparison between vaccinated and not vaccinated patients with similar characteristics.
“However, it was done in a large population,” he noted, “and its results confirm that the major risk for patients with HF is not receiving vaccination for COVID-19.”
95% of patients with HF in Denmark double vaccinated
The group did not analyze the types of all-cause death in their study, Dr. Sindet-Pedersen clarified in an interview.
Other studies have shown that vaccines are associated with improved survival, she noted. For example, bacillus Calmette-Guérin vaccines and the measles vaccines have been linked with a decreased risk for nonspecific mortality in children, and influenza vaccines are associated with decreased all-cause mortality in patients with HF.
The rates of vaccination in this study were much higher than those for patients with HF in the United States.
In a study of 7,094 patients with HF seen at the Mount Sinai Health System between January 2021 and January 2022, 31% of patients were fully vaccinated with two doses and 14.8% had also received a booster, as per Centers for Disease Control and Prevention guidance. However, another 9.1% of patients were only partially vaccinated with one dose, and 45% remained unvaccinated by January 2022,
In the current study, “the uptake was very high,” Dr. Sindet-Pedersen noted, that is, “95% of the prevalent heart failure patients in 2021 received a vaccine.”
“It might be that the last 5% of the patients that did not receive a vaccine were too ill [terminal] to receive the vaccine,” she speculated, “or that was due to personal reasons.”
The researchers identified 50,893 patients with HF who were double vaccinated in 2021 and they matched them with 50,893 unvaccinated patients with HF in 2019 (prepandemic), with the same age, sex, HF duration, use of HF medications, ischemic heart disease, cancer, diabetes, atrial fibrillation, and admission with HF within 90 days.
Almost all patients in the vaccinated group received the Pfizer/BioNTech mRNA vaccine (92%) and the rest received the Moderna mRNA vaccine (8%), in 2021.
The patients had a mean age of 74, and 64% were men. They had HF for a median of 4.1 years.
During the 90-day follow-up, 1,311 patients in the unvaccinated cohort (2.56%) and 1,113 patients in the vaccinated cohort (2.23%) died; there was a significantly lower risk for all-cause death in the vaccinated cohort versus the unvaccinated cohort (–0.33 percentage points; 95% CI, –0.52 to –0.15 percentage points).
The risk for worsening heart failure was 1.1% in each group; myocarditis and venous thromboembolism were extremely rare, and risks for these conditions were not significantly different in the two groups.
The researchers and Dr. Metra declared they have no relevant financial disclosures. Dr. Metra is editor-in-chief of the European Journal of Heart Failure and senior consulting editor of the European Heart Journal.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
AXIOMATIC-SSP: Cautious optimism on factor XI inhibitor in stroke
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.
Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.
Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.
There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.
“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.
Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
New generation
Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.
This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.
“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”
Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.
The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.
Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.
The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.
They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.
The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).
However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).
The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.
Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
Incremental improvement
On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.
“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.
He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.
In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.
Both drugs are now believed to be going forward into phase 3 trials.
Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.
She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials
“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”
The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022