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Psychological safety in cardiology training
Training in medicine has long been thought of as a tough process, but the issue of creating a psychologically safe environment for young doctors is now being highlighted as an important way of providing an improved learning environment, which will ultimately lead to better patient care. And cardiology is one field that needs to work harder on this.
“We all remember attendings who made our training experience memorable, who made us excited to come to work and learn, and who inspired us to become better,” Vivek Kulkarni, MD, wrote in a recent commentary. “Unfortunately, we also all remember the learning environments where we were terrified, where thriving took a backseat to surviving, and where learning was an afterthought.”
Writing in an article in the Journal of the American College of Cardiology, Dr. Kulkarni asked the question: “Why are some learning environments better than others, and what can we do to improve the learning environment for our trainees?”
Dr. Kulkarni, director of the training program for cardiology fellows at Cooper University Hospital, Camden, New Jersey, said “There may be some people in some institutions that do pay attention to this but as wider field we could do better.”
Dr. Kulkarni explained that psychological safety is the comfort to engage with others genuinely, with honesty and without fear.
It has been defined as a “willingness to take interpersonal risks at work, whether to admit error, ask a question, seek help, or simply say ‘I don’t know,’ ” or as “the perception that a working environment is safe for team members to express a concern, ask a question, or acknowledge a mistake without fear of humiliation, retaliation, blame, or being ignored.”
“In the medical environment we usually work in teams: older doctors, younger doctors, nurses, other staff,” Dr. Kulkarni said in an interview. “A psychologically safe environment would be one where a trainee feels comfortable so that they can ask a question about something that they don’t understand. That comfort comes from the idea that it is okay to get something wrong or to not know something and to ask for help.
“The flip side of that is an environment in which people are so afraid to make a mistake out of fear of retribution or punishment that they don’t take risks, or they don’t openly acknowledge when they might need help with something,” he said. “That would be a psychologically unsafe environment.”
What exactly this looks like varies in different environments and culture of the group, he noted, “but in general, you can tell if you are part of a psychologically safe environment because you are excited to come to work and feel comfortable at work.”
Dr. Kulkarni added that a growing body of literature now shows that psychological safety is critical for optimal learning but that cardiovascular fellowship training poses unique barriers to psychological safety.
‘Arrogant, unkind, and unwelcoming’
First, he said that the “high-stakes” nature of cardiology, in which decisions often must be made quickly and can have life-or-death consequences, can create fear about making mistakes and that some trainees may be so afraid that they cannot speak up and ask for help when struggling or cannot incorporate feedback in real time.
Second, in medicine at large, there is a stereotype that cardiologists can be “arrogant, unkind, and unwelcoming,” which may discourage new fellows from honest interaction.
Third, cardiology involves many different technical skills that fellows have little to no previous experience with; this may contribute to a perceived sense of being judged when making mistakes or asking for help.
Finally, demographics may be a factor, with only one in eight cardiologists in the United States being women and only 7.5% of cardiologists being from traditionally underrepresented racial and ethnic minority groups, which Dr. Kulkarni said may lead to a lack of psychological safety because of “bias, microaggressions, or even just a lack of mentors of similar backgrounds.”
But he believes that the cardiology training culture is improving.
“I think it is getting better. Even the fact that I can publish this article is a positive sign. I think there’s an audience for this type of thing now.”
He believes that part of the reason for this is the availability of research and evidence showing there are better ways to teach than the old traditional approaches.
He noted that some teaching physicians receive training on how to teach and some don’t, and this is an area that could be improved.
“I think the knowledge of how to produce psychologically safe environments is already there,” he said. “It just has to be standardized and publicized. That would make the learning environment better.”
“Nothing about this is groundbreaking,” he added. “We all know psychologically unsafe environments exist. The novelty is just that it is now starting to be discussed. It’s one of those things that we can likely improve the ways our trainees learn and the kind of doctors we produce just by thinking a little bit more carefully about the way we interact with each other.”
Dr. Kulkarni said trainees often drop out because they have had a negative experience of feeling psychologically unsafe. “They may drop out of medicine all together or they may choose to pursue a career in a different part of medicine, where they perceive a more psychologically safe environment.”
He also suggested that this issue can affect patient care.
“If the medical team does not provide a psychologically safe environment for trainees, it is very likely that that team is not operating as effectively as it could, and it is very likely that patients being taken care of by that team may have missed opportunities for better care,” he concluded. Examples could include trainees recognizing errors and bringing things that might not be right to the attention of their superiors. “That is something that requires some degree of psychological safety.”
Action for improvement
Dr. Kulkarni suggested several strategies to promote psychological safety in cardiology training.
As a first step, institutions should investigate the culture of learning within their fellowship programs and gather feedback from anonymous surveys of fellows. They can then implement policies to address gaps.
He noted that, at Cooper University Hospital, standardized documents have been created that explicitly outline policies for attendings on teaching services, which establish expectations for all team members, encourage fellows to ask for help, set guidelines for feedback conversations with fellows, and delineate situations when calling the attending is expected.
Dr. Kulkarni also suggested that cardiologists involved in teaching fellows can try several strategies to promote psychological safety. These include setting clear expectations on their tasks and graded autonomy, inviting participation in decisions, acknowledging that gaps in knowledge are not a personal failure but rather a normal part of the growth process, encouraging fellows to seek help when they need it, fostering collegial relationships with fellows, acknowledging your own uncertainty in difficult situations, checking in about emotions after challenging situations, and seeking feedback on your own performance.
He added that changes on a larger scale are also needed, such as training for cardiology program directors including more on this issue as well as developing best practices.
“If we as a community could come together and agree on the things needed to create a psychologically safe environment for training, that would be a big improvement.”
Addressing the challenges of different generations
In a response to Dr. Kulkarni’s article, Margo Vassar, MD, The Queen’s Medical Center, Honolulu, and Sandra Lewis, MD, Legacy Health System, Portland, Ore., make the case that to succeed in providing psychological safety, the cardiovascular community also needs to address intergenerational cultural challenges.
“Twenty years ago, to have raised the idea of psychological safety in any phase of training would likely have been met with intergenerational pushback and complete disregard,” they say, adding that: “Asking senior Baby Boomer cardiologists to develop skills to implement psychological safety, with just a list of action items, to suddenly create safe environments, belies the challenges inherent in intergenerational understanding and collaboration.”
In an interview, Dr. Lewis elaborated: “Many cardiology training program directors are Baby Boomers, but there is a whole new group of younger people moving in, and the way they deal with things and communicate is quite different.”
Dr. Lewis gave an example of when she was in training the attending was the “be all and end all,” and it was not expected that fellows would ask questions. “I think there is more communication now and a willingness to take risks and ask questions.”
But she said because everyone is so busy now, building relationships within a team can be difficult.
“We don’t have the doctors’ lounge anymore. We don’t sit and have lunch together. Computers are taking over now, no one actually talks to each other anymore,” she said. “We need to try to get to know each other and become colleagues. It’s easy when you don’t know somebody to be abrupt or brusque; it’s harder when you’re friends.”
She noted that the Mayo Clinic is one institution that is doing a lot of work on this, arranging for groups of doctors to go out for dinner together to get to know each other.
“This bringing people together socially happens in a lot of workplaces, and it can happen in medicine.”
Dr. Lewis, who has some leadership positions at the American College of Cardiology, said the organization is focusing on “intergenerational opportunities and challenges” to help improve psychological safety for trainees.
Noting that a recent survey of medical residents found that “contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology,” Lewis said the ACC is also reaching out to medical residents who may think that cardiology is an unwelcoming environment to enter and to minority groups of medical residents such as women and ethnic minorities to try and attract them to become cardiology fellows.
“If fellows find in hard to speak up because they are in this hierarchical learning situation, that can be even more difficult if you feel you’re in a minority group. ... We need to create a culture of colleagues rather than perpetuating a culture of us and them, to provide a safe and thriving cardiovascular community,” she added.
A version of this article first appeared on Medscape.com.
Training in medicine has long been thought of as a tough process, but the issue of creating a psychologically safe environment for young doctors is now being highlighted as an important way of providing an improved learning environment, which will ultimately lead to better patient care. And cardiology is one field that needs to work harder on this.
“We all remember attendings who made our training experience memorable, who made us excited to come to work and learn, and who inspired us to become better,” Vivek Kulkarni, MD, wrote in a recent commentary. “Unfortunately, we also all remember the learning environments where we were terrified, where thriving took a backseat to surviving, and where learning was an afterthought.”
Writing in an article in the Journal of the American College of Cardiology, Dr. Kulkarni asked the question: “Why are some learning environments better than others, and what can we do to improve the learning environment for our trainees?”
Dr. Kulkarni, director of the training program for cardiology fellows at Cooper University Hospital, Camden, New Jersey, said “There may be some people in some institutions that do pay attention to this but as wider field we could do better.”
Dr. Kulkarni explained that psychological safety is the comfort to engage with others genuinely, with honesty and without fear.
It has been defined as a “willingness to take interpersonal risks at work, whether to admit error, ask a question, seek help, or simply say ‘I don’t know,’ ” or as “the perception that a working environment is safe for team members to express a concern, ask a question, or acknowledge a mistake without fear of humiliation, retaliation, blame, or being ignored.”
“In the medical environment we usually work in teams: older doctors, younger doctors, nurses, other staff,” Dr. Kulkarni said in an interview. “A psychologically safe environment would be one where a trainee feels comfortable so that they can ask a question about something that they don’t understand. That comfort comes from the idea that it is okay to get something wrong or to not know something and to ask for help.
“The flip side of that is an environment in which people are so afraid to make a mistake out of fear of retribution or punishment that they don’t take risks, or they don’t openly acknowledge when they might need help with something,” he said. “That would be a psychologically unsafe environment.”
What exactly this looks like varies in different environments and culture of the group, he noted, “but in general, you can tell if you are part of a psychologically safe environment because you are excited to come to work and feel comfortable at work.”
Dr. Kulkarni added that a growing body of literature now shows that psychological safety is critical for optimal learning but that cardiovascular fellowship training poses unique barriers to psychological safety.
‘Arrogant, unkind, and unwelcoming’
First, he said that the “high-stakes” nature of cardiology, in which decisions often must be made quickly and can have life-or-death consequences, can create fear about making mistakes and that some trainees may be so afraid that they cannot speak up and ask for help when struggling or cannot incorporate feedback in real time.
Second, in medicine at large, there is a stereotype that cardiologists can be “arrogant, unkind, and unwelcoming,” which may discourage new fellows from honest interaction.
Third, cardiology involves many different technical skills that fellows have little to no previous experience with; this may contribute to a perceived sense of being judged when making mistakes or asking for help.
Finally, demographics may be a factor, with only one in eight cardiologists in the United States being women and only 7.5% of cardiologists being from traditionally underrepresented racial and ethnic minority groups, which Dr. Kulkarni said may lead to a lack of psychological safety because of “bias, microaggressions, or even just a lack of mentors of similar backgrounds.”
But he believes that the cardiology training culture is improving.
“I think it is getting better. Even the fact that I can publish this article is a positive sign. I think there’s an audience for this type of thing now.”
He believes that part of the reason for this is the availability of research and evidence showing there are better ways to teach than the old traditional approaches.
He noted that some teaching physicians receive training on how to teach and some don’t, and this is an area that could be improved.
“I think the knowledge of how to produce psychologically safe environments is already there,” he said. “It just has to be standardized and publicized. That would make the learning environment better.”
“Nothing about this is groundbreaking,” he added. “We all know psychologically unsafe environments exist. The novelty is just that it is now starting to be discussed. It’s one of those things that we can likely improve the ways our trainees learn and the kind of doctors we produce just by thinking a little bit more carefully about the way we interact with each other.”
Dr. Kulkarni said trainees often drop out because they have had a negative experience of feeling psychologically unsafe. “They may drop out of medicine all together or they may choose to pursue a career in a different part of medicine, where they perceive a more psychologically safe environment.”
He also suggested that this issue can affect patient care.
“If the medical team does not provide a psychologically safe environment for trainees, it is very likely that that team is not operating as effectively as it could, and it is very likely that patients being taken care of by that team may have missed opportunities for better care,” he concluded. Examples could include trainees recognizing errors and bringing things that might not be right to the attention of their superiors. “That is something that requires some degree of psychological safety.”
Action for improvement
Dr. Kulkarni suggested several strategies to promote psychological safety in cardiology training.
As a first step, institutions should investigate the culture of learning within their fellowship programs and gather feedback from anonymous surveys of fellows. They can then implement policies to address gaps.
He noted that, at Cooper University Hospital, standardized documents have been created that explicitly outline policies for attendings on teaching services, which establish expectations for all team members, encourage fellows to ask for help, set guidelines for feedback conversations with fellows, and delineate situations when calling the attending is expected.
Dr. Kulkarni also suggested that cardiologists involved in teaching fellows can try several strategies to promote psychological safety. These include setting clear expectations on their tasks and graded autonomy, inviting participation in decisions, acknowledging that gaps in knowledge are not a personal failure but rather a normal part of the growth process, encouraging fellows to seek help when they need it, fostering collegial relationships with fellows, acknowledging your own uncertainty in difficult situations, checking in about emotions after challenging situations, and seeking feedback on your own performance.
He added that changes on a larger scale are also needed, such as training for cardiology program directors including more on this issue as well as developing best practices.
“If we as a community could come together and agree on the things needed to create a psychologically safe environment for training, that would be a big improvement.”
Addressing the challenges of different generations
In a response to Dr. Kulkarni’s article, Margo Vassar, MD, The Queen’s Medical Center, Honolulu, and Sandra Lewis, MD, Legacy Health System, Portland, Ore., make the case that to succeed in providing psychological safety, the cardiovascular community also needs to address intergenerational cultural challenges.
“Twenty years ago, to have raised the idea of psychological safety in any phase of training would likely have been met with intergenerational pushback and complete disregard,” they say, adding that: “Asking senior Baby Boomer cardiologists to develop skills to implement psychological safety, with just a list of action items, to suddenly create safe environments, belies the challenges inherent in intergenerational understanding and collaboration.”
In an interview, Dr. Lewis elaborated: “Many cardiology training program directors are Baby Boomers, but there is a whole new group of younger people moving in, and the way they deal with things and communicate is quite different.”
Dr. Lewis gave an example of when she was in training the attending was the “be all and end all,” and it was not expected that fellows would ask questions. “I think there is more communication now and a willingness to take risks and ask questions.”
But she said because everyone is so busy now, building relationships within a team can be difficult.
“We don’t have the doctors’ lounge anymore. We don’t sit and have lunch together. Computers are taking over now, no one actually talks to each other anymore,” she said. “We need to try to get to know each other and become colleagues. It’s easy when you don’t know somebody to be abrupt or brusque; it’s harder when you’re friends.”
She noted that the Mayo Clinic is one institution that is doing a lot of work on this, arranging for groups of doctors to go out for dinner together to get to know each other.
“This bringing people together socially happens in a lot of workplaces, and it can happen in medicine.”
Dr. Lewis, who has some leadership positions at the American College of Cardiology, said the organization is focusing on “intergenerational opportunities and challenges” to help improve psychological safety for trainees.
Noting that a recent survey of medical residents found that “contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology,” Lewis said the ACC is also reaching out to medical residents who may think that cardiology is an unwelcoming environment to enter and to minority groups of medical residents such as women and ethnic minorities to try and attract them to become cardiology fellows.
“If fellows find in hard to speak up because they are in this hierarchical learning situation, that can be even more difficult if you feel you’re in a minority group. ... We need to create a culture of colleagues rather than perpetuating a culture of us and them, to provide a safe and thriving cardiovascular community,” she added.
A version of this article first appeared on Medscape.com.
Training in medicine has long been thought of as a tough process, but the issue of creating a psychologically safe environment for young doctors is now being highlighted as an important way of providing an improved learning environment, which will ultimately lead to better patient care. And cardiology is one field that needs to work harder on this.
“We all remember attendings who made our training experience memorable, who made us excited to come to work and learn, and who inspired us to become better,” Vivek Kulkarni, MD, wrote in a recent commentary. “Unfortunately, we also all remember the learning environments where we were terrified, where thriving took a backseat to surviving, and where learning was an afterthought.”
Writing in an article in the Journal of the American College of Cardiology, Dr. Kulkarni asked the question: “Why are some learning environments better than others, and what can we do to improve the learning environment for our trainees?”
Dr. Kulkarni, director of the training program for cardiology fellows at Cooper University Hospital, Camden, New Jersey, said “There may be some people in some institutions that do pay attention to this but as wider field we could do better.”
Dr. Kulkarni explained that psychological safety is the comfort to engage with others genuinely, with honesty and without fear.
It has been defined as a “willingness to take interpersonal risks at work, whether to admit error, ask a question, seek help, or simply say ‘I don’t know,’ ” or as “the perception that a working environment is safe for team members to express a concern, ask a question, or acknowledge a mistake without fear of humiliation, retaliation, blame, or being ignored.”
“In the medical environment we usually work in teams: older doctors, younger doctors, nurses, other staff,” Dr. Kulkarni said in an interview. “A psychologically safe environment would be one where a trainee feels comfortable so that they can ask a question about something that they don’t understand. That comfort comes from the idea that it is okay to get something wrong or to not know something and to ask for help.
“The flip side of that is an environment in which people are so afraid to make a mistake out of fear of retribution or punishment that they don’t take risks, or they don’t openly acknowledge when they might need help with something,” he said. “That would be a psychologically unsafe environment.”
What exactly this looks like varies in different environments and culture of the group, he noted, “but in general, you can tell if you are part of a psychologically safe environment because you are excited to come to work and feel comfortable at work.”
Dr. Kulkarni added that a growing body of literature now shows that psychological safety is critical for optimal learning but that cardiovascular fellowship training poses unique barriers to psychological safety.
‘Arrogant, unkind, and unwelcoming’
First, he said that the “high-stakes” nature of cardiology, in which decisions often must be made quickly and can have life-or-death consequences, can create fear about making mistakes and that some trainees may be so afraid that they cannot speak up and ask for help when struggling or cannot incorporate feedback in real time.
Second, in medicine at large, there is a stereotype that cardiologists can be “arrogant, unkind, and unwelcoming,” which may discourage new fellows from honest interaction.
Third, cardiology involves many different technical skills that fellows have little to no previous experience with; this may contribute to a perceived sense of being judged when making mistakes or asking for help.
Finally, demographics may be a factor, with only one in eight cardiologists in the United States being women and only 7.5% of cardiologists being from traditionally underrepresented racial and ethnic minority groups, which Dr. Kulkarni said may lead to a lack of psychological safety because of “bias, microaggressions, or even just a lack of mentors of similar backgrounds.”
But he believes that the cardiology training culture is improving.
“I think it is getting better. Even the fact that I can publish this article is a positive sign. I think there’s an audience for this type of thing now.”
He believes that part of the reason for this is the availability of research and evidence showing there are better ways to teach than the old traditional approaches.
He noted that some teaching physicians receive training on how to teach and some don’t, and this is an area that could be improved.
“I think the knowledge of how to produce psychologically safe environments is already there,” he said. “It just has to be standardized and publicized. That would make the learning environment better.”
“Nothing about this is groundbreaking,” he added. “We all know psychologically unsafe environments exist. The novelty is just that it is now starting to be discussed. It’s one of those things that we can likely improve the ways our trainees learn and the kind of doctors we produce just by thinking a little bit more carefully about the way we interact with each other.”
Dr. Kulkarni said trainees often drop out because they have had a negative experience of feeling psychologically unsafe. “They may drop out of medicine all together or they may choose to pursue a career in a different part of medicine, where they perceive a more psychologically safe environment.”
He also suggested that this issue can affect patient care.
“If the medical team does not provide a psychologically safe environment for trainees, it is very likely that that team is not operating as effectively as it could, and it is very likely that patients being taken care of by that team may have missed opportunities for better care,” he concluded. Examples could include trainees recognizing errors and bringing things that might not be right to the attention of their superiors. “That is something that requires some degree of psychological safety.”
Action for improvement
Dr. Kulkarni suggested several strategies to promote psychological safety in cardiology training.
As a first step, institutions should investigate the culture of learning within their fellowship programs and gather feedback from anonymous surveys of fellows. They can then implement policies to address gaps.
He noted that, at Cooper University Hospital, standardized documents have been created that explicitly outline policies for attendings on teaching services, which establish expectations for all team members, encourage fellows to ask for help, set guidelines for feedback conversations with fellows, and delineate situations when calling the attending is expected.
Dr. Kulkarni also suggested that cardiologists involved in teaching fellows can try several strategies to promote psychological safety. These include setting clear expectations on their tasks and graded autonomy, inviting participation in decisions, acknowledging that gaps in knowledge are not a personal failure but rather a normal part of the growth process, encouraging fellows to seek help when they need it, fostering collegial relationships with fellows, acknowledging your own uncertainty in difficult situations, checking in about emotions after challenging situations, and seeking feedback on your own performance.
He added that changes on a larger scale are also needed, such as training for cardiology program directors including more on this issue as well as developing best practices.
“If we as a community could come together and agree on the things needed to create a psychologically safe environment for training, that would be a big improvement.”
Addressing the challenges of different generations
In a response to Dr. Kulkarni’s article, Margo Vassar, MD, The Queen’s Medical Center, Honolulu, and Sandra Lewis, MD, Legacy Health System, Portland, Ore., make the case that to succeed in providing psychological safety, the cardiovascular community also needs to address intergenerational cultural challenges.
“Twenty years ago, to have raised the idea of psychological safety in any phase of training would likely have been met with intergenerational pushback and complete disregard,” they say, adding that: “Asking senior Baby Boomer cardiologists to develop skills to implement psychological safety, with just a list of action items, to suddenly create safe environments, belies the challenges inherent in intergenerational understanding and collaboration.”
In an interview, Dr. Lewis elaborated: “Many cardiology training program directors are Baby Boomers, but there is a whole new group of younger people moving in, and the way they deal with things and communicate is quite different.”
Dr. Lewis gave an example of when she was in training the attending was the “be all and end all,” and it was not expected that fellows would ask questions. “I think there is more communication now and a willingness to take risks and ask questions.”
But she said because everyone is so busy now, building relationships within a team can be difficult.
“We don’t have the doctors’ lounge anymore. We don’t sit and have lunch together. Computers are taking over now, no one actually talks to each other anymore,” she said. “We need to try to get to know each other and become colleagues. It’s easy when you don’t know somebody to be abrupt or brusque; it’s harder when you’re friends.”
She noted that the Mayo Clinic is one institution that is doing a lot of work on this, arranging for groups of doctors to go out for dinner together to get to know each other.
“This bringing people together socially happens in a lot of workplaces, and it can happen in medicine.”
Dr. Lewis, who has some leadership positions at the American College of Cardiology, said the organization is focusing on “intergenerational opportunities and challenges” to help improve psychological safety for trainees.
Noting that a recent survey of medical residents found that “contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology,” Lewis said the ACC is also reaching out to medical residents who may think that cardiology is an unwelcoming environment to enter and to minority groups of medical residents such as women and ethnic minorities to try and attract them to become cardiology fellows.
“If fellows find in hard to speak up because they are in this hierarchical learning situation, that can be even more difficult if you feel you’re in a minority group. ... We need to create a culture of colleagues rather than perpetuating a culture of us and them, to provide a safe and thriving cardiovascular community,” she added.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
No benefit of colchicine after stroke, TIA: CHANCE-3
The anti-inflammatory agent in the CHANCE-3 trial.
The results were presented by Yongjun Wang, MD, Beijing Tiantan Hospital, Capital Medical University, at the annual World Stroke Congress, sponsored by the World Stroke Organization.
Dr. Wang noted that inflammation may be a key factor involved in the residual risk for recurrent stroke, with data from previous CHANCE trials suggesting a higher stroke recurrence rate in patients with higher levels of high-sensitivity C-reactive protein (hsCRP), a key marker of inflammation.
Low-dose colchicine, which acts as an anti-inflammatory agent, has recently been approved in many countries for patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease to reduce the risk for future cardiovascular events. This follows benefits seen in those populations in the LoDoCo-2 and COLCOT trials.
The CHANCE-3 study was conducted to evaluate whether similar benefits could be found in patients with acute ischemic stroke.
The trial involved 8,369 Chinese patients with minor to moderate ischemic stroke (National Institutes of Health Stroke Scale score ≤ 5) or high-risk TIA (ABCD2 score ≥ 4) who had an hsCRP level of at least 2 mg/L.
Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or placebo, on a background of optimal medical therapy.
The primary outcome was any stroke within 90 days. The key secondary outcomes included a composite of stroke, TIA, myocardial infarction, and vascular death within 90 days, and Modified Rankin Scale score greater than 1 at 90 days.
Results showed that the primary outcome of any stroke at 90 days occurred in 6.3% of the colchicine group versus 6.5% of the placebo group, a nonsignificant difference (P = .79).
All secondary outcomes were also neutral, with no differences between the two groups.
Addressing the different results in CHANCE-3, compared with those of the cardiovascular trials of colchicine, Dr. Wang pointed out that the cardiovascular trials had a much longer treatment and follow-up time (an average of 22 months), compared with just 3 months in CHANCE-3.
“Clinical trials with longer treatment times are needed to further assess the effects of colchicine after cerebrovascular events, but it may be that ischemic cerebrovascular disease and ischemic heart disease respond differently to colchicine treatment,” he concluded.
Commenting on the study, cochair of the WSC session at which it was presented, Ashkan Shoamanesh, MD, associate professor of medicine at McMaster University, Hamilton, Ont., said CHANCE-3 was a well-designed large phase 3 randomized trial and the first such trial to test colchicine for secondary stroke prevention.
He agreed with Dr. Wang that the follow-up duration for this initial analysis of 3-month outcomes may have been too short to see an effect.
“So, we require randomized trials with longer follow-up prior to abandoning this potential treatment,” he added.
Dr. Shoamanesh noted that several additional trials are currently ongoing testing colchicine for secondary prevention in patients with stroke. These include the CONVINCE, CASPER, CoVasc-ICH, and RIISC-THETIS trials.
He also pointed out that, in contrast to ischemic heart disease, which results from atherosclerosis, the mechanisms underlying ischemic stroke are more heterogeneous and include various vascular and cardioembolic pathologies.
The CHANCE-3 study was funded by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China, the Chinese Academy of Medical Sciences, and the Beijing Municipal Health Commission.
A version of this article first appeared on Medscape.com.
The anti-inflammatory agent in the CHANCE-3 trial.
The results were presented by Yongjun Wang, MD, Beijing Tiantan Hospital, Capital Medical University, at the annual World Stroke Congress, sponsored by the World Stroke Organization.
Dr. Wang noted that inflammation may be a key factor involved in the residual risk for recurrent stroke, with data from previous CHANCE trials suggesting a higher stroke recurrence rate in patients with higher levels of high-sensitivity C-reactive protein (hsCRP), a key marker of inflammation.
Low-dose colchicine, which acts as an anti-inflammatory agent, has recently been approved in many countries for patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease to reduce the risk for future cardiovascular events. This follows benefits seen in those populations in the LoDoCo-2 and COLCOT trials.
The CHANCE-3 study was conducted to evaluate whether similar benefits could be found in patients with acute ischemic stroke.
The trial involved 8,369 Chinese patients with minor to moderate ischemic stroke (National Institutes of Health Stroke Scale score ≤ 5) or high-risk TIA (ABCD2 score ≥ 4) who had an hsCRP level of at least 2 mg/L.
Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or placebo, on a background of optimal medical therapy.
The primary outcome was any stroke within 90 days. The key secondary outcomes included a composite of stroke, TIA, myocardial infarction, and vascular death within 90 days, and Modified Rankin Scale score greater than 1 at 90 days.
Results showed that the primary outcome of any stroke at 90 days occurred in 6.3% of the colchicine group versus 6.5% of the placebo group, a nonsignificant difference (P = .79).
All secondary outcomes were also neutral, with no differences between the two groups.
Addressing the different results in CHANCE-3, compared with those of the cardiovascular trials of colchicine, Dr. Wang pointed out that the cardiovascular trials had a much longer treatment and follow-up time (an average of 22 months), compared with just 3 months in CHANCE-3.
“Clinical trials with longer treatment times are needed to further assess the effects of colchicine after cerebrovascular events, but it may be that ischemic cerebrovascular disease and ischemic heart disease respond differently to colchicine treatment,” he concluded.
Commenting on the study, cochair of the WSC session at which it was presented, Ashkan Shoamanesh, MD, associate professor of medicine at McMaster University, Hamilton, Ont., said CHANCE-3 was a well-designed large phase 3 randomized trial and the first such trial to test colchicine for secondary stroke prevention.
He agreed with Dr. Wang that the follow-up duration for this initial analysis of 3-month outcomes may have been too short to see an effect.
“So, we require randomized trials with longer follow-up prior to abandoning this potential treatment,” he added.
Dr. Shoamanesh noted that several additional trials are currently ongoing testing colchicine for secondary prevention in patients with stroke. These include the CONVINCE, CASPER, CoVasc-ICH, and RIISC-THETIS trials.
He also pointed out that, in contrast to ischemic heart disease, which results from atherosclerosis, the mechanisms underlying ischemic stroke are more heterogeneous and include various vascular and cardioembolic pathologies.
The CHANCE-3 study was funded by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China, the Chinese Academy of Medical Sciences, and the Beijing Municipal Health Commission.
A version of this article first appeared on Medscape.com.
The anti-inflammatory agent in the CHANCE-3 trial.
The results were presented by Yongjun Wang, MD, Beijing Tiantan Hospital, Capital Medical University, at the annual World Stroke Congress, sponsored by the World Stroke Organization.
Dr. Wang noted that inflammation may be a key factor involved in the residual risk for recurrent stroke, with data from previous CHANCE trials suggesting a higher stroke recurrence rate in patients with higher levels of high-sensitivity C-reactive protein (hsCRP), a key marker of inflammation.
Low-dose colchicine, which acts as an anti-inflammatory agent, has recently been approved in many countries for patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease to reduce the risk for future cardiovascular events. This follows benefits seen in those populations in the LoDoCo-2 and COLCOT trials.
The CHANCE-3 study was conducted to evaluate whether similar benefits could be found in patients with acute ischemic stroke.
The trial involved 8,369 Chinese patients with minor to moderate ischemic stroke (National Institutes of Health Stroke Scale score ≤ 5) or high-risk TIA (ABCD2 score ≥ 4) who had an hsCRP level of at least 2 mg/L.
Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or placebo, on a background of optimal medical therapy.
The primary outcome was any stroke within 90 days. The key secondary outcomes included a composite of stroke, TIA, myocardial infarction, and vascular death within 90 days, and Modified Rankin Scale score greater than 1 at 90 days.
Results showed that the primary outcome of any stroke at 90 days occurred in 6.3% of the colchicine group versus 6.5% of the placebo group, a nonsignificant difference (P = .79).
All secondary outcomes were also neutral, with no differences between the two groups.
Addressing the different results in CHANCE-3, compared with those of the cardiovascular trials of colchicine, Dr. Wang pointed out that the cardiovascular trials had a much longer treatment and follow-up time (an average of 22 months), compared with just 3 months in CHANCE-3.
“Clinical trials with longer treatment times are needed to further assess the effects of colchicine after cerebrovascular events, but it may be that ischemic cerebrovascular disease and ischemic heart disease respond differently to colchicine treatment,” he concluded.
Commenting on the study, cochair of the WSC session at which it was presented, Ashkan Shoamanesh, MD, associate professor of medicine at McMaster University, Hamilton, Ont., said CHANCE-3 was a well-designed large phase 3 randomized trial and the first such trial to test colchicine for secondary stroke prevention.
He agreed with Dr. Wang that the follow-up duration for this initial analysis of 3-month outcomes may have been too short to see an effect.
“So, we require randomized trials with longer follow-up prior to abandoning this potential treatment,” he added.
Dr. Shoamanesh noted that several additional trials are currently ongoing testing colchicine for secondary prevention in patients with stroke. These include the CONVINCE, CASPER, CoVasc-ICH, and RIISC-THETIS trials.
He also pointed out that, in contrast to ischemic heart disease, which results from atherosclerosis, the mechanisms underlying ischemic stroke are more heterogeneous and include various vascular and cardioembolic pathologies.
The CHANCE-3 study was funded by grants from the National Natural Science Foundation of China, the Ministry of Science and Technology of China, the Chinese Academy of Medical Sciences, and the Beijing Municipal Health Commission.
A version of this article first appeared on Medscape.com.
FROM WSC 2023
Low-risk TAVR studies: Divergent long-term results
The PARTNER-3 and Evolut trials were heralded as a landmark advance in medicine when the 1-year results from the two studies were presented back in 2019. Both trials suggested benefits of the less-invasive TAVR approach over surgery.
But because these low-surgical-risk patients are younger and will likely have a longer lifespan than will higher risk patients for whom the TAVR technique was first established, patient outcomes and information on how the TAVR devices hold up over the long-term are critical to inform clinical decision-making.
Latest results from the two trials show that the initial benefits of TAVR over surgery seen in PARTNER-3 seem to have attenuated over the longer-term, with main outcomes looking very similar in both groups after 5 years.
However, in the Evolut trial, the early benefit in all-cause mortality or disabling stroke seen in the TAVR group is continuing to increase, with current results showing a 26% relative reduction in this endpoint with TAVR vs. surgery at 4 years.
The 5-year results of the PARTNER-3 trial and the 4-year results of the Evolut study were presented Transcatheter Cardiovascular Therapeutics annual meeting sponsored by the Cardiovascular Research Foundation. Both sets of results were simultaneously published online: PARTNER-3 in The New England Journal of Medicine and Evolut in JACC.
Marty Leon, MD, of NewYork-Presbyterian Columbia University Irving Medical Center, who presented the PARTNER-3 results, said in an interview that both trials are good news for TAVR:
“Both trials have clearly reaffirmed clinical and echocardiographic benefits of TAVR as a meaningful alternative therapy to surgery in low-risk severe symptomatic aortic stenosis patients.” Michael Reardon, MD, Houston Methodist Debakey Heart & Vascular Center, who presented the Evolut results, agreed that both trials were positive for TAVR “as TAVR just has to be as good as surgery to be a winner because clearly it is a lot less invasive.”
But Dr. Dr. Reardon added that, “In making that decision for younger lower-risk patients, then the Evolut valve is the only TAVR valve that has shown superior hemodynamics and durability at all time points with excellent outcomes and widening benefits compared with surgery over the first 4 years.”
PARTNER-3
The PARTNER-3 trial randomly assigned 1,000 patients with severe symptomatic aortic stenosis and low surgical risk to undergo either TAVR with the SAPIEN 3 transcatheter heart valve or surgery.
The results at 5 years show no difference in the two primary composite outcomes between TAVR and surgery patients.
The incidence of the composite end point of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure was similar in the TAVR group and the surgery group, occurring in 22.8% of patients in the TAVR group and 27.2% in the surgery group, which is a nonsignificant difference (P = .07).
The incidence of the individual components of the composite end point were also similar in the two groups. Death occurred in 10.0% in the TAVR group and 8.2% in the surgery group; stroke in 5.8% of the TAVR group and 6.4% of the surgery group; and rehospitalization in 13.7% and 17.4%, respectively.
Aortic-valve durability also looked similar in the two groups. The hemodynamic performance of the valve, assessed according to the mean valve gradient, was 12.8 mm Hg in the TAVR group and 11.7 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
Among the secondary end points, atrial fibrillation and bleeding appeared to be less frequent in the TAVR group than in the surgery group, whereas paravalvular aortic regurgitation, valve thrombosis, and pacemaker implantation appeared to be less frequent in the surgery group.
Functional and health-status outcomes assessed according to New York Heart Association class, quality of life scores, and the percentage of patients who were alive and well at 5 years appeared to be similar in the two groups.
“These data are reassuring,” Dr. Leon said. “Cardiovascular mortality occurred at a rate of about 1% per year with both therapies, strokes at the rate of 1% per year with both therapies, and hospitalization for cardiovascular reasons at about 3% per year with both therapies. For patients in their 70s, these are very good numbers.”
Along with showing similar outcomes for TAVR and surgery at 5 years, he added, “the need for re-intervention was particularly low (2%-3%) and equivalent for both approaches. And structural valve deterioration was also very low and equivalent in both groups.”
Evolut low-risk trial
The Evolut trial enrolled 1,414 patients with low surgical risk who were randomly assigned to TAVR, a self-expanding supra-annular CoreValve Evolut R PRO, or surgery.
By 4 years, the primary endpoint of all-cause mortality or disabling stroke had occurred in 10.7% of the TAVR group and 14.1% in the surgery group (hazard ratio, 0.74; P = .05), representing a 26% relative reduction with TAVR.
The absolute difference between treatment arms for the primary endpoint continued to increase over time: 1.8% at 1 year, 2.0% at 2 years, 2.9% at 3 years, and 3.4% at 4 years.
Rates of the primary endpoint components were all-cause mortality 9.0% with TAVR vs. 12.1% with surgery (P = .07); and disabling stroke was 2.9% with TAVR) vs. 3.8% for surgery (P = .32). Aortic valve rehospitalization was 10.3% with TAVR vs. 12.1% with surgery (P = .27).
The composite of all-cause mortality, disabling stroke, or aortic valve rehospitalization was significantly lower with TAVR, compared with surgery (18.0% vs. 22.4%; HR, 0.78; P = .04).
New permanent pacemaker implantation was significantly higher in the TAVR group (24.6% vs. 9.9%).
Indicators of valve performance including aortic valve reintervention (1.3% TAVR vs. 1.7% surgery); clinical or subclinical valve thrombosis (0.7% TAVR vs. 0.6% surgery); and valve endocarditis (0.9% TAVR vs. 2.2% surgery) were similarly low between groups, the authors report.
TAVR patients had sustained improvement in hemodynamics as measured by echocardiography, with significantly lower aortic valve mean gradients (9.8 mm Hg TAVR vs. 12.1 mm Hg surgery) and greater effective orifice area (2.1 cm2 TAVR vs. 2.0 cm2 surgery).
At 4 years, 84.7% of TAVR patients and 98.4% of surgery patients had no or trace paravalvular regurgitation, and there was no difference between groups in moderate or greater paravalvular regurgitation (0.4% TAVR vs. 0.0% surgery).
“The Evolut valve has shown a superior performance to surgery,” Dr. Reardon concluded. “It has less structural valve deterioration, less severe patient prosthetic mismatch, and superior hemodynamics, compared to surgery. All these factors are translating into a widening difference in clinical event curves year on year with the Evolut valve vs. surgery.”
Why the difference between trials?
The big question is why the early benefit seen with TAVR vs. surgery in both trials was attenuated by 5 years in PARTNER-3 but seemed to become greater each year in the Evolut trial. There were no definite explanations for these observations, but several possibilities were suggested.
Dr. Leon noted that with trials of intervention vs. surgery, it is common for the intervention group to do better in the beginning and for surgery to catch up a bit in later years. “So, it is not that much of a surprise to see outcomes plateauing in PARTNER-3.”
But he also suggested some other factors that may have played a role, one of which was the COVID pandemic.
“During the 2-year COVID period more than 75% of the deaths and strokes in the trial occurred in the TAVR patients,” he said. “Surgery patients were getting more anticoagulation because they had more paroxysmal [atrial fibrillation]. We know that COVID is a stimulus of thrombogenic events so in an odd way we think there may have been some cardioprotective effects from anticoagulation therapy in the surgery group.”
He also pointed out that though hospitalization and strokes were slightly lower with TAVR vs. surgery in the PARTNER-3 trial, mortality was slightly greater in the TAVR group.
“There was a 2:1 ratio in the TAVR and surgery groups in noncardiovascular deaths which influenced the all-cause mortality numbers,” he noted.
Mortality rates in the surgery groups
Dr. Leon also pointed out differences in the mortality rates in the surgery groups in the two trials, which he suggested may contribute to the explanation for the different longer-term results.
“The baseline characteristics for patients in these two trials were almost identical, and results at 1 year were very similar, but for whatever reason, over the course of a few years, the outcomes in the Evolut trial were different to those in PARTNER-3, and in particular the difference was in the surgical arms, with a higher event rate in the surgical arm in Evolut than in the surgery arm in PARTNER-3,” he said. “When the control does not perform well it is a lot easier to show that the experimental arm is better.”
“When you look at the TAVR arms in both studies at each time point they are either similar or PARTNER-3 is actually lower,” he added. “That is why it is so difficult to compare these two trials.”
But Dr. Reardon dismissed this argument.
“What determines long-term survival after a procedure is the intrinsic risk level of the patients,” he said. “Overall mortality rates differ between the two trials because the PARTNER-3 trial enrolled a lower end of a low-risk population while Evolut enrolled an upper end of a low-risk population. You cannot look at absolute numbers between trials. That is intellectually and scientifically invalid.”
“It is the relative difference between surgery and TAVR that we are interested in, and we see in Evolut that the relative difference between the two procedures in terms of benefit with TAVR is widening every year,” he added. “That is because the superior valve performance and hemodynamics of the Evolut valve compared to surgery has translated into excellent clinical outcomes.
“In the PARTNER-3 trial – their curves are coming together. I think that is worrisome, but I don’t want to draw conclusions about their trial,” Dr. Reardon said. “All I know is that in our trial, we have excellent outcomes that are getting better year after year.”
Competition between valves
The different results of the two trials is inevitably producing some competition between the two products.
Dr. Reardon said: “In terms of which valve to use, clinicians will want to choose a valve that has the best durability and shows the best survival vs. surgery and that is clearly the Evolut valve. I think the writing is on the wall. Some clinicians are going to wait for longer term data, but the question is do we have enough long-term data now.”
But Dr. Leon countered: “There’s never been a head-to-head device to suggest that the self- expanding device performs better than the balloon expanding device. We always think about them as being similar in terms of performance. There is an aggressive effort to suggest that by virtue of the current trial results there was a superior outcome with the Medtronic device, but it’s hard to explain why that would be the case, and we should not compare between the two trials.”
Both Dr. Leon and Dr. Reardon stressed that longer-term follow-up is critical because some surgical valves are known to fail between 5-10 years, and it is not known how the TAVR valves will perform over that period.
Both the PARTNER-3 and Evolut trials are planning to keep following patients out to 10 years.
For the time being though, both Dr. Leon and Dr. Reardon agreed that these current results will probably accelerate the already rapid transition from surgery to TAVR in low-risk patients.
“TAVR will be the default therapy,” Dr. Leon commented. “It will be the first choice for patients. Whether TAVR is superior to surgery in terms of outcomes or just the same, there are sufficient benefits from a logistic and patient perspective that most people would prefer to have the less invasive therapy. TAVR is a one-day procedure, there is no need for general anesthetic, a lot of the secondary outcomes that are so problematic with surgery don’t exist, and the ability to be in a symptom-free state is dramatically accelerated.”
“This was the first serious foray into the low-risk population with TAVR,” he added. “We had an age cut of 65 years, but the vast majority of patients in both trials were over 70. We could now start looking at younger patient populations.”
But Dr. Reardon said that these younger patients are already being given TAVR, and future trials randomizing between TAVR and surgery may not be possible.
“Even though US guidelines still recommend surgery for patients under 65 years, patients want TAVR, and they get TAVR,” he said. “Recent data shows that in 2021, use of TAVR rose to 47.5% in patients under 65 needing isolated aortic valve replacement. That doesn’t meet the guidelines but there’s clearly a big shift going on. These results will just keep that momentum going.”
The PARTNER-3 trial was funded by Edwards Lifesciences. The Evolut study was funded by Medtronic. Dr. Leon reports grant support from Edwards Lifesciences and Medtronic. Dr. Reardon receives research grants from Medtronic.
A version of this article first appeared on Medscape.com.
The PARTNER-3 and Evolut trials were heralded as a landmark advance in medicine when the 1-year results from the two studies were presented back in 2019. Both trials suggested benefits of the less-invasive TAVR approach over surgery.
But because these low-surgical-risk patients are younger and will likely have a longer lifespan than will higher risk patients for whom the TAVR technique was first established, patient outcomes and information on how the TAVR devices hold up over the long-term are critical to inform clinical decision-making.
Latest results from the two trials show that the initial benefits of TAVR over surgery seen in PARTNER-3 seem to have attenuated over the longer-term, with main outcomes looking very similar in both groups after 5 years.
However, in the Evolut trial, the early benefit in all-cause mortality or disabling stroke seen in the TAVR group is continuing to increase, with current results showing a 26% relative reduction in this endpoint with TAVR vs. surgery at 4 years.
The 5-year results of the PARTNER-3 trial and the 4-year results of the Evolut study were presented Transcatheter Cardiovascular Therapeutics annual meeting sponsored by the Cardiovascular Research Foundation. Both sets of results were simultaneously published online: PARTNER-3 in The New England Journal of Medicine and Evolut in JACC.
Marty Leon, MD, of NewYork-Presbyterian Columbia University Irving Medical Center, who presented the PARTNER-3 results, said in an interview that both trials are good news for TAVR:
“Both trials have clearly reaffirmed clinical and echocardiographic benefits of TAVR as a meaningful alternative therapy to surgery in low-risk severe symptomatic aortic stenosis patients.” Michael Reardon, MD, Houston Methodist Debakey Heart & Vascular Center, who presented the Evolut results, agreed that both trials were positive for TAVR “as TAVR just has to be as good as surgery to be a winner because clearly it is a lot less invasive.”
But Dr. Dr. Reardon added that, “In making that decision for younger lower-risk patients, then the Evolut valve is the only TAVR valve that has shown superior hemodynamics and durability at all time points with excellent outcomes and widening benefits compared with surgery over the first 4 years.”
PARTNER-3
The PARTNER-3 trial randomly assigned 1,000 patients with severe symptomatic aortic stenosis and low surgical risk to undergo either TAVR with the SAPIEN 3 transcatheter heart valve or surgery.
The results at 5 years show no difference in the two primary composite outcomes between TAVR and surgery patients.
The incidence of the composite end point of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure was similar in the TAVR group and the surgery group, occurring in 22.8% of patients in the TAVR group and 27.2% in the surgery group, which is a nonsignificant difference (P = .07).
The incidence of the individual components of the composite end point were also similar in the two groups. Death occurred in 10.0% in the TAVR group and 8.2% in the surgery group; stroke in 5.8% of the TAVR group and 6.4% of the surgery group; and rehospitalization in 13.7% and 17.4%, respectively.
Aortic-valve durability also looked similar in the two groups. The hemodynamic performance of the valve, assessed according to the mean valve gradient, was 12.8 mm Hg in the TAVR group and 11.7 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
Among the secondary end points, atrial fibrillation and bleeding appeared to be less frequent in the TAVR group than in the surgery group, whereas paravalvular aortic regurgitation, valve thrombosis, and pacemaker implantation appeared to be less frequent in the surgery group.
Functional and health-status outcomes assessed according to New York Heart Association class, quality of life scores, and the percentage of patients who were alive and well at 5 years appeared to be similar in the two groups.
“These data are reassuring,” Dr. Leon said. “Cardiovascular mortality occurred at a rate of about 1% per year with both therapies, strokes at the rate of 1% per year with both therapies, and hospitalization for cardiovascular reasons at about 3% per year with both therapies. For patients in their 70s, these are very good numbers.”
Along with showing similar outcomes for TAVR and surgery at 5 years, he added, “the need for re-intervention was particularly low (2%-3%) and equivalent for both approaches. And structural valve deterioration was also very low and equivalent in both groups.”
Evolut low-risk trial
The Evolut trial enrolled 1,414 patients with low surgical risk who were randomly assigned to TAVR, a self-expanding supra-annular CoreValve Evolut R PRO, or surgery.
By 4 years, the primary endpoint of all-cause mortality or disabling stroke had occurred in 10.7% of the TAVR group and 14.1% in the surgery group (hazard ratio, 0.74; P = .05), representing a 26% relative reduction with TAVR.
The absolute difference between treatment arms for the primary endpoint continued to increase over time: 1.8% at 1 year, 2.0% at 2 years, 2.9% at 3 years, and 3.4% at 4 years.
Rates of the primary endpoint components were all-cause mortality 9.0% with TAVR vs. 12.1% with surgery (P = .07); and disabling stroke was 2.9% with TAVR) vs. 3.8% for surgery (P = .32). Aortic valve rehospitalization was 10.3% with TAVR vs. 12.1% with surgery (P = .27).
The composite of all-cause mortality, disabling stroke, or aortic valve rehospitalization was significantly lower with TAVR, compared with surgery (18.0% vs. 22.4%; HR, 0.78; P = .04).
New permanent pacemaker implantation was significantly higher in the TAVR group (24.6% vs. 9.9%).
Indicators of valve performance including aortic valve reintervention (1.3% TAVR vs. 1.7% surgery); clinical or subclinical valve thrombosis (0.7% TAVR vs. 0.6% surgery); and valve endocarditis (0.9% TAVR vs. 2.2% surgery) were similarly low between groups, the authors report.
TAVR patients had sustained improvement in hemodynamics as measured by echocardiography, with significantly lower aortic valve mean gradients (9.8 mm Hg TAVR vs. 12.1 mm Hg surgery) and greater effective orifice area (2.1 cm2 TAVR vs. 2.0 cm2 surgery).
At 4 years, 84.7% of TAVR patients and 98.4% of surgery patients had no or trace paravalvular regurgitation, and there was no difference between groups in moderate or greater paravalvular regurgitation (0.4% TAVR vs. 0.0% surgery).
“The Evolut valve has shown a superior performance to surgery,” Dr. Reardon concluded. “It has less structural valve deterioration, less severe patient prosthetic mismatch, and superior hemodynamics, compared to surgery. All these factors are translating into a widening difference in clinical event curves year on year with the Evolut valve vs. surgery.”
Why the difference between trials?
The big question is why the early benefit seen with TAVR vs. surgery in both trials was attenuated by 5 years in PARTNER-3 but seemed to become greater each year in the Evolut trial. There were no definite explanations for these observations, but several possibilities were suggested.
Dr. Leon noted that with trials of intervention vs. surgery, it is common for the intervention group to do better in the beginning and for surgery to catch up a bit in later years. “So, it is not that much of a surprise to see outcomes plateauing in PARTNER-3.”
But he also suggested some other factors that may have played a role, one of which was the COVID pandemic.
“During the 2-year COVID period more than 75% of the deaths and strokes in the trial occurred in the TAVR patients,” he said. “Surgery patients were getting more anticoagulation because they had more paroxysmal [atrial fibrillation]. We know that COVID is a stimulus of thrombogenic events so in an odd way we think there may have been some cardioprotective effects from anticoagulation therapy in the surgery group.”
He also pointed out that though hospitalization and strokes were slightly lower with TAVR vs. surgery in the PARTNER-3 trial, mortality was slightly greater in the TAVR group.
“There was a 2:1 ratio in the TAVR and surgery groups in noncardiovascular deaths which influenced the all-cause mortality numbers,” he noted.
Mortality rates in the surgery groups
Dr. Leon also pointed out differences in the mortality rates in the surgery groups in the two trials, which he suggested may contribute to the explanation for the different longer-term results.
“The baseline characteristics for patients in these two trials were almost identical, and results at 1 year were very similar, but for whatever reason, over the course of a few years, the outcomes in the Evolut trial were different to those in PARTNER-3, and in particular the difference was in the surgical arms, with a higher event rate in the surgical arm in Evolut than in the surgery arm in PARTNER-3,” he said. “When the control does not perform well it is a lot easier to show that the experimental arm is better.”
“When you look at the TAVR arms in both studies at each time point they are either similar or PARTNER-3 is actually lower,” he added. “That is why it is so difficult to compare these two trials.”
But Dr. Reardon dismissed this argument.
“What determines long-term survival after a procedure is the intrinsic risk level of the patients,” he said. “Overall mortality rates differ between the two trials because the PARTNER-3 trial enrolled a lower end of a low-risk population while Evolut enrolled an upper end of a low-risk population. You cannot look at absolute numbers between trials. That is intellectually and scientifically invalid.”
“It is the relative difference between surgery and TAVR that we are interested in, and we see in Evolut that the relative difference between the two procedures in terms of benefit with TAVR is widening every year,” he added. “That is because the superior valve performance and hemodynamics of the Evolut valve compared to surgery has translated into excellent clinical outcomes.
“In the PARTNER-3 trial – their curves are coming together. I think that is worrisome, but I don’t want to draw conclusions about their trial,” Dr. Reardon said. “All I know is that in our trial, we have excellent outcomes that are getting better year after year.”
Competition between valves
The different results of the two trials is inevitably producing some competition between the two products.
Dr. Reardon said: “In terms of which valve to use, clinicians will want to choose a valve that has the best durability and shows the best survival vs. surgery and that is clearly the Evolut valve. I think the writing is on the wall. Some clinicians are going to wait for longer term data, but the question is do we have enough long-term data now.”
But Dr. Leon countered: “There’s never been a head-to-head device to suggest that the self- expanding device performs better than the balloon expanding device. We always think about them as being similar in terms of performance. There is an aggressive effort to suggest that by virtue of the current trial results there was a superior outcome with the Medtronic device, but it’s hard to explain why that would be the case, and we should not compare between the two trials.”
Both Dr. Leon and Dr. Reardon stressed that longer-term follow-up is critical because some surgical valves are known to fail between 5-10 years, and it is not known how the TAVR valves will perform over that period.
Both the PARTNER-3 and Evolut trials are planning to keep following patients out to 10 years.
For the time being though, both Dr. Leon and Dr. Reardon agreed that these current results will probably accelerate the already rapid transition from surgery to TAVR in low-risk patients.
“TAVR will be the default therapy,” Dr. Leon commented. “It will be the first choice for patients. Whether TAVR is superior to surgery in terms of outcomes or just the same, there are sufficient benefits from a logistic and patient perspective that most people would prefer to have the less invasive therapy. TAVR is a one-day procedure, there is no need for general anesthetic, a lot of the secondary outcomes that are so problematic with surgery don’t exist, and the ability to be in a symptom-free state is dramatically accelerated.”
“This was the first serious foray into the low-risk population with TAVR,” he added. “We had an age cut of 65 years, but the vast majority of patients in both trials were over 70. We could now start looking at younger patient populations.”
But Dr. Reardon said that these younger patients are already being given TAVR, and future trials randomizing between TAVR and surgery may not be possible.
“Even though US guidelines still recommend surgery for patients under 65 years, patients want TAVR, and they get TAVR,” he said. “Recent data shows that in 2021, use of TAVR rose to 47.5% in patients under 65 needing isolated aortic valve replacement. That doesn’t meet the guidelines but there’s clearly a big shift going on. These results will just keep that momentum going.”
The PARTNER-3 trial was funded by Edwards Lifesciences. The Evolut study was funded by Medtronic. Dr. Leon reports grant support from Edwards Lifesciences and Medtronic. Dr. Reardon receives research grants from Medtronic.
A version of this article first appeared on Medscape.com.
The PARTNER-3 and Evolut trials were heralded as a landmark advance in medicine when the 1-year results from the two studies were presented back in 2019. Both trials suggested benefits of the less-invasive TAVR approach over surgery.
But because these low-surgical-risk patients are younger and will likely have a longer lifespan than will higher risk patients for whom the TAVR technique was first established, patient outcomes and information on how the TAVR devices hold up over the long-term are critical to inform clinical decision-making.
Latest results from the two trials show that the initial benefits of TAVR over surgery seen in PARTNER-3 seem to have attenuated over the longer-term, with main outcomes looking very similar in both groups after 5 years.
However, in the Evolut trial, the early benefit in all-cause mortality or disabling stroke seen in the TAVR group is continuing to increase, with current results showing a 26% relative reduction in this endpoint with TAVR vs. surgery at 4 years.
The 5-year results of the PARTNER-3 trial and the 4-year results of the Evolut study were presented Transcatheter Cardiovascular Therapeutics annual meeting sponsored by the Cardiovascular Research Foundation. Both sets of results were simultaneously published online: PARTNER-3 in The New England Journal of Medicine and Evolut in JACC.
Marty Leon, MD, of NewYork-Presbyterian Columbia University Irving Medical Center, who presented the PARTNER-3 results, said in an interview that both trials are good news for TAVR:
“Both trials have clearly reaffirmed clinical and echocardiographic benefits of TAVR as a meaningful alternative therapy to surgery in low-risk severe symptomatic aortic stenosis patients.” Michael Reardon, MD, Houston Methodist Debakey Heart & Vascular Center, who presented the Evolut results, agreed that both trials were positive for TAVR “as TAVR just has to be as good as surgery to be a winner because clearly it is a lot less invasive.”
But Dr. Dr. Reardon added that, “In making that decision for younger lower-risk patients, then the Evolut valve is the only TAVR valve that has shown superior hemodynamics and durability at all time points with excellent outcomes and widening benefits compared with surgery over the first 4 years.”
PARTNER-3
The PARTNER-3 trial randomly assigned 1,000 patients with severe symptomatic aortic stenosis and low surgical risk to undergo either TAVR with the SAPIEN 3 transcatheter heart valve or surgery.
The results at 5 years show no difference in the two primary composite outcomes between TAVR and surgery patients.
The incidence of the composite end point of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure was similar in the TAVR group and the surgery group, occurring in 22.8% of patients in the TAVR group and 27.2% in the surgery group, which is a nonsignificant difference (P = .07).
The incidence of the individual components of the composite end point were also similar in the two groups. Death occurred in 10.0% in the TAVR group and 8.2% in the surgery group; stroke in 5.8% of the TAVR group and 6.4% of the surgery group; and rehospitalization in 13.7% and 17.4%, respectively.
Aortic-valve durability also looked similar in the two groups. The hemodynamic performance of the valve, assessed according to the mean valve gradient, was 12.8 mm Hg in the TAVR group and 11.7 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
Among the secondary end points, atrial fibrillation and bleeding appeared to be less frequent in the TAVR group than in the surgery group, whereas paravalvular aortic regurgitation, valve thrombosis, and pacemaker implantation appeared to be less frequent in the surgery group.
Functional and health-status outcomes assessed according to New York Heart Association class, quality of life scores, and the percentage of patients who were alive and well at 5 years appeared to be similar in the two groups.
“These data are reassuring,” Dr. Leon said. “Cardiovascular mortality occurred at a rate of about 1% per year with both therapies, strokes at the rate of 1% per year with both therapies, and hospitalization for cardiovascular reasons at about 3% per year with both therapies. For patients in their 70s, these are very good numbers.”
Along with showing similar outcomes for TAVR and surgery at 5 years, he added, “the need for re-intervention was particularly low (2%-3%) and equivalent for both approaches. And structural valve deterioration was also very low and equivalent in both groups.”
Evolut low-risk trial
The Evolut trial enrolled 1,414 patients with low surgical risk who were randomly assigned to TAVR, a self-expanding supra-annular CoreValve Evolut R PRO, or surgery.
By 4 years, the primary endpoint of all-cause mortality or disabling stroke had occurred in 10.7% of the TAVR group and 14.1% in the surgery group (hazard ratio, 0.74; P = .05), representing a 26% relative reduction with TAVR.
The absolute difference between treatment arms for the primary endpoint continued to increase over time: 1.8% at 1 year, 2.0% at 2 years, 2.9% at 3 years, and 3.4% at 4 years.
Rates of the primary endpoint components were all-cause mortality 9.0% with TAVR vs. 12.1% with surgery (P = .07); and disabling stroke was 2.9% with TAVR) vs. 3.8% for surgery (P = .32). Aortic valve rehospitalization was 10.3% with TAVR vs. 12.1% with surgery (P = .27).
The composite of all-cause mortality, disabling stroke, or aortic valve rehospitalization was significantly lower with TAVR, compared with surgery (18.0% vs. 22.4%; HR, 0.78; P = .04).
New permanent pacemaker implantation was significantly higher in the TAVR group (24.6% vs. 9.9%).
Indicators of valve performance including aortic valve reintervention (1.3% TAVR vs. 1.7% surgery); clinical or subclinical valve thrombosis (0.7% TAVR vs. 0.6% surgery); and valve endocarditis (0.9% TAVR vs. 2.2% surgery) were similarly low between groups, the authors report.
TAVR patients had sustained improvement in hemodynamics as measured by echocardiography, with significantly lower aortic valve mean gradients (9.8 mm Hg TAVR vs. 12.1 mm Hg surgery) and greater effective orifice area (2.1 cm2 TAVR vs. 2.0 cm2 surgery).
At 4 years, 84.7% of TAVR patients and 98.4% of surgery patients had no or trace paravalvular regurgitation, and there was no difference between groups in moderate or greater paravalvular regurgitation (0.4% TAVR vs. 0.0% surgery).
“The Evolut valve has shown a superior performance to surgery,” Dr. Reardon concluded. “It has less structural valve deterioration, less severe patient prosthetic mismatch, and superior hemodynamics, compared to surgery. All these factors are translating into a widening difference in clinical event curves year on year with the Evolut valve vs. surgery.”
Why the difference between trials?
The big question is why the early benefit seen with TAVR vs. surgery in both trials was attenuated by 5 years in PARTNER-3 but seemed to become greater each year in the Evolut trial. There were no definite explanations for these observations, but several possibilities were suggested.
Dr. Leon noted that with trials of intervention vs. surgery, it is common for the intervention group to do better in the beginning and for surgery to catch up a bit in later years. “So, it is not that much of a surprise to see outcomes plateauing in PARTNER-3.”
But he also suggested some other factors that may have played a role, one of which was the COVID pandemic.
“During the 2-year COVID period more than 75% of the deaths and strokes in the trial occurred in the TAVR patients,” he said. “Surgery patients were getting more anticoagulation because they had more paroxysmal [atrial fibrillation]. We know that COVID is a stimulus of thrombogenic events so in an odd way we think there may have been some cardioprotective effects from anticoagulation therapy in the surgery group.”
He also pointed out that though hospitalization and strokes were slightly lower with TAVR vs. surgery in the PARTNER-3 trial, mortality was slightly greater in the TAVR group.
“There was a 2:1 ratio in the TAVR and surgery groups in noncardiovascular deaths which influenced the all-cause mortality numbers,” he noted.
Mortality rates in the surgery groups
Dr. Leon also pointed out differences in the mortality rates in the surgery groups in the two trials, which he suggested may contribute to the explanation for the different longer-term results.
“The baseline characteristics for patients in these two trials were almost identical, and results at 1 year were very similar, but for whatever reason, over the course of a few years, the outcomes in the Evolut trial were different to those in PARTNER-3, and in particular the difference was in the surgical arms, with a higher event rate in the surgical arm in Evolut than in the surgery arm in PARTNER-3,” he said. “When the control does not perform well it is a lot easier to show that the experimental arm is better.”
“When you look at the TAVR arms in both studies at each time point they are either similar or PARTNER-3 is actually lower,” he added. “That is why it is so difficult to compare these two trials.”
But Dr. Reardon dismissed this argument.
“What determines long-term survival after a procedure is the intrinsic risk level of the patients,” he said. “Overall mortality rates differ between the two trials because the PARTNER-3 trial enrolled a lower end of a low-risk population while Evolut enrolled an upper end of a low-risk population. You cannot look at absolute numbers between trials. That is intellectually and scientifically invalid.”
“It is the relative difference between surgery and TAVR that we are interested in, and we see in Evolut that the relative difference between the two procedures in terms of benefit with TAVR is widening every year,” he added. “That is because the superior valve performance and hemodynamics of the Evolut valve compared to surgery has translated into excellent clinical outcomes.
“In the PARTNER-3 trial – their curves are coming together. I think that is worrisome, but I don’t want to draw conclusions about their trial,” Dr. Reardon said. “All I know is that in our trial, we have excellent outcomes that are getting better year after year.”
Competition between valves
The different results of the two trials is inevitably producing some competition between the two products.
Dr. Reardon said: “In terms of which valve to use, clinicians will want to choose a valve that has the best durability and shows the best survival vs. surgery and that is clearly the Evolut valve. I think the writing is on the wall. Some clinicians are going to wait for longer term data, but the question is do we have enough long-term data now.”
But Dr. Leon countered: “There’s never been a head-to-head device to suggest that the self- expanding device performs better than the balloon expanding device. We always think about them as being similar in terms of performance. There is an aggressive effort to suggest that by virtue of the current trial results there was a superior outcome with the Medtronic device, but it’s hard to explain why that would be the case, and we should not compare between the two trials.”
Both Dr. Leon and Dr. Reardon stressed that longer-term follow-up is critical because some surgical valves are known to fail between 5-10 years, and it is not known how the TAVR valves will perform over that period.
Both the PARTNER-3 and Evolut trials are planning to keep following patients out to 10 years.
For the time being though, both Dr. Leon and Dr. Reardon agreed that these current results will probably accelerate the already rapid transition from surgery to TAVR in low-risk patients.
“TAVR will be the default therapy,” Dr. Leon commented. “It will be the first choice for patients. Whether TAVR is superior to surgery in terms of outcomes or just the same, there are sufficient benefits from a logistic and patient perspective that most people would prefer to have the less invasive therapy. TAVR is a one-day procedure, there is no need for general anesthetic, a lot of the secondary outcomes that are so problematic with surgery don’t exist, and the ability to be in a symptom-free state is dramatically accelerated.”
“This was the first serious foray into the low-risk population with TAVR,” he added. “We had an age cut of 65 years, but the vast majority of patients in both trials were over 70. We could now start looking at younger patient populations.”
But Dr. Reardon said that these younger patients are already being given TAVR, and future trials randomizing between TAVR and surgery may not be possible.
“Even though US guidelines still recommend surgery for patients under 65 years, patients want TAVR, and they get TAVR,” he said. “Recent data shows that in 2021, use of TAVR rose to 47.5% in patients under 65 needing isolated aortic valve replacement. That doesn’t meet the guidelines but there’s clearly a big shift going on. These results will just keep that momentum going.”
The PARTNER-3 trial was funded by Edwards Lifesciences. The Evolut study was funded by Medtronic. Dr. Leon reports grant support from Edwards Lifesciences and Medtronic. Dr. Reardon receives research grants from Medtronic.
A version of this article first appeared on Medscape.com.
FROM TCT 2023
COVID coronary plaque infection confirms CV risk
The findings may not only explain the link between COVID and the increased risk of cardiovascular events but mark a starting point for new therapeutic approaches.
“Our study shows there is persistence of viral debris in the artery,” senior investigator Chiara Giannarelli, MD, associate professor of medicine and pathology at NYU Langone Health, New York, said in an interview. “There is an important inflammatory response. We can now look at ways to control this inflammation,” she said.
Dr. Giannarelli says COVID is more than a respiratory virus and that it can affect the whole body. “Our study shows a remarkable ability of the virus to hijack the immune system,” she points out. “Our findings may explain how that happens.”
Dr. Giannarelli says it’s important for doctors and patients to be aware of an increased cardiovascular risk after a SARS-CoV-2 infection and to pay extra attention to traditional risk factors, such as blood pressure and cholesterol.
“This study showing that severe acute respiratory syndrome coronavirus directly infects coronary artery plaques, producing inflammatory substances, really joins the dots and helps our understanding on why we’re seeing so much heart disease in COVID patients,” Peter Hotez, MD, professor of molecular virology and microbiology at Baylor College of Medicine, Houston, said in an interview.
Asked whether this direct infection of vascular plaques was unique to SARS-CoV-2 or whether this may also occur with other viruses, both Dr. Giannarelli and Dr. Hotez said they believe this may be a specific COVID effect.
“I wouldn’t say it is likely that other viruses infect coronary arteries in this way, but I suppose it is possible,” Dr. Giannarelli said.
Dr. Hotez pointed out that other viruses can cause inflammation in the heart, such as myocarditis. “But I can’t think of another virus that stimulates the sequence of events in coronary artery inflammation like we’re seeing here.”
Dr. Giannarelli noted that influenza is also associated with an increased risk of cardiovascular events, but there has been no evidence to date that it directly affects coronary arteries.
Dr. Hotez added that the increased risk of cardiovascular events with influenza has also been reported to be prolonged after the acute infection. “These new findings with SARS-CoV-2 could stimulate a redoubling of efforts to look at this possibility with influenza,” he suggested.
Heart disease after COVID
In a recent article published online in Nature Cardiovascular Research, Dr. Giannarelli and colleagues analyzed human autopsy tissue samples from coronary arterial walls of patients who had died from COVID in the early stages of the pandemic in New York.
They found an accumulation of viral RNA in atherosclerotic plaques in the coronary arteries, which was particularly concentrated in lipid-rich macrophage foam cells present within the plaques.
“Our data conclusively demonstrate that severe acute respiratory syndrome coronavirus is capable of infecting and replicating in macrophages within the coronary vasculature,” the researchers report.
The virus preferentially replicates in foam cells, in comparison with other macrophages, they add, suggesting that these cells might act as a reservoir of viral debris in atherosclerotic plaque.
“We have shown that the virus is targeting lipid-rich macrophages in atherosclerotic lesions. This is the first time this has been shown, and we think this is a very important finding,” Dr. Giannarelli said in an interview.
“We also found that the virus persists in these foam cells that could be responsible for long-term, low-grade inflammation in the vasculature that could contribute to the long-term cardiovascular manifestations in patients who have recovered from COVID,” she said.
Viral reservoirs
Macrophages residing in vascular tissue can undergo self-renewal and can remain in the tissue for many years, the investigators point out. They suggest that these macrophages may act as viral reservoirs of SARS-CoV-2 RNA in atherosclerotic plaques.
Using an ex vivo model, the researchers also found that atherosclerotic tissue could be directly infected by the virus. And just as was seen in cultured macrophages and foam cells, infection of vascular tissue triggered an inflammatory response. That response induced the secretion of key proatherogenic cytokines, such as interleukin-6 and interleukin-1 beta, which have been implicated in the pathogenesis of atherosclerosis and in an increased risk of cardiovascular events.
“Considering that plaque inflammation promotes disease progression and contributes to plaque rupture, our results provide a molecular basis for how infection of coronary lesions can contribute to the acute cardiovascular manifestations of COVID-19, such as myocardial infarction,” the researchers report.
Another interesting finding was a higher accumulation of viral RNA in the coronary vasculature of the three patients with acute ischemic cardiovascular manifestations, which they say adds to evidence that infection may increase cardiovascular risk.
Dr. Giannarelli points out that the patients in their study died in New York early in the pandemic, before vaccines were available. “They were unvaccinated and likely had little immunity against initial viral strains.”
Dr. Hotez says that when COVID-19 first emerged, many in the medical and scientific communities thought it would closely resemble the original SARS viral infection, which was primarily a respiratory pathogen.
“But it became pretty clear early on this virus was causing a lot of cardiovascular and thromboembolic disease,” he says. “This study provides an insight into the mechanisms involved here.”
Affecting more than lungs
Dr. Hotez pointed out that a recent study reported a 5% increase in cardiovascular deaths during the years 2020-2022, compared with before the pandemic.
“Those peaks of cardiovascular deaths corresponded with specific waves of COVID – the first happening at the time of the initial wave with the original virus and second during the Delta wave. So, there’s no question that this virus is contributing to excess cardiovascular mortality, and this paper appears to explain the mechanism.”
Dr. Hotez pointed out that the new findings suggest the cardiovascular risk may be prolonged well after the acute infection resolves.
“In long COVID, a lot of people focus on the neurological effects – brain fog and depression. But cardiac insufficiency and other cardiovascular events can also be considered another element of long COVID,” he said.
Dr. Giannarelli says her group is now studying whether patients with long COVID have virus in their coronary arteries. She points out that the current studies were a result of a team effort between experts in cardiovascular disease and virology and infectious disease. “We need to collaborate more like this to understand better the impact of viral infection in patients and the clinical manifestations,” she said.
Dr. Hotez says he believes these new findings will have implications for the future.
“COVID hasn’t gone away. The numbers have been going up again steadily in the U.S. in the last few months. There are still a significant number of hospitalizations,” he said.
While it would be unwieldy to ask for a cardiology consult for every COVID patient, he acknowledged, “there is probably a subset of people – possibly those of older age and who have had a severe case of COVID – who we suspect are now going to be more prone to cardiovascular disease because of having COVID.
“We should be vigilant in looking for cardiovascular disease in these patients,” Dr. Hotez said, “and perhaps be a bit more aggressive about controlling their cardiovascular risk factors.”
The study was funded by the U.S. National Institutes of Health, the American Heart Association, and the Chan Zuckerberg Initiative.
A version of this article first appeared on Medscape.com .
The findings may not only explain the link between COVID and the increased risk of cardiovascular events but mark a starting point for new therapeutic approaches.
“Our study shows there is persistence of viral debris in the artery,” senior investigator Chiara Giannarelli, MD, associate professor of medicine and pathology at NYU Langone Health, New York, said in an interview. “There is an important inflammatory response. We can now look at ways to control this inflammation,” she said.
Dr. Giannarelli says COVID is more than a respiratory virus and that it can affect the whole body. “Our study shows a remarkable ability of the virus to hijack the immune system,” she points out. “Our findings may explain how that happens.”
Dr. Giannarelli says it’s important for doctors and patients to be aware of an increased cardiovascular risk after a SARS-CoV-2 infection and to pay extra attention to traditional risk factors, such as blood pressure and cholesterol.
“This study showing that severe acute respiratory syndrome coronavirus directly infects coronary artery plaques, producing inflammatory substances, really joins the dots and helps our understanding on why we’re seeing so much heart disease in COVID patients,” Peter Hotez, MD, professor of molecular virology and microbiology at Baylor College of Medicine, Houston, said in an interview.
Asked whether this direct infection of vascular plaques was unique to SARS-CoV-2 or whether this may also occur with other viruses, both Dr. Giannarelli and Dr. Hotez said they believe this may be a specific COVID effect.
“I wouldn’t say it is likely that other viruses infect coronary arteries in this way, but I suppose it is possible,” Dr. Giannarelli said.
Dr. Hotez pointed out that other viruses can cause inflammation in the heart, such as myocarditis. “But I can’t think of another virus that stimulates the sequence of events in coronary artery inflammation like we’re seeing here.”
Dr. Giannarelli noted that influenza is also associated with an increased risk of cardiovascular events, but there has been no evidence to date that it directly affects coronary arteries.
Dr. Hotez added that the increased risk of cardiovascular events with influenza has also been reported to be prolonged after the acute infection. “These new findings with SARS-CoV-2 could stimulate a redoubling of efforts to look at this possibility with influenza,” he suggested.
Heart disease after COVID
In a recent article published online in Nature Cardiovascular Research, Dr. Giannarelli and colleagues analyzed human autopsy tissue samples from coronary arterial walls of patients who had died from COVID in the early stages of the pandemic in New York.
They found an accumulation of viral RNA in atherosclerotic plaques in the coronary arteries, which was particularly concentrated in lipid-rich macrophage foam cells present within the plaques.
“Our data conclusively demonstrate that severe acute respiratory syndrome coronavirus is capable of infecting and replicating in macrophages within the coronary vasculature,” the researchers report.
The virus preferentially replicates in foam cells, in comparison with other macrophages, they add, suggesting that these cells might act as a reservoir of viral debris in atherosclerotic plaque.
“We have shown that the virus is targeting lipid-rich macrophages in atherosclerotic lesions. This is the first time this has been shown, and we think this is a very important finding,” Dr. Giannarelli said in an interview.
“We also found that the virus persists in these foam cells that could be responsible for long-term, low-grade inflammation in the vasculature that could contribute to the long-term cardiovascular manifestations in patients who have recovered from COVID,” she said.
Viral reservoirs
Macrophages residing in vascular tissue can undergo self-renewal and can remain in the tissue for many years, the investigators point out. They suggest that these macrophages may act as viral reservoirs of SARS-CoV-2 RNA in atherosclerotic plaques.
Using an ex vivo model, the researchers also found that atherosclerotic tissue could be directly infected by the virus. And just as was seen in cultured macrophages and foam cells, infection of vascular tissue triggered an inflammatory response. That response induced the secretion of key proatherogenic cytokines, such as interleukin-6 and interleukin-1 beta, which have been implicated in the pathogenesis of atherosclerosis and in an increased risk of cardiovascular events.
“Considering that plaque inflammation promotes disease progression and contributes to plaque rupture, our results provide a molecular basis for how infection of coronary lesions can contribute to the acute cardiovascular manifestations of COVID-19, such as myocardial infarction,” the researchers report.
Another interesting finding was a higher accumulation of viral RNA in the coronary vasculature of the three patients with acute ischemic cardiovascular manifestations, which they say adds to evidence that infection may increase cardiovascular risk.
Dr. Giannarelli points out that the patients in their study died in New York early in the pandemic, before vaccines were available. “They were unvaccinated and likely had little immunity against initial viral strains.”
Dr. Hotez says that when COVID-19 first emerged, many in the medical and scientific communities thought it would closely resemble the original SARS viral infection, which was primarily a respiratory pathogen.
“But it became pretty clear early on this virus was causing a lot of cardiovascular and thromboembolic disease,” he says. “This study provides an insight into the mechanisms involved here.”
Affecting more than lungs
Dr. Hotez pointed out that a recent study reported a 5% increase in cardiovascular deaths during the years 2020-2022, compared with before the pandemic.
“Those peaks of cardiovascular deaths corresponded with specific waves of COVID – the first happening at the time of the initial wave with the original virus and second during the Delta wave. So, there’s no question that this virus is contributing to excess cardiovascular mortality, and this paper appears to explain the mechanism.”
Dr. Hotez pointed out that the new findings suggest the cardiovascular risk may be prolonged well after the acute infection resolves.
“In long COVID, a lot of people focus on the neurological effects – brain fog and depression. But cardiac insufficiency and other cardiovascular events can also be considered another element of long COVID,” he said.
Dr. Giannarelli says her group is now studying whether patients with long COVID have virus in their coronary arteries. She points out that the current studies were a result of a team effort between experts in cardiovascular disease and virology and infectious disease. “We need to collaborate more like this to understand better the impact of viral infection in patients and the clinical manifestations,” she said.
Dr. Hotez says he believes these new findings will have implications for the future.
“COVID hasn’t gone away. The numbers have been going up again steadily in the U.S. in the last few months. There are still a significant number of hospitalizations,” he said.
While it would be unwieldy to ask for a cardiology consult for every COVID patient, he acknowledged, “there is probably a subset of people – possibly those of older age and who have had a severe case of COVID – who we suspect are now going to be more prone to cardiovascular disease because of having COVID.
“We should be vigilant in looking for cardiovascular disease in these patients,” Dr. Hotez said, “and perhaps be a bit more aggressive about controlling their cardiovascular risk factors.”
The study was funded by the U.S. National Institutes of Health, the American Heart Association, and the Chan Zuckerberg Initiative.
A version of this article first appeared on Medscape.com .
The findings may not only explain the link between COVID and the increased risk of cardiovascular events but mark a starting point for new therapeutic approaches.
“Our study shows there is persistence of viral debris in the artery,” senior investigator Chiara Giannarelli, MD, associate professor of medicine and pathology at NYU Langone Health, New York, said in an interview. “There is an important inflammatory response. We can now look at ways to control this inflammation,” she said.
Dr. Giannarelli says COVID is more than a respiratory virus and that it can affect the whole body. “Our study shows a remarkable ability of the virus to hijack the immune system,” she points out. “Our findings may explain how that happens.”
Dr. Giannarelli says it’s important for doctors and patients to be aware of an increased cardiovascular risk after a SARS-CoV-2 infection and to pay extra attention to traditional risk factors, such as blood pressure and cholesterol.
“This study showing that severe acute respiratory syndrome coronavirus directly infects coronary artery plaques, producing inflammatory substances, really joins the dots and helps our understanding on why we’re seeing so much heart disease in COVID patients,” Peter Hotez, MD, professor of molecular virology and microbiology at Baylor College of Medicine, Houston, said in an interview.
Asked whether this direct infection of vascular plaques was unique to SARS-CoV-2 or whether this may also occur with other viruses, both Dr. Giannarelli and Dr. Hotez said they believe this may be a specific COVID effect.
“I wouldn’t say it is likely that other viruses infect coronary arteries in this way, but I suppose it is possible,” Dr. Giannarelli said.
Dr. Hotez pointed out that other viruses can cause inflammation in the heart, such as myocarditis. “But I can’t think of another virus that stimulates the sequence of events in coronary artery inflammation like we’re seeing here.”
Dr. Giannarelli noted that influenza is also associated with an increased risk of cardiovascular events, but there has been no evidence to date that it directly affects coronary arteries.
Dr. Hotez added that the increased risk of cardiovascular events with influenza has also been reported to be prolonged after the acute infection. “These new findings with SARS-CoV-2 could stimulate a redoubling of efforts to look at this possibility with influenza,” he suggested.
Heart disease after COVID
In a recent article published online in Nature Cardiovascular Research, Dr. Giannarelli and colleagues analyzed human autopsy tissue samples from coronary arterial walls of patients who had died from COVID in the early stages of the pandemic in New York.
They found an accumulation of viral RNA in atherosclerotic plaques in the coronary arteries, which was particularly concentrated in lipid-rich macrophage foam cells present within the plaques.
“Our data conclusively demonstrate that severe acute respiratory syndrome coronavirus is capable of infecting and replicating in macrophages within the coronary vasculature,” the researchers report.
The virus preferentially replicates in foam cells, in comparison with other macrophages, they add, suggesting that these cells might act as a reservoir of viral debris in atherosclerotic plaque.
“We have shown that the virus is targeting lipid-rich macrophages in atherosclerotic lesions. This is the first time this has been shown, and we think this is a very important finding,” Dr. Giannarelli said in an interview.
“We also found that the virus persists in these foam cells that could be responsible for long-term, low-grade inflammation in the vasculature that could contribute to the long-term cardiovascular manifestations in patients who have recovered from COVID,” she said.
Viral reservoirs
Macrophages residing in vascular tissue can undergo self-renewal and can remain in the tissue for many years, the investigators point out. They suggest that these macrophages may act as viral reservoirs of SARS-CoV-2 RNA in atherosclerotic plaques.
Using an ex vivo model, the researchers also found that atherosclerotic tissue could be directly infected by the virus. And just as was seen in cultured macrophages and foam cells, infection of vascular tissue triggered an inflammatory response. That response induced the secretion of key proatherogenic cytokines, such as interleukin-6 and interleukin-1 beta, which have been implicated in the pathogenesis of atherosclerosis and in an increased risk of cardiovascular events.
“Considering that plaque inflammation promotes disease progression and contributes to plaque rupture, our results provide a molecular basis for how infection of coronary lesions can contribute to the acute cardiovascular manifestations of COVID-19, such as myocardial infarction,” the researchers report.
Another interesting finding was a higher accumulation of viral RNA in the coronary vasculature of the three patients with acute ischemic cardiovascular manifestations, which they say adds to evidence that infection may increase cardiovascular risk.
Dr. Giannarelli points out that the patients in their study died in New York early in the pandemic, before vaccines were available. “They were unvaccinated and likely had little immunity against initial viral strains.”
Dr. Hotez says that when COVID-19 first emerged, many in the medical and scientific communities thought it would closely resemble the original SARS viral infection, which was primarily a respiratory pathogen.
“But it became pretty clear early on this virus was causing a lot of cardiovascular and thromboembolic disease,” he says. “This study provides an insight into the mechanisms involved here.”
Affecting more than lungs
Dr. Hotez pointed out that a recent study reported a 5% increase in cardiovascular deaths during the years 2020-2022, compared with before the pandemic.
“Those peaks of cardiovascular deaths corresponded with specific waves of COVID – the first happening at the time of the initial wave with the original virus and second during the Delta wave. So, there’s no question that this virus is contributing to excess cardiovascular mortality, and this paper appears to explain the mechanism.”
Dr. Hotez pointed out that the new findings suggest the cardiovascular risk may be prolonged well after the acute infection resolves.
“In long COVID, a lot of people focus on the neurological effects – brain fog and depression. But cardiac insufficiency and other cardiovascular events can also be considered another element of long COVID,” he said.
Dr. Giannarelli says her group is now studying whether patients with long COVID have virus in their coronary arteries. She points out that the current studies were a result of a team effort between experts in cardiovascular disease and virology and infectious disease. “We need to collaborate more like this to understand better the impact of viral infection in patients and the clinical manifestations,” she said.
Dr. Hotez says he believes these new findings will have implications for the future.
“COVID hasn’t gone away. The numbers have been going up again steadily in the U.S. in the last few months. There are still a significant number of hospitalizations,” he said.
While it would be unwieldy to ask for a cardiology consult for every COVID patient, he acknowledged, “there is probably a subset of people – possibly those of older age and who have had a severe case of COVID – who we suspect are now going to be more prone to cardiovascular disease because of having COVID.
“We should be vigilant in looking for cardiovascular disease in these patients,” Dr. Hotez said, “and perhaps be a bit more aggressive about controlling their cardiovascular risk factors.”
The study was funded by the U.S. National Institutes of Health, the American Heart Association, and the Chan Zuckerberg Initiative.
A version of this article first appeared on Medscape.com .
FROM NATURE CARDIOVASCULAR RESEARCH
‘Diagnosis creep’: Are some AFib patients overtreated?
without those treatments having been validated in those particular groups.
This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.
U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.
The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.
The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.
“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.
“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.
This study was published online as a research letter in JAMA Network Open.
Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.
“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”
Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.
“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”
He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.
Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.
“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”
Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.
“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
What should clinicians do?
In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.
He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.
And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.
“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.
“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”
Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
Are new risk scores needed?
Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.
“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.
“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.
Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.
“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”
He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”
Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
without those treatments having been validated in those particular groups.
This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.
U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.
The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.
The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.
“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.
“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.
This study was published online as a research letter in JAMA Network Open.
Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.
“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”
Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.
“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”
He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.
Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.
“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”
Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.
“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
What should clinicians do?
In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.
He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.
And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.
“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.
“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”
Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
Are new risk scores needed?
Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.
“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.
“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.
Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.
“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”
He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”
Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
without those treatments having been validated in those particular groups.
This concern has been highlighted recently in the atrial fibrillation (AF) field, with the recent change in the definition of hypertension in the United States at lower levels of blood pressure causing a lot more patients to become eligible for oral anticoagulation at an earlier stage in their AF course.
U.S. researchers analyzed data from 316,388 patients with AF from the National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient quality improvement registry, and found that at 36 months’ follow-up, 83.5% of patients met the new 130/80 mm Hg definition of hypertension, while only 53.3% met the previous 140/90 mm Hg definition.
The diagnosis of hypertension gives 1 point in the CHA2DS2-VASc score, which is used to determine risk in AF patients, those with scores of 2 or more being eligible for oral anticoagulation.
The researchers report that in patients with an index CHA2DS2-VASc score of 1 (before the hypertension diagnosis), at 36 months, 83% fulfilled the 130/80 mm Hg definition of hypertension while the 140/90 mm Hg definition was met by only 50%, giving a large increase in the number of patients who could qualify for oral anticoagulation therapy.
“While the definition of hypertension has changed in response to landmark clinical trials, CHA2DS2-VASc was validated using an older hypertension definition, with limited ambulatory blood pressure monitoring and higher blood pressure goals for treatment,” the authors state.
“Now, patients with AF will meet the CHA2DS2-VASc threshold for oral anticoagulation earlier in their disease course. However, it is not known if patients with scores of 1 or 2 using the new hypertension definition have sufficient stroke risk to offset the bleeding risk of oral anticoagulation and will receive net clinical benefit,” they point out.
This study was published online as a research letter in JAMA Network Open.
Senior author of the report, Mintu Turakhia, MD, Stanford (Calif.) University/iRhythm Technologies Inc., said AF is a good example of how “diagnosis creep” may lead to patients receiving inappropriate treatment.
“Risk scores derived when risk variables were described in one way are starting to be applied based on a diagnosis made in a totally different way,” he said in an interview. “Diagnosis creep is a problem everywhere in medicine. The goal of this study was to quantify what this means for the new definition of hypertension in the context of risk scoring AF patients for anticoagulation treatment. We are calling attention to this issue so clinicians are aware of possible implications.”
Dr. Turakhia explained that the CHA2DS2-VASc score was formulated based on claims data so there was a record of hypertension on the clinical encounter. That hypertension diagnosis would have been based on the old definition of 140/90 mm Hg.
“But now we apply a label of hypertension in the office every time someone has a measurement of elevated blood pressure – treated or untreated – and the blood pressure threshold for a hypertension diagnosis has changed to 130/80 mm Hg,” he said. “We are asking what this means for risk stratification scores such as CHA2DS2-VASc, and how do we quantify what that means for anticoagulation eligibility?”
He said that while identifying hypertension at lower blood pressures may be beneficial with regard to starting antihypertensive treatment earlier with a consequent reduction in cardiovascular outcomes, when this also affects risk scores that determine treatment for other conditions, as is the case for AF, the case is not so clear.
Dr. Turakhia pointed out that with AF, there are additional factors causing diagnosis creep, including earlier detection of AF and identification of shorter episodes due to the use of higher sensitivity tools to detect abnormal rhythms.
“What about the patient who has been identified as having AF based on just a few seconds found on monitoring and who is aged 65 (so just over the age threshold for 1 point on the CHA2DS2-VASc score)?” he asked. “Now we’re going to throw in hypertension with a blood pressure measurement just over 130/80 mm Hg, and they will be eligible for anticoagulation.”
Dr. Turakhia noted that in addition to earlier classification of hypertension, other conditions contributing to the CHA2DS2-VASc score are also being detected earlier, including diabetes and reduced ejection fractions that are considered heart failure.
“I worry about the sum of the parts. We don’t know if the risk score performs equally well when we’re using these different thresholds. We have to be careful that we are not exposing patients to the bleeding risks of anticoagulation unnecessarily. There is a clear issue here,” he said.
What should clinicians do?
In a comment, Gregory Lip, MD, chair of cardiovascular medicine at the University of Liverpool, England, who helped develop the CHA2DS2-VASc score, said clinicians needed to think more broadly when considering hypertension as a risk factor for the score.
He points out that if a patient had a history of hypertension but is now controlled to below 130/80 mm Hg, they would still be considered to be at risk per the CHA2DS2-VASc score.
And for patients without a history of hypertension, and who have a current blood pressure measurement of around 130/80 mm Hg, Dr. Lip advises that it would be premature to diagnose hypertension immediately.
“Hypertension is not a yes/no diagnosis. If you look at the relationship between blood pressure and risk of stroke, it is like a continual dose-response. It doesn’t mean that at 129/79 there is no stroke risk but that at 130/80 there is a stroke risk. It’s not like that,” he said.
“I wouldn’t make a diagnosis on a one-off blood pressure measurement. I would want to monitor that patient and get them to do home measurements,” he commented. “If someone constantly has levels around that 130/80 mm Hg, I don’t necessarily rush in with a definite diagnosis of hypertension and start drug treatment. I would look at lifestyle first. And in such patients, I wouldn’t give them the 1 point for hypertension on the CHA2DS2-VASc score.”
Dr. Lip points out that a hypertension diagnosis is not just about blood pressure numbers. “We have to assess the patients much more completely before giving them a diagnosis and consider factors such as whether there is evidence of hypertension-related end-organ damage, and if lifestyle issues have been addressed.”
Are new risk scores needed?
Dr. Turakhia agreed that clinicians need to look at the bigger picture, but he also suggested that new risk scores may need to be developed.
“All of us in the medical community need to think about whether we should be recalibrating risk prediction with more contemporary evidence – based on our ability to detect disease now,” he commented.
“This could even be a different risk score altogether, possibly incorporating a wider range of parameters or perhaps incorporating machine learning. That’s really the question we need to be asking ourselves,” Dr. Turakhia added.
Dr. Lip noted that there are many stroke risk factors and only those that are most common and have been well validated go into clinical risk scores such as CHA2DS2-VASc.
“These risks scores are by design simplifications, and only have modest predictive value for identifying patients at high risk of stroke. You can always improve on clinical risk scores by adding in other variables,” he said. “There are some risk scores in AF with 26 variables. But the practical application of these more complex scores can be difficult in clinical practice. These risks scores are meant to be simple so that they can be used by busy clinicians in the outpatient clinic or on a ward round. It is not easy to input 26 different variables.”
He also noted that many guidelines are now veering away from categorizing patients at high, medium, or low risk of stroke, which he refers to as “artificial” classifications. “There is now more of a default position that patients should receive stroke prevention normally with a DOAC [direct oral anticoagulant] unless they are low risk.”
Dr. Turakhia agreed that it is imperative to look at the bigger picture when identifying AF patients for anticoagulation. “We have to be careful not to take things at face value. It is more important than ever to use clinical judgment to avoid overtreatment in borderline situations,” he concluded.
This study was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Turakhia reported employment from iRhythm Technologies; equity from AliveCor, Connect America, Evidently, and Forward; grants from U.S. Food and Drug Administration, American Heart Association, Bayer, Sanofi, Gilead, and Bristol Myers Squibb; and personal fees from Pfizer and JAMA Cardiology (prior associate editor) outside the submitted work. Dr. Lip has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Pragmatic solutions to ‘catastrophic’ global stroke burden
Deaths and disability because of stroke are expected to rise alarmingly over the next 30 years, with almost 10 million stroke deaths forecast annually by 2050, according to a new report from the World Stroke Organization–Lancet Neurology Commission Stroke Collaboration Group.
“This highlights the need for urgent measures to reduce stroke burden worldwide, with an emphasis on low- and middle-income countries,” the report authors stated.
These measures include an increase in trained health care workers who can implement effective primary prevention strategies, including the early detection and adequate management of hypertension.
On the basis of a review of evidence-based guidelines, recent surveys, and in-depth interviews with stroke experts around the world, the WSO–Lancet Neurology Commission made evidence-based pragmatic recommendations to reduce the global burden of stroke, including measures to improve surveillance, prevention, acute care, and rehabilitation.
The report was announced on Oct. 10 by WSO President, Sheila Martins, MD, at the World Stroke Conference in Toronto. The report was also published online in The Lancet Neurology.
“Stroke care has changed a lot in the last few years,” said Dr. Martins, who is chief of neurology and neurosurgery at Hospital Moinhos de Vento, Porto Alegre, Brazil, and founder and president of the Brazilian Stroke Network. “We know what we need to do to reduce the global burden of stroke, and high-income countries are making progress in that regard. But the situation in low- and middle-income countries is catastrophic, with mortality rates of up to 80% in individuals who have had a stroke in some countries. There is a very large gap between knowledge and implementation.”
Dr. Martins said that the commission is offering potential innovative suggestions on how to change this reality.
“While we have the knowledge on the strategies needed to reduce stroke burden, the mechanisms needed to implement this knowledge will be different in different countries and cultures. Our commission includes several representatives from low- and middle-income countries, and we will be working with local stakeholders in these countries to try and implement our recommendations,” Dr. Martins explained.
Stroke mortality and disability is on the rise
In the report, the authors pointed out that the global burden of stroke is “huge.” In 2020, stroke was the second leading cause of death (6.6 million deaths) and the third leading cause of disability – responsible for 143 million disability-adjusted life-years – after neonatal disorders and ischemic heart disease. Stroke is also a leading cause of depression and dementia.
The absolute number of people affected by stroke, which includes those who die or remain disabled, has almost doubled in the past 30 years, the report authors noted. Most of the contemporary stroke burden is in low- and middle-income countries, and the burden of disability after a stroke is increasing at a faster pace in low- and middle-income countries than in high-income countries. Alarmingly, the incidence of stroke is increasing in young and middle-aged people globally.
The commission forecasts the burden of stroke from 2020 to 2050, with projections estimating that stroke mortality will increase by 50% to 9.7 million and disability-adjusted life-years growing to over 189.3 million by 2050.
“Stroke exerts an enormous toll on the world’s population, leading to the death and permanent disability of millions of people each year, and costing billions of dollars,” said Valery L. Feigin, MD, of Auckland (New Zealand) University of Technology, and commission cochair. “Precisely forecasting the health and economic impacts of stroke decades into the future is inherently challenging given the levels of uncertainty involved, but these estimates are indicative of the ever-increasing burden we will see in the years ahead unless urgent, effective action is taken.”
The report authors explained that multiple factors contribute to the high burden of stroke in low- and middle-income countries, including undetected and uncontrolled hypertension; lack of easily accessible, high-quality health services; insufficient attention to and investment in prevention, air pollution; population growth; unhealthy lifestyles (for example, poor diet, smoking, sedentary lifestyle, obesity); an earlier age of stroke onset and greater proportion of hemorrhagic strokes than in high-income countries; and the burden of infectious diseases resulting in competition for limited health care resources.
The enormous financial cost of stroke
The total cost of stroke (both direct treatment and rehabilitation costs and indirect costs due to loss of income) is estimated to rise from $891 billion per year in 2017 to as much as $2.31 trillion by 2050. “These substantial increases in the costs associated with stroke will cause distressing financial circumstances for many communities and national health systems,” the authors said.
However, this increase can be avoided because stroke is highly preventable and treatable, they stressed. “These unsustainable trends in burden and costs of stroke underline the importance of identifying interventions to prevent and manage stroke more effectively.”
The Commission pointed out that population-wide primary prevention across the lifespan is extremely cost effective. It has been estimated that for every $1 spent on the prevention of stroke and cardiovascular disease, there is a more than $10 return on investment.
Additionally, primary prevention efforts directed at stroke would probably yield large gains because of the secondary effects of reducing the risk for heart disease, type 2 diabetes, dementia, and some types of cancer that share common risk factors, the authors noted.
“One of the most common problems in implementing stroke prevention and care recommendations is the lack of funding. Our commission recommends introducing legislative regulations and taxations of unhealthy products (such as salt, alcohol, sugary drinks, trans fats) by each and every government in the world,” Dr. Feigin said.
“Such taxation would not only reduce consumption of these products – and therefore lead to the reduction of burden from stroke and major other noncommunicable diseases – but also generate a large revenue sufficient to fund not only prevention programs and services for stroke and other major disorders, but also reduce poverty, inequality in health service provision, and improve wellbeing of the population,” he added.
Recommendations
The commission authors made the following recommendations for key priorities to reduce the burden of stroke:
Surveillance and prevention
- Incorporate stroke events and risk factor surveillance into national stroke action plans.
- Establish a system for population-wide primary and secondary stroke prevention, with emphasis on lifestyle modification for people at any level of risk of stroke and cardiovascular disease.
- Primary and secondary stroke prevention services should be freely accessible and supported by universal health coverage, with access to affordable drugs for management of hypertension, dyslipidemia, diabetes, and clotting disorders.
- Governments must allocate a fixed proportion of their annual health care funding for prevention of stroke and related noncommunicable diseases. This funding could come from taxation of tobacco, salt, alcohol, and sugar.
- Raise public awareness and take action to encourage a healthy lifestyle and prevent stroke via population-wide deployment of digital technologies with simple, inexpensive screening for cardiovascular disease and modifiable risk factors.
- Establish protocol-based shifting of tasks from highly trained health care professionals to supervised paramedical health care workers, to facilitate population-wide primary stroke prevention interventions across rural and urban settings.
Acute care
- Prioritize effective planning of acute stroke care services; capacity building, training, and certification of a multidisciplinary workforce; provision of evidence-based equipment and affordable medicines; and adequate resource allocation at national and regional levels.
- Establish regional networks and protocol-driven services, including community-wide awareness campaigns for early recognition of a stroke, regionally coordinated prehospital services, telemedicine networks, and stroke centers that can triage and treat all cases of acute stroke, and facilitate timely access to reperfusion therapy.
- Integrate acute care networks into the four pillars of the stroke “quadrangle” of resources, including surveillance, prevention, and rehabilitation services, by involving all relevant stakeholders (that is, communities, policy makers, nongovernmental organizations, national and regional stroke organizations, and public and private health care providers) in the stroke care continuum.
Rehabilitation
- Establish multidisciplinary rehabilitation services and adapt evidence-based recommendations to the local context, including the training, support, and supervision of community health care workers and caregivers to assist in long-term care.
- Invest in research to generate innovative low-cost interventions, in public awareness to improve demand for rehabilitation services, and in advocacy to mobilize resources for multidisciplinary rehabilitation.
- Promote the training of stroke rehabilitation professionals. Use digital portals to improve training and to extend the use of assessment tools – such as the Modified Rankin Scale and the U.S. National Institutes of Health Stroke Scale – and quality of life measures to assess functional impairment and monitor recovery.
The commission concluded that, “overall, if the recommendations of this Commission are implemented, the burden of stroke will be reduced substantially ... which will improve brain health and overall wellbeing worldwide.”
Dr. Martins said that the WSO is committed to supporting and accelerating the implementation of these recommendations globally through the WSO Implementation Task Force, with stroke experts to advise the establishment of stroke prevention and care and to contribute with educational programs, and through Global Stroke Alliance meetings facilitating the discussions between stroke experts and policy makers, giving technical support to governments to elaborate national plans for stroke and to include stroke care in universal health coverage packages.
The Commission received funding from the WSO, Bill and Melinda Gates Foundation, Health Research Council of New Zealand, and National Health & Medical Research Council of Australia and was supported by the NIH.
A version of this article first appeared on Medscape.com.
Deaths and disability because of stroke are expected to rise alarmingly over the next 30 years, with almost 10 million stroke deaths forecast annually by 2050, according to a new report from the World Stroke Organization–Lancet Neurology Commission Stroke Collaboration Group.
“This highlights the need for urgent measures to reduce stroke burden worldwide, with an emphasis on low- and middle-income countries,” the report authors stated.
These measures include an increase in trained health care workers who can implement effective primary prevention strategies, including the early detection and adequate management of hypertension.
On the basis of a review of evidence-based guidelines, recent surveys, and in-depth interviews with stroke experts around the world, the WSO–Lancet Neurology Commission made evidence-based pragmatic recommendations to reduce the global burden of stroke, including measures to improve surveillance, prevention, acute care, and rehabilitation.
The report was announced on Oct. 10 by WSO President, Sheila Martins, MD, at the World Stroke Conference in Toronto. The report was also published online in The Lancet Neurology.
“Stroke care has changed a lot in the last few years,” said Dr. Martins, who is chief of neurology and neurosurgery at Hospital Moinhos de Vento, Porto Alegre, Brazil, and founder and president of the Brazilian Stroke Network. “We know what we need to do to reduce the global burden of stroke, and high-income countries are making progress in that regard. But the situation in low- and middle-income countries is catastrophic, with mortality rates of up to 80% in individuals who have had a stroke in some countries. There is a very large gap between knowledge and implementation.”
Dr. Martins said that the commission is offering potential innovative suggestions on how to change this reality.
“While we have the knowledge on the strategies needed to reduce stroke burden, the mechanisms needed to implement this knowledge will be different in different countries and cultures. Our commission includes several representatives from low- and middle-income countries, and we will be working with local stakeholders in these countries to try and implement our recommendations,” Dr. Martins explained.
Stroke mortality and disability is on the rise
In the report, the authors pointed out that the global burden of stroke is “huge.” In 2020, stroke was the second leading cause of death (6.6 million deaths) and the third leading cause of disability – responsible for 143 million disability-adjusted life-years – after neonatal disorders and ischemic heart disease. Stroke is also a leading cause of depression and dementia.
The absolute number of people affected by stroke, which includes those who die or remain disabled, has almost doubled in the past 30 years, the report authors noted. Most of the contemporary stroke burden is in low- and middle-income countries, and the burden of disability after a stroke is increasing at a faster pace in low- and middle-income countries than in high-income countries. Alarmingly, the incidence of stroke is increasing in young and middle-aged people globally.
The commission forecasts the burden of stroke from 2020 to 2050, with projections estimating that stroke mortality will increase by 50% to 9.7 million and disability-adjusted life-years growing to over 189.3 million by 2050.
“Stroke exerts an enormous toll on the world’s population, leading to the death and permanent disability of millions of people each year, and costing billions of dollars,” said Valery L. Feigin, MD, of Auckland (New Zealand) University of Technology, and commission cochair. “Precisely forecasting the health and economic impacts of stroke decades into the future is inherently challenging given the levels of uncertainty involved, but these estimates are indicative of the ever-increasing burden we will see in the years ahead unless urgent, effective action is taken.”
The report authors explained that multiple factors contribute to the high burden of stroke in low- and middle-income countries, including undetected and uncontrolled hypertension; lack of easily accessible, high-quality health services; insufficient attention to and investment in prevention, air pollution; population growth; unhealthy lifestyles (for example, poor diet, smoking, sedentary lifestyle, obesity); an earlier age of stroke onset and greater proportion of hemorrhagic strokes than in high-income countries; and the burden of infectious diseases resulting in competition for limited health care resources.
The enormous financial cost of stroke
The total cost of stroke (both direct treatment and rehabilitation costs and indirect costs due to loss of income) is estimated to rise from $891 billion per year in 2017 to as much as $2.31 trillion by 2050. “These substantial increases in the costs associated with stroke will cause distressing financial circumstances for many communities and national health systems,” the authors said.
However, this increase can be avoided because stroke is highly preventable and treatable, they stressed. “These unsustainable trends in burden and costs of stroke underline the importance of identifying interventions to prevent and manage stroke more effectively.”
The Commission pointed out that population-wide primary prevention across the lifespan is extremely cost effective. It has been estimated that for every $1 spent on the prevention of stroke and cardiovascular disease, there is a more than $10 return on investment.
Additionally, primary prevention efforts directed at stroke would probably yield large gains because of the secondary effects of reducing the risk for heart disease, type 2 diabetes, dementia, and some types of cancer that share common risk factors, the authors noted.
“One of the most common problems in implementing stroke prevention and care recommendations is the lack of funding. Our commission recommends introducing legislative regulations and taxations of unhealthy products (such as salt, alcohol, sugary drinks, trans fats) by each and every government in the world,” Dr. Feigin said.
“Such taxation would not only reduce consumption of these products – and therefore lead to the reduction of burden from stroke and major other noncommunicable diseases – but also generate a large revenue sufficient to fund not only prevention programs and services for stroke and other major disorders, but also reduce poverty, inequality in health service provision, and improve wellbeing of the population,” he added.
Recommendations
The commission authors made the following recommendations for key priorities to reduce the burden of stroke:
Surveillance and prevention
- Incorporate stroke events and risk factor surveillance into national stroke action plans.
- Establish a system for population-wide primary and secondary stroke prevention, with emphasis on lifestyle modification for people at any level of risk of stroke and cardiovascular disease.
- Primary and secondary stroke prevention services should be freely accessible and supported by universal health coverage, with access to affordable drugs for management of hypertension, dyslipidemia, diabetes, and clotting disorders.
- Governments must allocate a fixed proportion of their annual health care funding for prevention of stroke and related noncommunicable diseases. This funding could come from taxation of tobacco, salt, alcohol, and sugar.
- Raise public awareness and take action to encourage a healthy lifestyle and prevent stroke via population-wide deployment of digital technologies with simple, inexpensive screening for cardiovascular disease and modifiable risk factors.
- Establish protocol-based shifting of tasks from highly trained health care professionals to supervised paramedical health care workers, to facilitate population-wide primary stroke prevention interventions across rural and urban settings.
Acute care
- Prioritize effective planning of acute stroke care services; capacity building, training, and certification of a multidisciplinary workforce; provision of evidence-based equipment and affordable medicines; and adequate resource allocation at national and regional levels.
- Establish regional networks and protocol-driven services, including community-wide awareness campaigns for early recognition of a stroke, regionally coordinated prehospital services, telemedicine networks, and stroke centers that can triage and treat all cases of acute stroke, and facilitate timely access to reperfusion therapy.
- Integrate acute care networks into the four pillars of the stroke “quadrangle” of resources, including surveillance, prevention, and rehabilitation services, by involving all relevant stakeholders (that is, communities, policy makers, nongovernmental organizations, national and regional stroke organizations, and public and private health care providers) in the stroke care continuum.
Rehabilitation
- Establish multidisciplinary rehabilitation services and adapt evidence-based recommendations to the local context, including the training, support, and supervision of community health care workers and caregivers to assist in long-term care.
- Invest in research to generate innovative low-cost interventions, in public awareness to improve demand for rehabilitation services, and in advocacy to mobilize resources for multidisciplinary rehabilitation.
- Promote the training of stroke rehabilitation professionals. Use digital portals to improve training and to extend the use of assessment tools – such as the Modified Rankin Scale and the U.S. National Institutes of Health Stroke Scale – and quality of life measures to assess functional impairment and monitor recovery.
The commission concluded that, “overall, if the recommendations of this Commission are implemented, the burden of stroke will be reduced substantially ... which will improve brain health and overall wellbeing worldwide.”
Dr. Martins said that the WSO is committed to supporting and accelerating the implementation of these recommendations globally through the WSO Implementation Task Force, with stroke experts to advise the establishment of stroke prevention and care and to contribute with educational programs, and through Global Stroke Alliance meetings facilitating the discussions between stroke experts and policy makers, giving technical support to governments to elaborate national plans for stroke and to include stroke care in universal health coverage packages.
The Commission received funding from the WSO, Bill and Melinda Gates Foundation, Health Research Council of New Zealand, and National Health & Medical Research Council of Australia and was supported by the NIH.
A version of this article first appeared on Medscape.com.
Deaths and disability because of stroke are expected to rise alarmingly over the next 30 years, with almost 10 million stroke deaths forecast annually by 2050, according to a new report from the World Stroke Organization–Lancet Neurology Commission Stroke Collaboration Group.
“This highlights the need for urgent measures to reduce stroke burden worldwide, with an emphasis on low- and middle-income countries,” the report authors stated.
These measures include an increase in trained health care workers who can implement effective primary prevention strategies, including the early detection and adequate management of hypertension.
On the basis of a review of evidence-based guidelines, recent surveys, and in-depth interviews with stroke experts around the world, the WSO–Lancet Neurology Commission made evidence-based pragmatic recommendations to reduce the global burden of stroke, including measures to improve surveillance, prevention, acute care, and rehabilitation.
The report was announced on Oct. 10 by WSO President, Sheila Martins, MD, at the World Stroke Conference in Toronto. The report was also published online in The Lancet Neurology.
“Stroke care has changed a lot in the last few years,” said Dr. Martins, who is chief of neurology and neurosurgery at Hospital Moinhos de Vento, Porto Alegre, Brazil, and founder and president of the Brazilian Stroke Network. “We know what we need to do to reduce the global burden of stroke, and high-income countries are making progress in that regard. But the situation in low- and middle-income countries is catastrophic, with mortality rates of up to 80% in individuals who have had a stroke in some countries. There is a very large gap between knowledge and implementation.”
Dr. Martins said that the commission is offering potential innovative suggestions on how to change this reality.
“While we have the knowledge on the strategies needed to reduce stroke burden, the mechanisms needed to implement this knowledge will be different in different countries and cultures. Our commission includes several representatives from low- and middle-income countries, and we will be working with local stakeholders in these countries to try and implement our recommendations,” Dr. Martins explained.
Stroke mortality and disability is on the rise
In the report, the authors pointed out that the global burden of stroke is “huge.” In 2020, stroke was the second leading cause of death (6.6 million deaths) and the third leading cause of disability – responsible for 143 million disability-adjusted life-years – after neonatal disorders and ischemic heart disease. Stroke is also a leading cause of depression and dementia.
The absolute number of people affected by stroke, which includes those who die or remain disabled, has almost doubled in the past 30 years, the report authors noted. Most of the contemporary stroke burden is in low- and middle-income countries, and the burden of disability after a stroke is increasing at a faster pace in low- and middle-income countries than in high-income countries. Alarmingly, the incidence of stroke is increasing in young and middle-aged people globally.
The commission forecasts the burden of stroke from 2020 to 2050, with projections estimating that stroke mortality will increase by 50% to 9.7 million and disability-adjusted life-years growing to over 189.3 million by 2050.
“Stroke exerts an enormous toll on the world’s population, leading to the death and permanent disability of millions of people each year, and costing billions of dollars,” said Valery L. Feigin, MD, of Auckland (New Zealand) University of Technology, and commission cochair. “Precisely forecasting the health and economic impacts of stroke decades into the future is inherently challenging given the levels of uncertainty involved, but these estimates are indicative of the ever-increasing burden we will see in the years ahead unless urgent, effective action is taken.”
The report authors explained that multiple factors contribute to the high burden of stroke in low- and middle-income countries, including undetected and uncontrolled hypertension; lack of easily accessible, high-quality health services; insufficient attention to and investment in prevention, air pollution; population growth; unhealthy lifestyles (for example, poor diet, smoking, sedentary lifestyle, obesity); an earlier age of stroke onset and greater proportion of hemorrhagic strokes than in high-income countries; and the burden of infectious diseases resulting in competition for limited health care resources.
The enormous financial cost of stroke
The total cost of stroke (both direct treatment and rehabilitation costs and indirect costs due to loss of income) is estimated to rise from $891 billion per year in 2017 to as much as $2.31 trillion by 2050. “These substantial increases in the costs associated with stroke will cause distressing financial circumstances for many communities and national health systems,” the authors said.
However, this increase can be avoided because stroke is highly preventable and treatable, they stressed. “These unsustainable trends in burden and costs of stroke underline the importance of identifying interventions to prevent and manage stroke more effectively.”
The Commission pointed out that population-wide primary prevention across the lifespan is extremely cost effective. It has been estimated that for every $1 spent on the prevention of stroke and cardiovascular disease, there is a more than $10 return on investment.
Additionally, primary prevention efforts directed at stroke would probably yield large gains because of the secondary effects of reducing the risk for heart disease, type 2 diabetes, dementia, and some types of cancer that share common risk factors, the authors noted.
“One of the most common problems in implementing stroke prevention and care recommendations is the lack of funding. Our commission recommends introducing legislative regulations and taxations of unhealthy products (such as salt, alcohol, sugary drinks, trans fats) by each and every government in the world,” Dr. Feigin said.
“Such taxation would not only reduce consumption of these products – and therefore lead to the reduction of burden from stroke and major other noncommunicable diseases – but also generate a large revenue sufficient to fund not only prevention programs and services for stroke and other major disorders, but also reduce poverty, inequality in health service provision, and improve wellbeing of the population,” he added.
Recommendations
The commission authors made the following recommendations for key priorities to reduce the burden of stroke:
Surveillance and prevention
- Incorporate stroke events and risk factor surveillance into national stroke action plans.
- Establish a system for population-wide primary and secondary stroke prevention, with emphasis on lifestyle modification for people at any level of risk of stroke and cardiovascular disease.
- Primary and secondary stroke prevention services should be freely accessible and supported by universal health coverage, with access to affordable drugs for management of hypertension, dyslipidemia, diabetes, and clotting disorders.
- Governments must allocate a fixed proportion of their annual health care funding for prevention of stroke and related noncommunicable diseases. This funding could come from taxation of tobacco, salt, alcohol, and sugar.
- Raise public awareness and take action to encourage a healthy lifestyle and prevent stroke via population-wide deployment of digital technologies with simple, inexpensive screening for cardiovascular disease and modifiable risk factors.
- Establish protocol-based shifting of tasks from highly trained health care professionals to supervised paramedical health care workers, to facilitate population-wide primary stroke prevention interventions across rural and urban settings.
Acute care
- Prioritize effective planning of acute stroke care services; capacity building, training, and certification of a multidisciplinary workforce; provision of evidence-based equipment and affordable medicines; and adequate resource allocation at national and regional levels.
- Establish regional networks and protocol-driven services, including community-wide awareness campaigns for early recognition of a stroke, regionally coordinated prehospital services, telemedicine networks, and stroke centers that can triage and treat all cases of acute stroke, and facilitate timely access to reperfusion therapy.
- Integrate acute care networks into the four pillars of the stroke “quadrangle” of resources, including surveillance, prevention, and rehabilitation services, by involving all relevant stakeholders (that is, communities, policy makers, nongovernmental organizations, national and regional stroke organizations, and public and private health care providers) in the stroke care continuum.
Rehabilitation
- Establish multidisciplinary rehabilitation services and adapt evidence-based recommendations to the local context, including the training, support, and supervision of community health care workers and caregivers to assist in long-term care.
- Invest in research to generate innovative low-cost interventions, in public awareness to improve demand for rehabilitation services, and in advocacy to mobilize resources for multidisciplinary rehabilitation.
- Promote the training of stroke rehabilitation professionals. Use digital portals to improve training and to extend the use of assessment tools – such as the Modified Rankin Scale and the U.S. National Institutes of Health Stroke Scale – and quality of life measures to assess functional impairment and monitor recovery.
The commission concluded that, “overall, if the recommendations of this Commission are implemented, the burden of stroke will be reduced substantially ... which will improve brain health and overall wellbeing worldwide.”
Dr. Martins said that the WSO is committed to supporting and accelerating the implementation of these recommendations globally through the WSO Implementation Task Force, with stroke experts to advise the establishment of stroke prevention and care and to contribute with educational programs, and through Global Stroke Alliance meetings facilitating the discussions between stroke experts and policy makers, giving technical support to governments to elaborate national plans for stroke and to include stroke care in universal health coverage packages.
The Commission received funding from the WSO, Bill and Melinda Gates Foundation, Health Research Council of New Zealand, and National Health & Medical Research Council of Australia and was supported by the NIH.
A version of this article first appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Factor XI inhibitors: The promise of a truly safe anticoagulant?
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
Trial halted for bleeding reduction with abelacimab vs. rivaroxaban in AFib
– major and clinically relevant nonmajor bleeding – in patients taking abelacimab versus those on rivaroxaban.
The announcement of topline results of the AZALEA-TIMI 71 trial was made by Anthos Therapeutics, the company developing abelacimab.
“The AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to the standard-of-care anticoagulant,” Marc Sabatine, MD, chair of cardiovascular medicine at Brigham and Women’s Hospital and chair of the TIMI study group, both in Boston, stated in the Anthos press release.
“With a median of 21 months of follow-up, spanning more than 2,000 patient years, AZALEA-TIMI 71 represents a landmark study confirming the promise of Factor XI inhibition as causing substantially less bleeding than a current standard-of-care,” Dr. Sabatine added.
Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against factor XI and its active form, factor XIa. At the 150-mg dose given subcutaneously once monthly, the drug maintains around 98% inhibition of factor XI, in line with the benign bleeding profile of patients with genetic factor XI deficiency, the company notes.
The AZALEA-TIMI 71 study is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in 1,287 patients with AFib who are at moderate to high risk for stroke. Full results of the study will be presented at an upcoming scientific congress.
Patients in the rivaroxaban arm can transition to abelacimab in an extension study.
In a previous proof-of-concept study published in The New England Journal of Medicine, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism versus enoxaparin in patients undergoing knee surgery.
A phase 3 trial in AFib patients is now planned. The LILAC-TIMI 76 study is an event-driven, randomized trial to evaluate the efficacy and safety of abelacimab relative to placebo on the rate of ischemic stroke or systemic embolism in AFib patients who have been deemed to be unsuitable for currently available anticoagulation therapy. Patients will be randomized to receive abelacimab 150 mg subcutaneously or matching placebo once monthly. The researchers aim to enroll approximately 1,900 patients from North America, Europe, Latin America, the Middle East, and Asia.
Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said that, “Abelacimab embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions.”
It is estimated that 12.1 million people in the United States will have AFib by 2030, but 40%-60% of patients with AFib are not prescribed anticoagulants today, one of the main reasons being concerns about bleeding, the company notes.
“Abelacimab has the potential to provide a game-changing treatment option for all those patients who live with the daily fear of bleeding while taking current anticoagulants,” said Leslie Lake, president of the National Blood Clot Alliance.
Abelacimab has been granted a fast-track designation by the U.S. Food and Drug Administration for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Several other Factor XI inhibitors are in development and have also shown promising results in terms of a more benign bleeding profile than current standard-of-care anticoagulants.
A version of this article first appeared on Medscape.com.
– major and clinically relevant nonmajor bleeding – in patients taking abelacimab versus those on rivaroxaban.
The announcement of topline results of the AZALEA-TIMI 71 trial was made by Anthos Therapeutics, the company developing abelacimab.
“The AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to the standard-of-care anticoagulant,” Marc Sabatine, MD, chair of cardiovascular medicine at Brigham and Women’s Hospital and chair of the TIMI study group, both in Boston, stated in the Anthos press release.
“With a median of 21 months of follow-up, spanning more than 2,000 patient years, AZALEA-TIMI 71 represents a landmark study confirming the promise of Factor XI inhibition as causing substantially less bleeding than a current standard-of-care,” Dr. Sabatine added.
Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against factor XI and its active form, factor XIa. At the 150-mg dose given subcutaneously once monthly, the drug maintains around 98% inhibition of factor XI, in line with the benign bleeding profile of patients with genetic factor XI deficiency, the company notes.
The AZALEA-TIMI 71 study is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in 1,287 patients with AFib who are at moderate to high risk for stroke. Full results of the study will be presented at an upcoming scientific congress.
Patients in the rivaroxaban arm can transition to abelacimab in an extension study.
In a previous proof-of-concept study published in The New England Journal of Medicine, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism versus enoxaparin in patients undergoing knee surgery.
A phase 3 trial in AFib patients is now planned. The LILAC-TIMI 76 study is an event-driven, randomized trial to evaluate the efficacy and safety of abelacimab relative to placebo on the rate of ischemic stroke or systemic embolism in AFib patients who have been deemed to be unsuitable for currently available anticoagulation therapy. Patients will be randomized to receive abelacimab 150 mg subcutaneously or matching placebo once monthly. The researchers aim to enroll approximately 1,900 patients from North America, Europe, Latin America, the Middle East, and Asia.
Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said that, “Abelacimab embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions.”
It is estimated that 12.1 million people in the United States will have AFib by 2030, but 40%-60% of patients with AFib are not prescribed anticoagulants today, one of the main reasons being concerns about bleeding, the company notes.
“Abelacimab has the potential to provide a game-changing treatment option for all those patients who live with the daily fear of bleeding while taking current anticoagulants,” said Leslie Lake, president of the National Blood Clot Alliance.
Abelacimab has been granted a fast-track designation by the U.S. Food and Drug Administration for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Several other Factor XI inhibitors are in development and have also shown promising results in terms of a more benign bleeding profile than current standard-of-care anticoagulants.
A version of this article first appeared on Medscape.com.
– major and clinically relevant nonmajor bleeding – in patients taking abelacimab versus those on rivaroxaban.
The announcement of topline results of the AZALEA-TIMI 71 trial was made by Anthos Therapeutics, the company developing abelacimab.
“The AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to the standard-of-care anticoagulant,” Marc Sabatine, MD, chair of cardiovascular medicine at Brigham and Women’s Hospital and chair of the TIMI study group, both in Boston, stated in the Anthos press release.
“With a median of 21 months of follow-up, spanning more than 2,000 patient years, AZALEA-TIMI 71 represents a landmark study confirming the promise of Factor XI inhibition as causing substantially less bleeding than a current standard-of-care,” Dr. Sabatine added.
Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against factor XI and its active form, factor XIa. At the 150-mg dose given subcutaneously once monthly, the drug maintains around 98% inhibition of factor XI, in line with the benign bleeding profile of patients with genetic factor XI deficiency, the company notes.
The AZALEA-TIMI 71 study is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in 1,287 patients with AFib who are at moderate to high risk for stroke. Full results of the study will be presented at an upcoming scientific congress.
Patients in the rivaroxaban arm can transition to abelacimab in an extension study.
In a previous proof-of-concept study published in The New England Journal of Medicine, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism versus enoxaparin in patients undergoing knee surgery.
A phase 3 trial in AFib patients is now planned. The LILAC-TIMI 76 study is an event-driven, randomized trial to evaluate the efficacy and safety of abelacimab relative to placebo on the rate of ischemic stroke or systemic embolism in AFib patients who have been deemed to be unsuitable for currently available anticoagulation therapy. Patients will be randomized to receive abelacimab 150 mg subcutaneously or matching placebo once monthly. The researchers aim to enroll approximately 1,900 patients from North America, Europe, Latin America, the Middle East, and Asia.
Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said that, “Abelacimab embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions.”
It is estimated that 12.1 million people in the United States will have AFib by 2030, but 40%-60% of patients with AFib are not prescribed anticoagulants today, one of the main reasons being concerns about bleeding, the company notes.
“Abelacimab has the potential to provide a game-changing treatment option for all those patients who live with the daily fear of bleeding while taking current anticoagulants,” said Leslie Lake, president of the National Blood Clot Alliance.
Abelacimab has been granted a fast-track designation by the U.S. Food and Drug Administration for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Several other Factor XI inhibitors are in development and have also shown promising results in terms of a more benign bleeding profile than current standard-of-care anticoagulants.
A version of this article first appeared on Medscape.com.
SGLT2 inhibitors: No benefit or harm in hospitalized COVID-19
A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.
However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.
“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.
He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.
“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, ,” he added.
The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.
Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.
“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.
“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.
Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.
“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.
The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.
“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.
“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.
In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.
SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.
To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.
Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.
By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.
Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.
The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.
The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.
The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.
A version of this article first appeared on Medscape.com.
A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.
However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.
“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.
He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.
“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, ,” he added.
The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.
Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.
“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.
“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.
Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.
“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.
The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.
“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.
“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.
In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.
SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.
To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.
Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.
By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.
Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.
The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.
The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.
The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.
A version of this article first appeared on Medscape.com.
A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.
However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.
“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.
He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.
“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, ,” he added.
The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.
Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.
“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.
“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.
Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.
“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.
The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.
“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.
“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.
In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.
SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.
To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.
Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.
By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.
Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.
The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.
The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.
The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2023
New ESC ACS guideline combines STEMI and NSTE-ACS
AMSTERDAM –
The new guideline was released at the annual congress of the European Society of Cardiology, and was published online in the European Heart Journal.
“We found that it was realized by the cardiology community that patients with STEMI, NSTEMI, or unstable angina represent a spectrum,” the chair of the guideline task force, Robert Byrne, MD, chair of cardiovascular research at the RCSI University of Medicine and Health Sciences, Dublin, explained to this news organization. “After the initial triage and management decisions, then most of the rest of the care follows a common pathway so it would make sense to consider everything in one guideline.”
Dr. Byrne noted that for all patients with a suspected ACS, the guideline recommendation is to administer an ECG within 10 minutes of presentation. The time is critical particularly for those with an occluded epicardial vessel. If there are features on the ECG that suggest an acutely occluded epicardial vessel, then the patient needs immediate angiography or primary angioplasty.
“The 10-minute guidance has been maintained from previous guidelines, but the nuance in the new guideline is that typically when we think of an occluded epicardial vessel we think of ST-elevation on the ECG,” Byrne said. “While this captures most occluded epicardial vessels, it doesn’t capture all of them. So, we have provided some guidance on alternative ECG patterns which might be indicative of an acute occlusion of the epicardial vessel and should be dealt with in the same way as an ST-elevation MI. This is a new concept.”
This situation could arise when a patient has an occluded circumflex artery and the regular ECG may not show ST elevation but the patient has ongoing pain, he noted. “There are additional ECG leads that can be looked at that might identify patients who need an immediate invasive strategy.
“This is one more reason why all ACS patients should be considered as part of one spectrum, and while the ECG gives us important information, it is not the only thing to consider. Dividing the conditions up as to whether a patient has ST elevation or not does not always make pathophysiological sense,” he added.
Dr. Byrne noted that the new guidelines have tried to reach a wider stakeholder group that includes emergency doctors, internal medicine physicians, general practitioners, and surgeons, as well as cardiologists. The document includes animations in an effort to increase the reach of the guidelines to noncardiology stakeholders, and for the first time, the task force included a patient representative.
“As part of this strategy, we have put more structure in to emphasize the importance that at first contact, we already want to be thinking of antithrombotic therapy and whether the patient needs urgent transfer to the nearest cath lab. We also want to be thinking straight away about preventing the next heart attack by implementing strong secondary prevention measures,” he commented.
Dr. Byrne highlighted a few changes to individual recommendations in the new guidelines.
Invasive management in NSTE-ACS
He pointed out that a small change has been made in the advice on invasive management for patients with non–ST-elevation ACS.
Dr. Byrne explained that patients with ST elevation should be sent immediately to a cath lab for PCI. If this is not possible within 120 minutes, then the patient should receive thrombolysis. This recommendation is the same as in previous guidelines.
He added, however, that there is some novelty in recommendations for patients who don’t have ST elevation but do have a positive troponin. For this group, previous guidelines gave a Class I recommendation that all such patients undergo an angiogram within the first 24 hours. However, an additional meta-analysis that was published in 2022 showed that the evidence for triaging all patients to the cath lab within 24 hours is somewhat limited, Dr. Byrne noted.
“At the end of the day, the task force felt that a Class I recommendation to get all patients to the cath lab within 24 hours was too strong and couldn’t be sustained, so it has been downgraded to a Class IIa recommendation, which we thought was more appropriate,” he said.
“So, while all patients should still have an angiogram during the hospital admission, if they are high-risk ACS, the imperative to get everyone to the cath lab within 24 hours – which many of our colleagues were finding difficult to achieve – does not seem to be backed up by the evidence,” he added.
Antithrombotic therapy
Addressing administration of antithrombotics, the guidelines emphasize that at the time of initial diagnosis, all patients should receive antithrombotic therapy, usually aspirin and a parenteral antithrombotic, such as heparin, enoxaparin, bivalirudin, or fondaparinux. Dr. Byrne noted that the guidelines have a new algorithm as to which of these antithrombotics to give, depending on the clinical presentation of the patient.
On the use of upfront P2Y12 inhibitors, Dr. Byrne said the new guidelines only give a weak recommendation for this.
“Giving a P2Y12 inhibitor up front does not have a strong evidence base, and it’s not unreasonable to wait, do the angiogram, see where you are, and then start the P2Y12 inhibitor. This is something that’s not widely done in clinical practice,” he commented.
“The last 2020 guideline gave a Class III recommendation for upfront P2Y12 inhibitor therapy for ACS patients who do not have STEMI. We’ve generally maintained that with the introduction of the exception that if you are in a health care system where there is a long wait to get to the cath lab – 5 ,6 or 7 days – then it’s reasonable to make an exception and give a P2Y12 inhibitor, but otherwise we’ve sustained the Class III recommendation,” he noted.
Also, for patients who have STEMI, there is a new Class IIb recommendation that upfront P2Y12 inhibitors may be considered.
“This is also rather a weak recommendation. There isn’t a strong rationale to give a P2Y12 inhibitor it in ST elevation either. It’s also reasonable to wait,” he added.
Don’t rush cardiac arrest patients to the cath lab
Another update in the guidelines involves the management of patients with cardiac arrest who have been resuscitated. Dr. Byrne explained that these patients would all receive an immediate ECG, and if it is found that they have ST elevation, they would be sent immediately to the cath lab. But a series of randomized trials has suggested that for patients who don’t have ST elevation, it is not necessary to rush these patients to the cath lab.
“We’ve given a Class III recommendation for this, saying it may be better to stabilize the patients first in the ICU. This is in recognition that a large proportion of these patients turn out not to have an MI. They have had a cardiac arrest for another reason,” Dr. Byrne noted. “Moving them to the cath lab when they are still unstable could be harming these patients rather than helping them.”
Revascularization for multivessel disease
Dr. Byrne notes that revascularization remains a critical element in the care for patients with STEMI, and there is a new recommendation in this area for patients with multivessel disease.
“Up to half of patients presenting with STEMI have multivessel disease, and we now have five randomized trials to say that these patients should have complete revascularization rather than just the culprit vessel. There is a new Class I recommendation for this,” he said.
However, the optimal timing of revascularization (immediate vs. staged) has still not been investigated in adequately sized randomized trials, and no recommendation has been made on this, the task force notes.
Dr. Byrne commented: “If you want to do everything in one go, that’s fine, but it’s also okay to do the culprit lesion first and then the other vessels at a later date within 45 days. This might depend on individual circumstances. For example, if there are complex lesions or the vessels are heavily calcified, then it may be best to get the culprit lesion fixed first and let the patient recover, then bring them back in for the rest.”
He pointed out that the results of the MULTISTARS trial, which were not available when the task force was formulating the guidelines, were reported at the ESC Congress and confirmed their recommendation.
DAPT after PCI
On the duration of dual antiplatelet therapy (DAPT) after PCI, the new guidelines have largely retained prior recommendations for a default strategy of 12 months for the combination of aspirin and a P2Y12 inhibitor.
“This was the subject of some discussion, as there have been several trials now looking at shorter durations of DAPT and deescalating after a few months to just one of these treatments. And while there is a rationale to do this, we think it’s best to be kept as an alternative strategy rather than the default strategy,” Dr. Byrne said.
He explained that the trials of DAPT deescalation tended to enroll lower-risk patients, which reduced the generalizability of the results.
Most of the trials only randomly assigned patients to shorter durations of DAPT when they were event-free for some period, she said.
“This is a dynamic decision-making process and reflects the real world to some extent. We think it is best to recommend the standard aspirin and a P2Y12 inhibitor for the 12-month duration, but at 3 months, if the patient is doing well but you may be worried about bleeding risk, then you could decide to deescalate to single antiplatelet therapy,” she noted. “So, there is Class IIa recommendation that this can be considered, but it is not recommended as the default position.”
Polypill for secondary prevention
Another innovation in the new guidelines is a new Class IIa recommendation for prescription of a polypill containing secondary prevention medications for patients on discharge from hospital.
This recommendation follows a trial that showed that the use of such a polypill helps patients be more adherent to the therapies prescribed.
Byrne explains that such a polypill may contain aspirin, an ACE inhibitor, and a statin. Several varieties are available in most European countries, but they are not widely used.
On secondary prevention, he stressed, “Prevention of the next heart attack starts before the patient leaves hospital. It is important to make sure the patient has the right medication on board, including a high-dose, high-intensity statin, and has been referred to a cardiac rehabilitation program. These are largely maintained recommendations from previous guidelines, but they are very important.”
A version of this article appeared on Medscape.com.
AMSTERDAM –
The new guideline was released at the annual congress of the European Society of Cardiology, and was published online in the European Heart Journal.
“We found that it was realized by the cardiology community that patients with STEMI, NSTEMI, or unstable angina represent a spectrum,” the chair of the guideline task force, Robert Byrne, MD, chair of cardiovascular research at the RCSI University of Medicine and Health Sciences, Dublin, explained to this news organization. “After the initial triage and management decisions, then most of the rest of the care follows a common pathway so it would make sense to consider everything in one guideline.”
Dr. Byrne noted that for all patients with a suspected ACS, the guideline recommendation is to administer an ECG within 10 minutes of presentation. The time is critical particularly for those with an occluded epicardial vessel. If there are features on the ECG that suggest an acutely occluded epicardial vessel, then the patient needs immediate angiography or primary angioplasty.
“The 10-minute guidance has been maintained from previous guidelines, but the nuance in the new guideline is that typically when we think of an occluded epicardial vessel we think of ST-elevation on the ECG,” Byrne said. “While this captures most occluded epicardial vessels, it doesn’t capture all of them. So, we have provided some guidance on alternative ECG patterns which might be indicative of an acute occlusion of the epicardial vessel and should be dealt with in the same way as an ST-elevation MI. This is a new concept.”
This situation could arise when a patient has an occluded circumflex artery and the regular ECG may not show ST elevation but the patient has ongoing pain, he noted. “There are additional ECG leads that can be looked at that might identify patients who need an immediate invasive strategy.
“This is one more reason why all ACS patients should be considered as part of one spectrum, and while the ECG gives us important information, it is not the only thing to consider. Dividing the conditions up as to whether a patient has ST elevation or not does not always make pathophysiological sense,” he added.
Dr. Byrne noted that the new guidelines have tried to reach a wider stakeholder group that includes emergency doctors, internal medicine physicians, general practitioners, and surgeons, as well as cardiologists. The document includes animations in an effort to increase the reach of the guidelines to noncardiology stakeholders, and for the first time, the task force included a patient representative.
“As part of this strategy, we have put more structure in to emphasize the importance that at first contact, we already want to be thinking of antithrombotic therapy and whether the patient needs urgent transfer to the nearest cath lab. We also want to be thinking straight away about preventing the next heart attack by implementing strong secondary prevention measures,” he commented.
Dr. Byrne highlighted a few changes to individual recommendations in the new guidelines.
Invasive management in NSTE-ACS
He pointed out that a small change has been made in the advice on invasive management for patients with non–ST-elevation ACS.
Dr. Byrne explained that patients with ST elevation should be sent immediately to a cath lab for PCI. If this is not possible within 120 minutes, then the patient should receive thrombolysis. This recommendation is the same as in previous guidelines.
He added, however, that there is some novelty in recommendations for patients who don’t have ST elevation but do have a positive troponin. For this group, previous guidelines gave a Class I recommendation that all such patients undergo an angiogram within the first 24 hours. However, an additional meta-analysis that was published in 2022 showed that the evidence for triaging all patients to the cath lab within 24 hours is somewhat limited, Dr. Byrne noted.
“At the end of the day, the task force felt that a Class I recommendation to get all patients to the cath lab within 24 hours was too strong and couldn’t be sustained, so it has been downgraded to a Class IIa recommendation, which we thought was more appropriate,” he said.
“So, while all patients should still have an angiogram during the hospital admission, if they are high-risk ACS, the imperative to get everyone to the cath lab within 24 hours – which many of our colleagues were finding difficult to achieve – does not seem to be backed up by the evidence,” he added.
Antithrombotic therapy
Addressing administration of antithrombotics, the guidelines emphasize that at the time of initial diagnosis, all patients should receive antithrombotic therapy, usually aspirin and a parenteral antithrombotic, such as heparin, enoxaparin, bivalirudin, or fondaparinux. Dr. Byrne noted that the guidelines have a new algorithm as to which of these antithrombotics to give, depending on the clinical presentation of the patient.
On the use of upfront P2Y12 inhibitors, Dr. Byrne said the new guidelines only give a weak recommendation for this.
“Giving a P2Y12 inhibitor up front does not have a strong evidence base, and it’s not unreasonable to wait, do the angiogram, see where you are, and then start the P2Y12 inhibitor. This is something that’s not widely done in clinical practice,” he commented.
“The last 2020 guideline gave a Class III recommendation for upfront P2Y12 inhibitor therapy for ACS patients who do not have STEMI. We’ve generally maintained that with the introduction of the exception that if you are in a health care system where there is a long wait to get to the cath lab – 5 ,6 or 7 days – then it’s reasonable to make an exception and give a P2Y12 inhibitor, but otherwise we’ve sustained the Class III recommendation,” he noted.
Also, for patients who have STEMI, there is a new Class IIb recommendation that upfront P2Y12 inhibitors may be considered.
“This is also rather a weak recommendation. There isn’t a strong rationale to give a P2Y12 inhibitor it in ST elevation either. It’s also reasonable to wait,” he added.
Don’t rush cardiac arrest patients to the cath lab
Another update in the guidelines involves the management of patients with cardiac arrest who have been resuscitated. Dr. Byrne explained that these patients would all receive an immediate ECG, and if it is found that they have ST elevation, they would be sent immediately to the cath lab. But a series of randomized trials has suggested that for patients who don’t have ST elevation, it is not necessary to rush these patients to the cath lab.
“We’ve given a Class III recommendation for this, saying it may be better to stabilize the patients first in the ICU. This is in recognition that a large proportion of these patients turn out not to have an MI. They have had a cardiac arrest for another reason,” Dr. Byrne noted. “Moving them to the cath lab when they are still unstable could be harming these patients rather than helping them.”
Revascularization for multivessel disease
Dr. Byrne notes that revascularization remains a critical element in the care for patients with STEMI, and there is a new recommendation in this area for patients with multivessel disease.
“Up to half of patients presenting with STEMI have multivessel disease, and we now have five randomized trials to say that these patients should have complete revascularization rather than just the culprit vessel. There is a new Class I recommendation for this,” he said.
However, the optimal timing of revascularization (immediate vs. staged) has still not been investigated in adequately sized randomized trials, and no recommendation has been made on this, the task force notes.
Dr. Byrne commented: “If you want to do everything in one go, that’s fine, but it’s also okay to do the culprit lesion first and then the other vessels at a later date within 45 days. This might depend on individual circumstances. For example, if there are complex lesions or the vessels are heavily calcified, then it may be best to get the culprit lesion fixed first and let the patient recover, then bring them back in for the rest.”
He pointed out that the results of the MULTISTARS trial, which were not available when the task force was formulating the guidelines, were reported at the ESC Congress and confirmed their recommendation.
DAPT after PCI
On the duration of dual antiplatelet therapy (DAPT) after PCI, the new guidelines have largely retained prior recommendations for a default strategy of 12 months for the combination of aspirin and a P2Y12 inhibitor.
“This was the subject of some discussion, as there have been several trials now looking at shorter durations of DAPT and deescalating after a few months to just one of these treatments. And while there is a rationale to do this, we think it’s best to be kept as an alternative strategy rather than the default strategy,” Dr. Byrne said.
He explained that the trials of DAPT deescalation tended to enroll lower-risk patients, which reduced the generalizability of the results.
Most of the trials only randomly assigned patients to shorter durations of DAPT when they were event-free for some period, she said.
“This is a dynamic decision-making process and reflects the real world to some extent. We think it is best to recommend the standard aspirin and a P2Y12 inhibitor for the 12-month duration, but at 3 months, if the patient is doing well but you may be worried about bleeding risk, then you could decide to deescalate to single antiplatelet therapy,” she noted. “So, there is Class IIa recommendation that this can be considered, but it is not recommended as the default position.”
Polypill for secondary prevention
Another innovation in the new guidelines is a new Class IIa recommendation for prescription of a polypill containing secondary prevention medications for patients on discharge from hospital.
This recommendation follows a trial that showed that the use of such a polypill helps patients be more adherent to the therapies prescribed.
Byrne explains that such a polypill may contain aspirin, an ACE inhibitor, and a statin. Several varieties are available in most European countries, but they are not widely used.
On secondary prevention, he stressed, “Prevention of the next heart attack starts before the patient leaves hospital. It is important to make sure the patient has the right medication on board, including a high-dose, high-intensity statin, and has been referred to a cardiac rehabilitation program. These are largely maintained recommendations from previous guidelines, but they are very important.”
A version of this article appeared on Medscape.com.
AMSTERDAM –
The new guideline was released at the annual congress of the European Society of Cardiology, and was published online in the European Heart Journal.
“We found that it was realized by the cardiology community that patients with STEMI, NSTEMI, or unstable angina represent a spectrum,” the chair of the guideline task force, Robert Byrne, MD, chair of cardiovascular research at the RCSI University of Medicine and Health Sciences, Dublin, explained to this news organization. “After the initial triage and management decisions, then most of the rest of the care follows a common pathway so it would make sense to consider everything in one guideline.”
Dr. Byrne noted that for all patients with a suspected ACS, the guideline recommendation is to administer an ECG within 10 minutes of presentation. The time is critical particularly for those with an occluded epicardial vessel. If there are features on the ECG that suggest an acutely occluded epicardial vessel, then the patient needs immediate angiography or primary angioplasty.
“The 10-minute guidance has been maintained from previous guidelines, but the nuance in the new guideline is that typically when we think of an occluded epicardial vessel we think of ST-elevation on the ECG,” Byrne said. “While this captures most occluded epicardial vessels, it doesn’t capture all of them. So, we have provided some guidance on alternative ECG patterns which might be indicative of an acute occlusion of the epicardial vessel and should be dealt with in the same way as an ST-elevation MI. This is a new concept.”
This situation could arise when a patient has an occluded circumflex artery and the regular ECG may not show ST elevation but the patient has ongoing pain, he noted. “There are additional ECG leads that can be looked at that might identify patients who need an immediate invasive strategy.
“This is one more reason why all ACS patients should be considered as part of one spectrum, and while the ECG gives us important information, it is not the only thing to consider. Dividing the conditions up as to whether a patient has ST elevation or not does not always make pathophysiological sense,” he added.
Dr. Byrne noted that the new guidelines have tried to reach a wider stakeholder group that includes emergency doctors, internal medicine physicians, general practitioners, and surgeons, as well as cardiologists. The document includes animations in an effort to increase the reach of the guidelines to noncardiology stakeholders, and for the first time, the task force included a patient representative.
“As part of this strategy, we have put more structure in to emphasize the importance that at first contact, we already want to be thinking of antithrombotic therapy and whether the patient needs urgent transfer to the nearest cath lab. We also want to be thinking straight away about preventing the next heart attack by implementing strong secondary prevention measures,” he commented.
Dr. Byrne highlighted a few changes to individual recommendations in the new guidelines.
Invasive management in NSTE-ACS
He pointed out that a small change has been made in the advice on invasive management for patients with non–ST-elevation ACS.
Dr. Byrne explained that patients with ST elevation should be sent immediately to a cath lab for PCI. If this is not possible within 120 minutes, then the patient should receive thrombolysis. This recommendation is the same as in previous guidelines.
He added, however, that there is some novelty in recommendations for patients who don’t have ST elevation but do have a positive troponin. For this group, previous guidelines gave a Class I recommendation that all such patients undergo an angiogram within the first 24 hours. However, an additional meta-analysis that was published in 2022 showed that the evidence for triaging all patients to the cath lab within 24 hours is somewhat limited, Dr. Byrne noted.
“At the end of the day, the task force felt that a Class I recommendation to get all patients to the cath lab within 24 hours was too strong and couldn’t be sustained, so it has been downgraded to a Class IIa recommendation, which we thought was more appropriate,” he said.
“So, while all patients should still have an angiogram during the hospital admission, if they are high-risk ACS, the imperative to get everyone to the cath lab within 24 hours – which many of our colleagues were finding difficult to achieve – does not seem to be backed up by the evidence,” he added.
Antithrombotic therapy
Addressing administration of antithrombotics, the guidelines emphasize that at the time of initial diagnosis, all patients should receive antithrombotic therapy, usually aspirin and a parenteral antithrombotic, such as heparin, enoxaparin, bivalirudin, or fondaparinux. Dr. Byrne noted that the guidelines have a new algorithm as to which of these antithrombotics to give, depending on the clinical presentation of the patient.
On the use of upfront P2Y12 inhibitors, Dr. Byrne said the new guidelines only give a weak recommendation for this.
“Giving a P2Y12 inhibitor up front does not have a strong evidence base, and it’s not unreasonable to wait, do the angiogram, see where you are, and then start the P2Y12 inhibitor. This is something that’s not widely done in clinical practice,” he commented.
“The last 2020 guideline gave a Class III recommendation for upfront P2Y12 inhibitor therapy for ACS patients who do not have STEMI. We’ve generally maintained that with the introduction of the exception that if you are in a health care system where there is a long wait to get to the cath lab – 5 ,6 or 7 days – then it’s reasonable to make an exception and give a P2Y12 inhibitor, but otherwise we’ve sustained the Class III recommendation,” he noted.
Also, for patients who have STEMI, there is a new Class IIb recommendation that upfront P2Y12 inhibitors may be considered.
“This is also rather a weak recommendation. There isn’t a strong rationale to give a P2Y12 inhibitor it in ST elevation either. It’s also reasonable to wait,” he added.
Don’t rush cardiac arrest patients to the cath lab
Another update in the guidelines involves the management of patients with cardiac arrest who have been resuscitated. Dr. Byrne explained that these patients would all receive an immediate ECG, and if it is found that they have ST elevation, they would be sent immediately to the cath lab. But a series of randomized trials has suggested that for patients who don’t have ST elevation, it is not necessary to rush these patients to the cath lab.
“We’ve given a Class III recommendation for this, saying it may be better to stabilize the patients first in the ICU. This is in recognition that a large proportion of these patients turn out not to have an MI. They have had a cardiac arrest for another reason,” Dr. Byrne noted. “Moving them to the cath lab when they are still unstable could be harming these patients rather than helping them.”
Revascularization for multivessel disease
Dr. Byrne notes that revascularization remains a critical element in the care for patients with STEMI, and there is a new recommendation in this area for patients with multivessel disease.
“Up to half of patients presenting with STEMI have multivessel disease, and we now have five randomized trials to say that these patients should have complete revascularization rather than just the culprit vessel. There is a new Class I recommendation for this,” he said.
However, the optimal timing of revascularization (immediate vs. staged) has still not been investigated in adequately sized randomized trials, and no recommendation has been made on this, the task force notes.
Dr. Byrne commented: “If you want to do everything in one go, that’s fine, but it’s also okay to do the culprit lesion first and then the other vessels at a later date within 45 days. This might depend on individual circumstances. For example, if there are complex lesions or the vessels are heavily calcified, then it may be best to get the culprit lesion fixed first and let the patient recover, then bring them back in for the rest.”
He pointed out that the results of the MULTISTARS trial, which were not available when the task force was formulating the guidelines, were reported at the ESC Congress and confirmed their recommendation.
DAPT after PCI
On the duration of dual antiplatelet therapy (DAPT) after PCI, the new guidelines have largely retained prior recommendations for a default strategy of 12 months for the combination of aspirin and a P2Y12 inhibitor.
“This was the subject of some discussion, as there have been several trials now looking at shorter durations of DAPT and deescalating after a few months to just one of these treatments. And while there is a rationale to do this, we think it’s best to be kept as an alternative strategy rather than the default strategy,” Dr. Byrne said.
He explained that the trials of DAPT deescalation tended to enroll lower-risk patients, which reduced the generalizability of the results.
Most of the trials only randomly assigned patients to shorter durations of DAPT when they were event-free for some period, she said.
“This is a dynamic decision-making process and reflects the real world to some extent. We think it is best to recommend the standard aspirin and a P2Y12 inhibitor for the 12-month duration, but at 3 months, if the patient is doing well but you may be worried about bleeding risk, then you could decide to deescalate to single antiplatelet therapy,” she noted. “So, there is Class IIa recommendation that this can be considered, but it is not recommended as the default position.”
Polypill for secondary prevention
Another innovation in the new guidelines is a new Class IIa recommendation for prescription of a polypill containing secondary prevention medications for patients on discharge from hospital.
This recommendation follows a trial that showed that the use of such a polypill helps patients be more adherent to the therapies prescribed.
Byrne explains that such a polypill may contain aspirin, an ACE inhibitor, and a statin. Several varieties are available in most European countries, but they are not widely used.
On secondary prevention, he stressed, “Prevention of the next heart attack starts before the patient leaves hospital. It is important to make sure the patient has the right medication on board, including a high-dose, high-intensity statin, and has been referred to a cardiac rehabilitation program. These are largely maintained recommendations from previous guidelines, but they are very important.”
A version of this article appeared on Medscape.com.
AT ESC CONGRESS 2023