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Another FDA class I recall of Cardiosave Hybrid/Rescue IABPs
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.
Clinician violence: Virtual reality to the rescue?
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
This discussion was recorded on Feb. 21, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Welcome, Dr. Salazar. It’s a pleasure to have you join us today.
Gilberto A. Salazar, MD: The pleasure is all mine, Dr. Glatter. Thank you so much for having me.
Dr. Glatter: This is such an important topic, as you can imagine. Workplace violence is affecting so many providers in hospital emergency departments but also throughout other parts of the hospital.
First, can you describe how the virtual reality (VR) program was designed that you developed and what type of situations it simulates?
Dr. Salazar: We worked in conjunction with the University of Texas at Dallas. They help people like me, subject matter experts in health care, to bring ideas to reality. I worked very closely with a group of engineers from their department in designing a module specifically designed to tackle, as you mentioned, one of our biggest threats in workplace violence.
We decided to bring in a series of competencies and proficiencies that we wanted to bring into the virtual reality space. In leveraging the technology and the expertise from UT Dallas, we were able to make that happen.
Dr. Glatter: I think it’s important to understand, in terms of virtual reality, what type of environment the program creates. Can you describe what a provider who puts the goggles on is experiencing? Do they feel anything? Is there technology that enables this?
Dr. Salazar: Yes, absolutely. We were able to bring to reality a series of scenarios very common from what you and I see in the emergency department on a daily basis. We wanted to immerse a learner into that specific environment. We didn’t feel that a module or something on a computer or a slide set could really bring the reality of what it’s like to interact with a patient who may be escalating or may be aggressive.
We are immersing learners into an actual hospital room to our specifications, very similar to exactly where we practice each and every day, and taking the learners through different situations that we designed with various levels of escalation and aggression, and asking the learner to manage that situation as best as they possibly can using the competencies and proficiencies that we taught them.
Dr. Glatter: Haptic feedback is an important part of the program and also the approach and technique that you’re using. Can you describe what haptic feedback means and what people actually feel?
Dr. Salazar: Absolutely. One of the most unfortunate things in my professional career is physical abuse suffered by people like me and you and our colleagues, nursing personnel, technicians, and others, resulting in injury.
We wanted to provide the most realistic experience that we could design. Haptics engage digital senses other than your auditory and your visuals. They really engage your tactile senses. These haptic vests and gloves and technology allow us to provide a third set of sensory stimuli for the learner.
At one of the modules, we have an actual physical assault that takes place, and the learner is actually able to feel in their body the strikes – of course, not painful – but just bringing in those senses and that stimulus, really leaving the learner with an experience that’s going to be long-lasting.
Dr. Glatter: Feeling that stimulus certainly affects your vital signs. Do you monitor a provider’s vital signs, such as their blood pressure and heart rate, as the situation and the threat escalate? That could potentially trigger some issues in people with prior PTSD or people with other mental health issues. Has that ever been considered in the design of your program?
Dr. Salazar: Yes, 100%. The beautiful thing about haptics is that they can be tailored to our specific parameters. The sensory stimulus that’s provided is actually very mild. It feels more like a tap than an actual strike. It just reminds us that when we’re having or experiencing an actual physical attack, we’re really engaging the senses.
We have an emergency physician or an EMT-paramedic on site at all times during the training so that we can monitor our subjects and make sure that they’re comfortable and healthy.
Dr. Glatter: Do they have actual sensors attached to their bodies that are part of your program or distinct in terms of monitoring their vital signs?
Dr. Salazar: It’s completely different. We have two different systems that we are planning on utilizing. Frankly, in the final version of this virtual reality module, we may not even involve the haptics. We’re going to study it and see how our learners behave and how much information they’re able to acquire and retain.
It may be very possible that just the visuals – the auditory and the immersion taking place within the hospital room – may be enough. It’s very possible that, in the next final version of this, we may find that haptics bring in quite a bit of value, and we may incorporate that. If that is the case, then we will, of course, acquire different technology to monitor the patient’s vital signs.
Dr. Glatter: Clearly, when situations escalate in the department, everyone gets more concerned about the patient, but providers are part of this equation, as you allude to.
In 2022, there was a poll by the American College of Emergency Physicians that stated that 85% of emergency physicians reported an increase in violent activity in their ERs in the past 5 years. Nearly two-thirds of nearly 3,000 emergency physicians surveyed reported being assaulted in the past year. This is an important module that we integrate into training providers in terms of these types of tense situations that can result not only in mental anguish but also in physical injury.
Dr. Salazar: One hundred percent. I frankly got tired of seeing my friends and my colleagues suffer both the physical and mental effects of verbal and physical abuse, and I wanted to design a project that was very patient centric while allowing our personnel to really manage these situations a little bit better.
Frankly, we don’t receive great training in this space, and I wanted to rewrite that narrative and make things better for our clinicians out there while remaining patient centric. I wanted to do something about it, and hopefully this dream will become a reality.
Dr. Glatter: Absolutely. There are other data from the Bureau of Labor Statistics stating that health care workers are five times more likely than employees in any other area of work to experience workplace violence. This could, again, range from verbal to physical violence. This is a very important module that you’re developing.
Are there any thoughts to extend this to active-shooter scenarios or any other high-stakes scenarios that you can imagine in the department?
Dr. Salazar: We’re actually working with the same developer that’s helping us with this VR module in developing a mass-casualty incident module so that we can get better training in responding to these very unfortunate high-stakes situations.
Dr. Glatter: In terms of using the module remotely, certainly not requiring resources or having to be in a physical place, can providers in your plan be able to take such a headset home and practice on their own in the sense of being able to deal with a situation? Would this be more reserved for in-department use?
Dr. Salazar: That’s a phenomenal question. I wanted to create the most flexible module that I possibly could. Ideally, a dream scenario is leveraging a simulation center at an academic center and not just do the VR module but also have a brief didactics incorporating a small slide set, some feedback, and some standardized patients. I wanted it to be flexible enough so that folks here in my state, a different state, or even internationally could take advantage of this technology and do it from the comfort of their home.
As you mentioned, this is going to strike some people. It’s going to hit them heavier than others in terms of prior experience as PTSD. For some people, it may be more comfortable to do it in the comfort of their homes. I wanted to create something very flexible and dynamic.
Dr. Glatter: I think that’s ideal. Just one other point. Can you discuss the different levels of competencies involved in this module and how that would be attained?
Dr. Salazar: It’s all evidence based, so we borrowed from literature and the specialties of emergency medicine. We collaborated with psychiatrists within our medical center. We looked at all available literature and methods, proficiencies, competencies, and best practices, and we took all of them together to form something that we think is organized and concise.
We were able to create our own algorithm, but it’s not brand new. We’re just borrowing what we think is the best to create something that the majority of health care personnel are going to be able to relate to and be able to really be proficient at.
This includes things like active listening, bargaining, how to respond, where to put yourself in a situation, and the best possible situation to respond to a scenario, how to prevent things – how to get out of a chokehold, for example. We’re borrowing from several different disciplines and creating something that can be very concise and organized.
Dr. Glatter: Does this program that you’ve developed allow the provider to get feedback in the sense that when they’re in such a danger, their life could be at risk? For example, if they don’t remove themselves in a certain amount of time, this could be lethal.
Dr. Salazar: Yes, 100%. Probably the one thing that differentiates our project from any others is the ability to customize the experience so that a learner who is doing the things that we ask them to do in terms of safety and response is able to get out of a situation successfully within the environment. If they don’t, they get some kind of feedback.
Not to spoil the surprise here, but we’re going to be doing things like looking at decibel meters to see what the volume in the room is doing and how you’re managing the volume and the stimulation within the room. If you are able to maintain the decibel readings at a specific level, you’re going to succeed through the module. If you don’t, we keep the patient escalation going.
Dr. Glatter: There is a debrief built into this type of approach where, in other words, learning points are emphasized – where you could have done better and such.
Dr. Salazar: Yes, absolutely. We are going to be able to get individualized data for each learner so that we can tailor the debrief to their own performance and be able to give them actionable items to work on. It’s a debrief that’s productive and individualized, and folks can walk away with something useful in the end.
Dr. Glatter: Are the data shared or confidential at present?
Dr. Salazar: At this very moment, the data are confidential. We are going to look at how to best use this. We’re hoping to eventually write this up and see how this information can be best used to train personnel.
Eventually, we may see that some of the advice that we’re giving is very common to most folks. Others may require some individualized type of feedback. That said, it remains to be seen, but right now, it’s confidential.
Dr. Glatter: Is this currently being implemented as part of your curriculum for emergency medicine residents?
Dr. Salazar: We’re going to study it first. We’re very excited to include our emergency medicine residents as one of our cohorts that’s going to be undergoing the module, and we’re going to be studying other forms of workplace violence mitigation strategies. We’re really excited about the possibility of this eventually becoming the standard of education for not only our emergency medicine residents, but also health care personnel all over the world.
Dr. Glatter: I’m glad you mentioned that, because obviously nurses, clerks in the department, and anyone who’s working in the department, for that matter, and who interfaces with patients really should undergo such training.
Dr. Salazar: Absolutely. The folks at intake, at check-in, and at kiosks. Do they go through a separate area for screening? You’re absolutely right. There are many folks who interface with patients and all of us are potential victims of workplace violence. We want to give our health care family the best opportunity to succeed in these situations.
Dr. Glatter:: Absolutely. Even EMS providers, being on the front lines and encountering patients in such situations, would benefit, in my opinion.
Dr. Salazar: Yes, absolutely. Behavioral health emergencies and organically induced altered mental status results in injury, both physical and mental, to EMS professionals as well, and there’s good evidence of that. I’ll be very glad to see this type of education make it out to our initial and continuing education efforts for EMS as well.
Dr. Glatter: I want to thank you. This has been very helpful. It’s such an important task that you’ve started to explore, and I look forward to follow-up on this. Again, thank you for your time.
Dr. Salazar: It was my pleasure. Thank you so much for having me.
Dr. Glatter is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, N.Y. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes. Dr. Salazar is a board-certified emergency physician and associate professor at UT Southwestern Medicine Center in Dallas. He is involved with the UTSW Emergency Medicine Education Program and serves as the medical director to teach both initial and continuing the emergency medicine education for emergency medical technicians and paramedics, which trains most of the Dallas Fire Rescue personnel and the vast majority for EMS providers in the Dallas County. In addition, he serves as an associate chief of service at Parkland’s emergency department, and liaison to surgical services. A version of this article originally appeared on Medscape.com.
‘Keto-like’ diet linked to doubling of heart disease risk
Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.
“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.
“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.
Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.
In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.
“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”
He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.”
For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.
They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.
On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.
Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).
Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).
Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004). Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).
After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.
After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
‘Closer monitoring needed’
“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”
He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.
“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”
He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001).
“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”
Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.
“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
Jury still out
Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”
Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.
“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said.
“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.
The authors of the study reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.
“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.
“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.
Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.
In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.
“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”
He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.”
For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.
They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.
On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.
Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).
Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).
Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004). Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).
After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.
After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
‘Closer monitoring needed’
“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”
He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.
“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”
He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001).
“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”
Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.
“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
Jury still out
Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”
Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.
“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said.
“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.
The authors of the study reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Consumption of a low-carbohydrate, high-fat diet, dubbed a “keto-like” diet, was associated with an increase in LDL levels and a twofold increase in the risk for future cardiovascular events, in a new observational study.
“To our knowledge this is the first study to demonstrate an association between a carbohydrate-restricted dietary platform and greater risk of atherosclerotic cardiovascular disease,” said study investigator Iulia Iatan, MD, PhD, University of British Columbia, Vancouver.
“Hypercholesterolemia occurring during a low-carb, high-fat diet should not be assumed to be benign,” she concluded.
Dr. Iatan presented the study March 5 at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The presentation received much media attention, with headlines implying a causal relationship with cardiac events based on these observational results. But lipid expert Steven Nissen, MD, of the Cleveland Clinic, warned against paying much attention to the headlines or to the study’s conclusions.
In an interview, Dr. Nissen pointed out that the LDL increase in the “keto-like” diet group was relatively small and “certainly not enough to produce a doubling in cardiovascular risk.
“The people who were on the ‘keto-like’ diet in this study were different than those who were on the standard diet,” he said. “Those on the ‘keto-like’ diet were on it for a reason – they were more overweight, they had a higher incidence of diabetes, so their risk profile was completely different. Even though the researchers tried to adjust for other cardiovascular risk factors, there will be unmeasured confounding in a study like this.”
He said he doesn’t think this study “answers any significant questions in a way that we want to have them answered. I’m not a big fan of this type of diet, but I don’t think it doubles the risk of adverse cardiovascular events, and I don’t think this study tells us one way or another.”
For the study, Dr. Iatan and colleagues defined a low-carbohydrate, high-fat diet as consisting of no more than 25% of total daily energy from carbohydrates and more than 45% of total daily calories from fat. This is somewhat higher in carbohydrates and lower in fat than a strict ketogenic diet but could be thought of as a ‘keto-like’ diet.
They analyzed data from the UK Biobank, a large-scale prospective database with health information from over half a million people living in the United Kingdom who were followed for at least 10 years.
On enrollment in the Biobank, participants completed a one-time, self-reported 24-hour diet questionnaire and, at the same time, had blood drawn to check their levels of cholesterol. The researchers identified 305 participants whose questionnaire responses indicated that they followed a low-carbohydrate, high-fat diet. These participants were matched by age and sex with 1,220 individuals who reported being on a standard diet.
Of the study population, 73% were women and the average age was 54 years. Those on a low carbohydrate/high fat diet had a higher average body mass index (27.7 vs. 26.7) and a higher incidence of diabetes (4.9% vs. 1.7%).
Results showed that compared with participants on a standard diet, those on the “keto-like” diet had significantly higher levels of both LDL cholesterol and apolipoprotein B (ApoB).
Levels of LDL were 3.80 mmol/L (147 mg/dL) in the keto-like group vs. 3.64 mmol/L (141 mg/dL) in the standard group (P = .004). Levels of ApoB were 1.09 g/L (109 mg/dL) in the keto-like group and 1.04 g/L (104 mg/dL) in the standard group (P < .001).
After an average of 11.8 years of follow-up, 9.8% of participants on the low-carbohydrate/high-fat diet vs. 4.3% in the standard diet group experienced one of the events included in the composite event endpoint: Angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization.
After adjustment for other risk factors for heart disease – diabetes, hypertension, obesity, and smoking – individuals on a low-carbohydrate, high-fat diet were found to have a twofold risk of having a cardiovascular event (HR, 2.18; P < .001).
‘Closer monitoring needed’
“Our results have shown, I think for the first time, that there is an association between this increasingly popular dietary pattern and high LDL cholesterol and an increased future risk of cardiovascular events,” senior author Liam Brunham, MD, of the University of British Columbia, said in an interview. “This is concerning as there are many people out there following this type of diet, and I think it suggests there is a need for closer monitoring of these people.”
He explained that while it would be expected for cholesterol levels to rise on a high-fat diet, “there has been a perception by some that this is not worrisome as it is reflecting certain metabolic changes. What we’ve shown in this study is that if your cholesterol does increase significantly on this diet then you should not assume that this is not a problem.
“For some people with diabetes this diet can help lower blood sugar and some people can lose weight on it,” he noted, “but what our data show is that there is a subgroup of people who experience high levels of LDL and ApoB and that seems to be driving the risk.”
He pointed out that overall the mean level of LDL was only slightly increased in the individuals on the low-carb/high-fat diet but severe high cholesterol (more than 5 mmol/L or 190 mg/dL) was about doubled in that group (10% vs. 5%). And these patients had a sixfold increase in risk of cardiovascular disease (P < .001).
“This suggests that there is a subgroup of people who are susceptible to this exacerbation of hypercholesterolemia in response to a low-carb/high-fat diet.”
Dr. Brunham said his advice would be that if people choose to follow this diet, they should have their cholesterol monitored, and manage their cardiovascular risk factors.
“I wouldn’t say it is not appropriate to follow this diet based on this study,” he added. “This is just an observational study. It is not definitive. But if people do want to follow this dietary pattern because they feel there would be some benefits, then they should be aware of the potential risks and take steps to mitigate those risks.”
Jury still out
Dr. Nissen said in his view “the jury was still out” on this type of diet. “I’m open to the possibility that, particularly in the short run, a ‘keto-like’ diet may help some people lose weight and that’s a good thing. But I do not generally recommend this type of diet.”
Rather, he advises patients to follow a Mediterranean diet, which has been proven to reduce cardiovascular events in a randomized study, the PREDIMED trial.
“We can’t make decisions on what type of diet to recommend to patients based on observational studies like this where there is a lot of subtlety missing. But when studies like this are reported, the mass media seize on it. That’s not the way the public needs to be educated,” Dr. Nissen said.
“We refer to this type of study as hypothesis-generating. It raises a hypothesis. It doesn’t answer the question. It is worth looking at the question of whether a ketogenic-like diet is harmful. We don’t know at present, and I don’t think we know any more after this study,” he added.
The authors of the study reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM ACC 2023
20 years of clinical research in cardiology
In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”
In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”
In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”
Causal AI quantifies CV risk, providing patient-specific goals
NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).
Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.
The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
Causal AI trained on nearly 2 million patients
This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.
To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.
When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.
Providing examples, Dr. Ference explained that a PGS in the 80th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.
Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.
Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.
Even though family history is equivalent to having PGS above the 95th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.
Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.
According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
Treatments become understandable to patients
“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.
A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.
Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.
By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.
With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.
She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.
Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.
NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).
Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.
The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
Causal AI trained on nearly 2 million patients
This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.
To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.
When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.
Providing examples, Dr. Ference explained that a PGS in the 80th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.
Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.
Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.
Even though family history is equivalent to having PGS above the 95th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.
Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.
According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
Treatments become understandable to patients
“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.
A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.
Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.
By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.
With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.
She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.
Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.
NEW ORLEANS – Causal artificial intelligence (AI) can translate polygenic scores (PGS) and other genetic information into risk reduction strategies for coronary artery disease (CAD) that is tailored for each individual patient, according to an analysis presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Tested for LDL cholesterol (LDL-C) and systolic blood pressure (SBP), causal AI explained how much each of these risk factors must improve at the level of each individual patient “to overcome overall inherited risk,” reported Brian Ference, MD, MPhil, director of translational therapeutics, University of Cambridge (England).
Unlike the “black box” risk assessments common to machine learning, which relies on disparate forms of information of often unknown relative significance, causal AI explains cause and effect. In the case of CAD, its ability to encode the biological causes means that it can “both predict outcomes and prescribe specific actions to change those outcomes,” Dr. Ference explained.
The concept is testable against observed biology using randomized evidence, which was the objective of the study Dr. Ference presented in the late-breaker session.
Causal AI trained on nearly 2 million patients
This study employed a causal AI platform trained on roughly 1.3 million participants in Mendelian randomization studies, as well as more than 500,000 participants in randomized clinical trials. The PGS estimate of inherited risk was constructed from almost 4.1 million variants from genomewide association studies.
To test the ability of causal AI to reveal how much LDL-C or SBP had to be reduced to overcome the inherited risk of CAD based on PGS, it was applied to 445,765 participants of European ancestry in the UK Biobank. The goal was to determine how much those with greater than average risk would need to lower their LDL-C or SBP to achieve average CAD risk.
When validated against observed rates of events, causal AI accurately characterized risk before estimating what reductions in LDL-C, SBP, or both would attenuate that risk.
Providing examples, Dr. Ference explained that a PGS in the 80th percentile can be overcome by lowering LDL-C by 14 mg/dL. Alternatively, the 80th percentile risk could also be overcome by simultaneously lowering LDL-C and SBP by 7 mg/dL and 2.5 mm Hg, respectively.
Required risk factor reductions increase with age because of the increased risk of the events. For example, while a 14.8 mg/dL reduction in LDL-C would be adequate to overcome risk defined by a PGS in the 80th percentile at age 35, reductions of 18.2 mg/dL, 28.9 mg/dL, and 42.6 mg/dL would be required, respectively, at ages 45, 55, and 65 years. The values climb similarly for SBP.
Family history of CAD adds an independent variable that further contributes to the ability of causal AI to estimate risk and the degree of risk factor attenuation to overcome the risk.
Even though family history is equivalent to having PGS above the 95th percentile, it is an independent and additive variable, according to Dr. Ference. As a result, inherited risk of CAD depends on both.
Still when family history is factored into the analysis, “causal AI accurately estimated the magnitude of lower LDL-C, SBP, or both needed to overcome overall inherited risk at all levels of higher or lower PGS,” he reported.
According to Dr. Ference, the value of causal AI is that it can generate very specific goals for each patient regarding modifiable risk factors. Causal effects of risk factors encoded in time units of exposure allow the patient and the clinician to understand the biology and the basis of the disease burden.
Treatments become understandable to patients
“Encoding biology creates algorithms that are deeply explainable because they reveal why a person is at risk, how to reduce that risk, and how much each person will benefit from specific actions to reduce risk,” Dr. Ference said.
A real-world, randomized trial to confirm that the information from causal AI can reduce the risk of CAD is expected to start in 2023, but Dr. Ference thinks that causal AI for managing CAD risk, independent of this planned trial, is essentially inevitable. PGS, which he thinks will be performed routinely in all individuals within 10 years, is only likely to improve. He foresees large advantages of this form of personalized medicine.
Ami Bhatt, MD, chief innovation officer for the American College of Cardiology, Washington, agreed, seeing a direct relationship between precision health as the pathway to improvements in population health.
By explaining risk factors in terms of mechanisms and specific goals to ameliorate these risks, it “engages our patients with agency,” said Dr. Bhatt. She suggested that the information provided by causal AI has the potential to empower patients while creating a collaborative approach with clinicians to CAD prevention.
With patient-specific information provided in the context of the disease biology, “you increase the sense of transparency,” Dr. Bhatt said.
She suggested this direction of research is wholly consistent with initiatives such as those from the World Health Organization to improve precision medicine as a step toward equipping patients to manage their own health.
Dr. Ference reported financial relationships with Amgen, AstraZeneca, CiVi Pharma, Daiichi Sankyo, DalCOR, Esperion, Eli Lilly, Ionis Pharmaceuticals, KrKA, Medicines Company, Merck, Mylan, Novo Nordisk, Novartis, and Sanofi, and Viatris. Dr. Bhatt reported no potential conflicts of interest.
AT ACC 2023
NUDGE-FLU: Electronic ‘nudges’ boost flu shot uptake in seniors
Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.
And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.
The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older. 
Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet
The subanalysis in patients with CVD was published online March 5 in Circulation.
“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”
They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.
Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.
In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.
Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”
“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”
“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.
“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.
‘Small but important effect’
In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”
A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”
Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes.
However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.
Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.
First-of-its kind, nationwide pragmatic trial
The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.
They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.
This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.
Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:
- Standard electronic letter
- Standard electronic letter sent at randomization and again 14 days later (repeated letter)
- Depersonalized letter without the recipient’s name
- Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
- Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
- Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)
- Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
- Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
- Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)
The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.
All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022.
The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.
The analyses were done in one randomly selected individual per household.
Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).
These two strategies also improved vaccination rates across major subgroups.
The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.
The seven other letter strategies did not increase flu shot uptake.
Subanalysis in CVD
In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).
The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).
Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”
Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”
NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.
A version of this article first appeared on Medscape.com.
Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.
And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.
The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older.
Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet
The subanalysis in patients with CVD was published online March 5 in Circulation.
“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”
They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.
Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.
In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.
Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”
“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”
“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.
“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.
‘Small but important effect’
In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”
A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”
Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes.
However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.
Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.
First-of-its kind, nationwide pragmatic trial
The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.
They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.
This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.
Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:
- Standard electronic letter
- Standard electronic letter sent at randomization and again 14 days later (repeated letter)
- Depersonalized letter without the recipient’s name
- Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
- Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
- Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)
- Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
- Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
- Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)
The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.
All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022.
The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.
The analyses were done in one randomly selected individual per household.
Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).
These two strategies also improved vaccination rates across major subgroups.
The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.
The seven other letter strategies did not increase flu shot uptake.
Subanalysis in CVD
In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).
The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).
Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”
Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”
NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.
A version of this article first appeared on Medscape.com.
Two types of electronically delivered letter strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination and a repeat reminder letter – increased flu shot uptake, compared with usual care alone, in a national study of seniors in Denmark.
And in a prespecified subanalysis focusing on older adults with cardiovascular disease, these two strategies were also effective in boosting vaccine uptake in those with or without CVD.
The findings are from the Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU) trial, which compared usual care alone with one of nine different electronic letter “behavioral nudge” strategies during the 2022-2023 flu season in people aged 65 years and older.
Niklas Dyrby Johansen, MD, Hospital–Herlev and Gentofte and Copenhagen University, presented the main study findings in a late-breaking clinical trial session at the joint scientific sessions of the American College of Cardiology and the World Heart Federation, and the article was simultaneously published in The Lancet
The subanalysis in patients with CVD was published online March 5 in Circulation.
“Despite modest effect sizes, the results may have important implications when translated to a population level,” Dr. Dyrby Johansen concluded during his presentation. Still, the authors write, “the low-touch (no person-to-person interaction), inexpensive, and highly scalable nature of these electronic letters might have important population-level public health implications.”
They note that, among approximately 63 million Medicare beneficiaries in the United States, a 0.89–percentage point absolute increase in vaccination rate achieved through the most successful electronic letter in NUDGE-FLU, the one highlighting cardiovascular gain, would be expected to lead to 500,000 additional vaccinations and potentially prevent 7,849 illnesses, 4,395 medical visits, 714 hospitalizations, and 66 deaths each year.
Electronic letter systems similar to the one used in this trial are already in place in several European countries, including Sweden, Norway, and Ireland, the researchers note.
In countries such as the United States, where implementing a nationwide government electronic letter system might not be feasible, nudges could be done via email, text message, or other systems, but whether this would be as effective remains to be seen.
Commenting on the findings, David Cho, MD, UCLA Health and chair of the ACC Health Care Innovation Council, commended the researchers on engaging patients with more than a million separate nudges sent out during one flu season, and randomly assigning participants to 10 different types of nudges, calling it “impressive.”
“I think the concept that the nudge is to plant an idea that leads to an action is pretty much the basis of a lot of these health care interventions, which seems like a small way to have a big impact at outcome,” Dr. Cho noted. “The behavioral science aspects of the nudges are also fascinating to me personally, and I think to a lot of the cardiologists in the audience – about how you actually get people to act. I think it’s been a lifelong question for people in general, how do you get people to follow through on an action?”
“So I found the fact that secondary gain from a cardiovascular health standpoint, but also the repeated nudges were sort of simple ways that you could have people take ownership and get their flu vaccination,” he said.
“This is ACC, this is a cardiovascular conference, but the influence of vaccine is not just a primary care problem, it is also directly affecting cardiovascular disease,” Dr. Cho concluded.
‘Small but important effect’
In an accompanying editorial (Lancet. 2023 Mar 5. doi: 10.1016/S0140-6736(23)00453-1), Melissa Stockwell, MD, Columbia University, New York, writes, “The study by Johansen and colleagues highlights the small but still important effect of scalable, digital interventions across an entire at-risk population.”
A difference of 0.89% in the entire study population of over 960,000 adults age 65 years or older would be more than 8,500 additional adults protected, she notes. “That increase is important for a scalable intervention that has a low cost per letter.”
Moreover, “that the cardiovascular gain–framed messages worked best in those who had not been vaccinated in the previous season further highlights the potential impact on a more vaccine-hesitant population,” Dr. Stockwell notes.
However, with the mandatory government electronic notification system in Denmark, “notifications are sent via regular email and SMS message, and recipients log in through a portal or smartphone app to view the letter.” Similar studies in the United States that included this extra step of needing to sign in online have not been effective in older populations.
Another limitation is that the intervention may have a different effect in populations for which there is a digital divide between people with or without Internet access of sufficient data on their mobile phones.
First-of-its kind, nationwide pragmatic trial
The NUDGE-FLU protocol was previously published in the American Heart Journal. NUDGE-FLU is a first-of-its kind nationwide, pragmatic, registry-based, cluster-randomized implementation trial of electronically delivered nudges to increase influenza vaccination uptake, the researchers note.
They identified 964,870 individuals who were 65 years or older (or would turn 65 by Jan. 15, 2023) who lived in one of 691,820 households in Denmark.
This excluded individuals who lived in a nursing home or were exempt from the government’s mandatory electronic letter system that is used for official communications.
Households were randomly assigned 9:1:1:1:1:1:1:1:1:1 to receive usual care alone or to one of nine electronic letter strategies based on different behavioral science approaches to encourage influenza vaccination uptake:
- Standard electronic letter
- Standard electronic letter sent at randomization and again 14 days later (repeated letter)
- Depersonalized letter without the recipient’s name
- Gain-framing nudge (“Vaccinations help end pandemics, like COVID-19 and the flu. Protect yourself and your loved ones.”)
- Loss-framing nudge (“When too few people get vaccinated, pandemics from diseases like COVID-19 and the flu can spread and place you and your loved ones at risk.”)
- Collective-goal nudge (“78% of Danes 65 and above were vaccinated against influenza last year. Help us achieve an even higher goal this year.”)
- Active choice or implementation-intention prompt (“We encourage you to record your appointment time here.”)
- Cardiovascular gain–framing nudge (“In addition to its protection against influenza infection, influenza vaccination also seems to protect against cardiovascular disease such as heart attacks and heart failure.”)
- Expert-authority statement (“I recommend everyone over the age of 65 years to get vaccinated against influenza – Tyra Grove Krause, Executive Vice President, Statens Serum Institut.”)
The electronic letters were sent out Sept. 16, 2022, and the primary endpoint was vaccine receipt on or before Jan. 1, 2023.
All individuals received an informative vaccination encouragement letter from the Danish Health Authority (usual care) delivered via the same electronic letter system during Sept. 17 through Sept. 21, 2022.
The individuals had a mean age of 73.8 years, 51.5% were women, and 27.4% had chronic cardiovascular disease.
The analyses were done in one randomly selected individual per household.
Influenza vaccination rates were significantly higher in the cardiovascular gain–framing nudge group vs. usual care (81.00% vs. 80.12%; difference, 0.89 percentage points; P < .0001) and in the repeat-letter group vs. usual care (80.85% vs 80.12%; difference, 0.73 percentage points; P = .0006).
These two strategies also improved vaccination rates across major subgroups.
The cardiovascular gain–framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season.
The seven other letter strategies did not increase flu shot uptake.
Subanalysis in CVD
In the prespecified subanalysis of the NUDGE-FLU trial of patients aged 65 and older that focused on patients with CVD, Daniel Modin, MB, and colleagues report that 83.1% of patients with CVD vs. 79.2% of patients without CVD received influenza vaccination within the requested time (P < .0001).
The two nudging strategies – a letter highlighting potential cardiovascular benefits of influenza vaccination or a repeat letter – that were effective in boosting flu shot rates in the main analysis were also effective in all major CVD subgroups (ischemic heart disease, pulmonary heart disease, heart failure, atrial fibrillation, cerebrovascular disease, atherosclerotic CVD, embolic or thrombotic disease, and congenital heart disease).
Despite strong guideline endorsement, “influenza vaccination rates remain suboptimal in patients with high-risk cardiovascular disease,” Dr. Morin and colleagues write, possibly because of “insufficient knowledge among patients and providers of potential clinical benefits, concerns about vaccine safety, and other forms of vaccine hesitancy.”
Their findings suggest that “select digital behaviorally informed nudges delivered in advance of vaccine availability might be utilized to increase influenza vaccinate uptake in individuals with cardiovascular disease.”
NUDGE-HF was funded by Sanofi. Dr. Johansen and Dr. Modin have no disclosures. The disclosures of the other authors are listed with the articles. Dr. Stockwell has no disclosures.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
BIOVASC: Immediate complete revascularization beneficial in ACS
Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.
In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.
The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.
“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”
They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”
The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.
“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.
Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.
The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.
They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).
The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.
The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.
Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.
In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use.
In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.
Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).
Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).
However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).
One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%) and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).
The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.
Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.
High rate of MI in staged group
Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”
She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.
He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”
He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.”
Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.
Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”
Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question “Can we fix it all at once?” and the results suggest “Yes, we can.”
He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”
But he pointed out that for some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.
CABG still needs to be considered
In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease.
They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”
But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.
They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”
The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.
A version of this article first appeared on Medscape.com.
Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.
In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.
The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.
“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”
They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”
The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.
“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.
Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.
The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.
They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).
The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.
The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.
Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.
In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use.
In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.
Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).
Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).
However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).
One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%) and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).
The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.
Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.
High rate of MI in staged group
Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”
She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.
He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”
He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.”
Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.
Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”
Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question “Can we fix it all at once?” and the results suggest “Yes, we can.”
He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”
But he pointed out that for some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.
CABG still needs to be considered
In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease.
They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”
But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.
They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”
The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.
A version of this article first appeared on Medscape.com.
Immediate complete revascularization during the index procedure might become the new treatment paradigm in patients with an acute coronary syndrome (ACS) and multivessel disease, based on results of the BIOVASC trial.
In the trial, in patients presenting with ACS and multivessel disease, immediate complete revascularization was noninferior to staged complete revascularization for the primary composite outcome and was associated with a reduction in myocardial infarction and unplanned ischemia-driven revascularization.
The BIOVASC trial was presented on March 5 by Roberto Diletti, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The study was simultaneously published online in The Lancet.
“We did not detect an early safety signal against an immediate complete revascularization strategy,” the authors state in the Lancet paper, adding: “Treating physicians should not be concerned about potential risks associated with immediate treatment of nonculprit lesions.”
They note, “This strategy might be particularly effective in patients with only two-vessel disease and reasonably simple lesions, with a high likelihood of procedural success without excessive use of radiation, contrast dye, or other resources.”
The trial also showed a shorter hospital stay with an immediate complete revascularization strategy.
“Immediate complete revascularization might have potential health economic benefits because of the lower rate of myocardial infarction, including spontaneous myocardial infarction, and unplanned revascularizations, and the shorter overall hospital stay,” the researchers conclude.
Introducing his presentation, Dr. Diletti explained that multiple studies have established the clinical benefit of complete coronary revascularization as compared with exclusive reperfusion of the culprit lesion, but the optimal timing for nonculprit lesion revascularization remains unclear.
The BIOVASC trial, conducted in Belgium, Italy, the Netherlands, and Spain, involved 1,525 patients with ST-segment elevation MI (STEMI) or non-STEMI ACS and multivessel coronary artery disease with a clearly identifiable culprit lesion.
They were randomly assigned to undergo immediate complete revascularization (percutaneous coronary intervention [PCI] of the culprit lesion first, followed by other nonculprit lesions deemed to be clinically significant by the operator during the index procedure) or staged complete revascularization (PCI of only the culprit lesion during the index procedure and PCI of all nonculprit lesions deemed to be clinically significant within 6 weeks after the index procedure).
The primary outcome was the composite of all-cause mortality, MI, any unplanned ischemia-driven revascularization, or cerebrovascular events at 1 year after the index procedure.
The trial had a noninferiority design, with noninferiority of immediate to staged complete revascularization considered to be met if the upper boundary of the 95% confidence interval of the hazard ratio for the primary outcome did not exceed 1.39.
Among the trial population, 40% of patients had STEMI, 52% had non-STEMI, and 8% had unstable angina.
In the immediate complete revascularization group, 16 patients did not receive complete revascularization during the index procedure primarily because of prolonged procedure time, procedural complexity, or excessive contrast dye use.
In the staged group, 30% of patients underwent all subsequent procedures during the index hospitalization.
Results showed that the primary composite outcome at 1 year occurred in 7.6% of the immediate revascularization group and in 9.4% of the staged group, meeting the noninferiority criteria (HR, 0.78; 95% CI, 0.55-1.11; P for noninferiority = .0011).
Superiority of the immediate over the staged complete revascularization strategy was not met at 1-year follow-up (P for superiority = .17).
However, in the prespecified analysis of clinical events at 30 days after the index procedure, immediate complete revascularization was superior to staged revascularization in terms of the composite primary outcome (2.2% vs. 5.8%; HR, 0.38; P for superiority = .0007).
One-year results showed no difference in all-cause death between the two groups, but the immediate complete revascularization group appeared to have a reduction in MI (1.9% vs. 4.5%) and fewer unplanned ischemia-driven revascularizations (4.2% vs. 6.7%).
The difference in MI was mainly driven by spontaneous MIs (not procedure related) that predominantly occurred in the time window between the index procedure and the planned date for the staged intervention, and an originally nonculprit lesion was identified as the cause for these events in almost all cases.
Subgroup analysis showed similar results across the patient population, including age, sex, and STEMI vs. non-STEMI presentation.
High rate of MI in staged group
Discussant of the study at the ACC session, Dipti Itchhaporia, MD, University of California, Irvine, said this was a “very important trial.”
She expressed surprise over the “remarkably high rate” of MI in the staged procedure group and asked Dr. Diletti why that might have occurred.
He responded that the operator may have misjudged the culprit lesion or that patients with ACS may have multiple unstable plaques and “treating the culprit lesion alone does not do the job.”
He added: “We need to look at the data more thoroughly to better understand this, but in both scenarios, immediate complete revascularization would prevent these events.”
Dr. Itchhaporia also pointed out a low rate of functional imaging used in the study.
Dr. Diletti replied that this reflected current European practice, but he acknowledged that, “in my opinion this reduces our ability to detect the culprit lesion.”
Commenting at an ACC press conference, David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., said the trial poses the question “Can we fix it all at once?” and the results suggest “Yes, we can.”
He said this approach had the advantage of removing any uncertainly as to which was the culprit lesion. “We just fix everything – leave no blockage behind.”
But he pointed out that for some patients this may not be appropriate, such as those with compromised renal function, in whom excessive amounts of contrast material should be avoided.
CABG still needs to be considered
In a comment accompanying the Lancet publication, Tobias Pustjens, MD, Pieter Vriesendorp, MD, and Arnoud W.J. van’t Hof, MD, Cardiovascular Research Institute Maastricht (the Netherlands), note that more than half of the patients presenting with an ACS have multivessel coronary disease.
They say the trial results suggest that “pursuing an immediate complete revascularisation strategy, especially in times of reduced hospital capacity and staff scarcity, not only benefits the individual patient in clinical outcomes but can also safely reduce the pressure on health care systems.”
But they also point out that the possibility of coronary artery bypass grafting (CABG) should not be omitted, and that CABG is still the treatment of choice in patients with diabetes or complex coronary artery disease.
They conclude: “The results of the BIOVASC study move clinical practice forward from culprit-only to an immediate, complete revascularisation strategy. … However, further fine tuning of this treatment strategy to substantiate a role for intracoronary physiology assessment, intracoronary imaging, and guidance of the heart team decision is needed.”
The BIOVASC trial was supported by an unrestricted research grant from Biotronik AG. Dr. Diletti has received institutional research grants from Biotronik, Medtronic, ACIST Medical Systems, and Boston Scientific. Dr. van’t Hof has received institutional research grants from Biotronik.
A version of this article first appeared on Medscape.com.
FROM ACS 2023
When intravascular imaging guides complex PCI, MACE risk is lowered
NEW ORLEANS – In patients undergoing percutaneous intervention (PCI) for complex coronary lesions, intravascular imaging is superior to angiography for reducing the risk of target lesion failure (TLF), according to results of a randomized trial.
Previous studies have produced the same conclusion, but the advantage was demonstrated this time in a multicenter well-powered randomized trial, principal investigator Joo Yong Hahn, MD, PhD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The earlier studies “were not definitive,” said Dr. Hahn, pointing out that even those that were randomized lacked sufficient duration of follow-up or were not inclusive of a broad array of types of complex PCI.
In this clinical outcomes–driven study, called RENOVATE-COMPLEX-PCI, 1,639 patients undergoing complex PCI in 20 South Korean treatment centers were randomized in a 2:1 ratio to PCI guided by intravascular imaging or angiography alone. There were nine types of complex PCI eligible for trial entry, including bifurcated lesions, long lesions (expected stent length ≥ 38 mm), total coronary occlusions, lesions requiring multiple stents, severely calcified lesions, and lesions in multiple vessels.
Intravascular imaging in the experimental arm could be performed with either intravascular ultrasound (IVUS) or optical coherence tomography (OCT), according to Dr. Hahn. Because one might be better than the other for specific patient and lesions characteristics, the type of intravascular imaging in the experimental group was selected at the discretion of the treating investigator, reported Dr. Hahn, of the Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University, Seoul.
The primary TLF endpoint was defined as death from cardiovascular causes, target-vessel-related MI, and target-vessel revascularization.
Risk reduction of > 35% observed
After a median of 2.1 years of follow-up, the lower TLF incidence in the group with PCI guided by intravascular imaging (7.7% vs. 12.3%) translated into a 36% reduction in risk (hazard ratio, 0.64; P = .008).
Intravascular imaging was associated with a numerical reduction of each component of TLF. In the case of death from cardiovascular causes, the confidence interval remained below the line of unity (HR 0.47; 95% CI, 0.24-0.93).
Although this was not true for target vessel–related MI (HR, 0.74, 95% CI, 0.45-1.22) or target vessel revascularization (HR, 0.66; 95% CI, 0.36-1.22), it was also true of TLF without procedural-related MI (HR, 0.59; 95% CI, 0.39-0.90) and cardiac death or target vessel–related MI (HR, 0.63; 95% CI, 0.42-0.93).
With few exceptions, all of the secondary outcomes “moved in the right direction” to favor intravascular imaging, including death from any cause (HR 0.71, 95% CI, 0.44-1.15), reported Dr. Hahn, who noted that the results were simultaneously published in the New England Journal of Medicine.
When compared, there were no major baseline differences in the 1,092 patients with PCI guided by intravascular imaging relative to the 547 guided by angiography. The median age was 65.5 years. Most (79%) were male. About half (51%) had an acute coronary syndrome and the remainder had stable ischemic heart disease. The proportions of patients with hypertension (61%), dyslipidemia (51%), and diabetes (38%) were substantial. About 18% of patients were current smokers, 24% had a previous PCI, and 7% had a previous MI.
Stent types were similar in the two groups, and they were delivered by radial access. Procedural success was achieved in about 98% of both groups. Almost all patients were discharged on a statin, aspirin, and a P2Y12 inhibitor, and the other specific postprocedural medications were comparable in the two groups.
Advantage of intravascular imaging consistent
Of the complex lesions, most (55%) had diffuse long coronary artery lesions, but other types of complex PCI, including bifurcated lesions (22%), chronic total occlusions (20%), severely calcified lesions (14%), and ostial lesions of a major coronary artery (15%) were represented. Across these lesion types, intravascular imaging was favored over angiography for TLF at least numerically. The potential exceptions were lesions requiring at least three stents (HR, 1.24; 95% CI, 0.49-3.18), but confidence intervals were wide.
The trial was unblinded, but Dr. Hahn reported that imaging analyses were performed at a core laboratory and events were adjudicated by a committee with members unaware of trial group assignments.
One unanswered question is cost. Because intravascular imaging adds cost to PCI relative to angiography, cost-effectiveness analyses are needed to provide context for the decision to use this approach in all complex PCI patients. These analyses are planned.
Based on the consistency of these trial results with previous studies, almost all of which showed the same thing, “the intravascular imaging world has spoken,” said Wayne B. Batchelor, MD, director of interventional cardiology, Inova Heart and Vascular Institute, Fairfax, Va. “The only question now is when will the interventional community is going to listen.”
Dr. Batchelor predicted that these data will change the mindset of many practitioners “to shift the debate to why not do it [intravascular imaging] from why do it.”
“Only about 15% of PCI is performed with intravascular imaging in the United States, and these [results] argue that this number needs to go up,” Dr. Batchelor said. Although he said there are technical reasons, such as diffuse lesions or small vessels, that prevent intravascular imaging from being used in every complex patient, he suggested the data are compelling.
“If you apply this to the one million patients undergoing PCI in the United States, this will translate potentially into tens of thousands of patients protected from the TVF endpoint,” Dr. Batchelor said.
Dr. Hahn reports no potential conflicts of interest, but this investigator-initiated trial received funding from Boston Scientific and Abbott Vascular. Dr. Batchelor reports financial relationships with Abbott Vascular, Boston Scientific, Idorsia, Medtronic, and V-Wave Medical.
NEW ORLEANS – In patients undergoing percutaneous intervention (PCI) for complex coronary lesions, intravascular imaging is superior to angiography for reducing the risk of target lesion failure (TLF), according to results of a randomized trial.
Previous studies have produced the same conclusion, but the advantage was demonstrated this time in a multicenter well-powered randomized trial, principal investigator Joo Yong Hahn, MD, PhD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The earlier studies “were not definitive,” said Dr. Hahn, pointing out that even those that were randomized lacked sufficient duration of follow-up or were not inclusive of a broad array of types of complex PCI.
In this clinical outcomes–driven study, called RENOVATE-COMPLEX-PCI, 1,639 patients undergoing complex PCI in 20 South Korean treatment centers were randomized in a 2:1 ratio to PCI guided by intravascular imaging or angiography alone. There were nine types of complex PCI eligible for trial entry, including bifurcated lesions, long lesions (expected stent length ≥ 38 mm), total coronary occlusions, lesions requiring multiple stents, severely calcified lesions, and lesions in multiple vessels.
Intravascular imaging in the experimental arm could be performed with either intravascular ultrasound (IVUS) or optical coherence tomography (OCT), according to Dr. Hahn. Because one might be better than the other for specific patient and lesions characteristics, the type of intravascular imaging in the experimental group was selected at the discretion of the treating investigator, reported Dr. Hahn, of the Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University, Seoul.
The primary TLF endpoint was defined as death from cardiovascular causes, target-vessel-related MI, and target-vessel revascularization.
Risk reduction of > 35% observed
After a median of 2.1 years of follow-up, the lower TLF incidence in the group with PCI guided by intravascular imaging (7.7% vs. 12.3%) translated into a 36% reduction in risk (hazard ratio, 0.64; P = .008).
Intravascular imaging was associated with a numerical reduction of each component of TLF. In the case of death from cardiovascular causes, the confidence interval remained below the line of unity (HR 0.47; 95% CI, 0.24-0.93).
Although this was not true for target vessel–related MI (HR, 0.74, 95% CI, 0.45-1.22) or target vessel revascularization (HR, 0.66; 95% CI, 0.36-1.22), it was also true of TLF without procedural-related MI (HR, 0.59; 95% CI, 0.39-0.90) and cardiac death or target vessel–related MI (HR, 0.63; 95% CI, 0.42-0.93).
With few exceptions, all of the secondary outcomes “moved in the right direction” to favor intravascular imaging, including death from any cause (HR 0.71, 95% CI, 0.44-1.15), reported Dr. Hahn, who noted that the results were simultaneously published in the New England Journal of Medicine.
When compared, there were no major baseline differences in the 1,092 patients with PCI guided by intravascular imaging relative to the 547 guided by angiography. The median age was 65.5 years. Most (79%) were male. About half (51%) had an acute coronary syndrome and the remainder had stable ischemic heart disease. The proportions of patients with hypertension (61%), dyslipidemia (51%), and diabetes (38%) were substantial. About 18% of patients were current smokers, 24% had a previous PCI, and 7% had a previous MI.
Stent types were similar in the two groups, and they were delivered by radial access. Procedural success was achieved in about 98% of both groups. Almost all patients were discharged on a statin, aspirin, and a P2Y12 inhibitor, and the other specific postprocedural medications were comparable in the two groups.
Advantage of intravascular imaging consistent
Of the complex lesions, most (55%) had diffuse long coronary artery lesions, but other types of complex PCI, including bifurcated lesions (22%), chronic total occlusions (20%), severely calcified lesions (14%), and ostial lesions of a major coronary artery (15%) were represented. Across these lesion types, intravascular imaging was favored over angiography for TLF at least numerically. The potential exceptions were lesions requiring at least three stents (HR, 1.24; 95% CI, 0.49-3.18), but confidence intervals were wide.
The trial was unblinded, but Dr. Hahn reported that imaging analyses were performed at a core laboratory and events were adjudicated by a committee with members unaware of trial group assignments.
One unanswered question is cost. Because intravascular imaging adds cost to PCI relative to angiography, cost-effectiveness analyses are needed to provide context for the decision to use this approach in all complex PCI patients. These analyses are planned.
Based on the consistency of these trial results with previous studies, almost all of which showed the same thing, “the intravascular imaging world has spoken,” said Wayne B. Batchelor, MD, director of interventional cardiology, Inova Heart and Vascular Institute, Fairfax, Va. “The only question now is when will the interventional community is going to listen.”
Dr. Batchelor predicted that these data will change the mindset of many practitioners “to shift the debate to why not do it [intravascular imaging] from why do it.”
“Only about 15% of PCI is performed with intravascular imaging in the United States, and these [results] argue that this number needs to go up,” Dr. Batchelor said. Although he said there are technical reasons, such as diffuse lesions or small vessels, that prevent intravascular imaging from being used in every complex patient, he suggested the data are compelling.
“If you apply this to the one million patients undergoing PCI in the United States, this will translate potentially into tens of thousands of patients protected from the TVF endpoint,” Dr. Batchelor said.
Dr. Hahn reports no potential conflicts of interest, but this investigator-initiated trial received funding from Boston Scientific and Abbott Vascular. Dr. Batchelor reports financial relationships with Abbott Vascular, Boston Scientific, Idorsia, Medtronic, and V-Wave Medical.
NEW ORLEANS – In patients undergoing percutaneous intervention (PCI) for complex coronary lesions, intravascular imaging is superior to angiography for reducing the risk of target lesion failure (TLF), according to results of a randomized trial.
Previous studies have produced the same conclusion, but the advantage was demonstrated this time in a multicenter well-powered randomized trial, principal investigator Joo Yong Hahn, MD, PhD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The earlier studies “were not definitive,” said Dr. Hahn, pointing out that even those that were randomized lacked sufficient duration of follow-up or were not inclusive of a broad array of types of complex PCI.
In this clinical outcomes–driven study, called RENOVATE-COMPLEX-PCI, 1,639 patients undergoing complex PCI in 20 South Korean treatment centers were randomized in a 2:1 ratio to PCI guided by intravascular imaging or angiography alone. There were nine types of complex PCI eligible for trial entry, including bifurcated lesions, long lesions (expected stent length ≥ 38 mm), total coronary occlusions, lesions requiring multiple stents, severely calcified lesions, and lesions in multiple vessels.
Intravascular imaging in the experimental arm could be performed with either intravascular ultrasound (IVUS) or optical coherence tomography (OCT), according to Dr. Hahn. Because one might be better than the other for specific patient and lesions characteristics, the type of intravascular imaging in the experimental group was selected at the discretion of the treating investigator, reported Dr. Hahn, of the Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University, Seoul.
The primary TLF endpoint was defined as death from cardiovascular causes, target-vessel-related MI, and target-vessel revascularization.
Risk reduction of > 35% observed
After a median of 2.1 years of follow-up, the lower TLF incidence in the group with PCI guided by intravascular imaging (7.7% vs. 12.3%) translated into a 36% reduction in risk (hazard ratio, 0.64; P = .008).
Intravascular imaging was associated with a numerical reduction of each component of TLF. In the case of death from cardiovascular causes, the confidence interval remained below the line of unity (HR 0.47; 95% CI, 0.24-0.93).
Although this was not true for target vessel–related MI (HR, 0.74, 95% CI, 0.45-1.22) or target vessel revascularization (HR, 0.66; 95% CI, 0.36-1.22), it was also true of TLF without procedural-related MI (HR, 0.59; 95% CI, 0.39-0.90) and cardiac death or target vessel–related MI (HR, 0.63; 95% CI, 0.42-0.93).
With few exceptions, all of the secondary outcomes “moved in the right direction” to favor intravascular imaging, including death from any cause (HR 0.71, 95% CI, 0.44-1.15), reported Dr. Hahn, who noted that the results were simultaneously published in the New England Journal of Medicine.
When compared, there were no major baseline differences in the 1,092 patients with PCI guided by intravascular imaging relative to the 547 guided by angiography. The median age was 65.5 years. Most (79%) were male. About half (51%) had an acute coronary syndrome and the remainder had stable ischemic heart disease. The proportions of patients with hypertension (61%), dyslipidemia (51%), and diabetes (38%) were substantial. About 18% of patients were current smokers, 24% had a previous PCI, and 7% had a previous MI.
Stent types were similar in the two groups, and they were delivered by radial access. Procedural success was achieved in about 98% of both groups. Almost all patients were discharged on a statin, aspirin, and a P2Y12 inhibitor, and the other specific postprocedural medications were comparable in the two groups.
Advantage of intravascular imaging consistent
Of the complex lesions, most (55%) had diffuse long coronary artery lesions, but other types of complex PCI, including bifurcated lesions (22%), chronic total occlusions (20%), severely calcified lesions (14%), and ostial lesions of a major coronary artery (15%) were represented. Across these lesion types, intravascular imaging was favored over angiography for TLF at least numerically. The potential exceptions were lesions requiring at least three stents (HR, 1.24; 95% CI, 0.49-3.18), but confidence intervals were wide.
The trial was unblinded, but Dr. Hahn reported that imaging analyses were performed at a core laboratory and events were adjudicated by a committee with members unaware of trial group assignments.
One unanswered question is cost. Because intravascular imaging adds cost to PCI relative to angiography, cost-effectiveness analyses are needed to provide context for the decision to use this approach in all complex PCI patients. These analyses are planned.
Based on the consistency of these trial results with previous studies, almost all of which showed the same thing, “the intravascular imaging world has spoken,” said Wayne B. Batchelor, MD, director of interventional cardiology, Inova Heart and Vascular Institute, Fairfax, Va. “The only question now is when will the interventional community is going to listen.”
Dr. Batchelor predicted that these data will change the mindset of many practitioners “to shift the debate to why not do it [intravascular imaging] from why do it.”
“Only about 15% of PCI is performed with intravascular imaging in the United States, and these [results] argue that this number needs to go up,” Dr. Batchelor said. Although he said there are technical reasons, such as diffuse lesions or small vessels, that prevent intravascular imaging from being used in every complex patient, he suggested the data are compelling.
“If you apply this to the one million patients undergoing PCI in the United States, this will translate potentially into tens of thousands of patients protected from the TVF endpoint,” Dr. Batchelor said.
Dr. Hahn reports no potential conflicts of interest, but this investigator-initiated trial received funding from Boston Scientific and Abbott Vascular. Dr. Batchelor reports financial relationships with Abbott Vascular, Boston Scientific, Idorsia, Medtronic, and V-Wave Medical.
AT ACC 2023
Viability-guided PCI doubted in stable severe CAD: REVIVED-BCIS2
There is no magical amount of viable ventricular myocardium that makes percutaneous coronary intervention (PCI) an effective addition to optimal medical therapy (OMT) in stable patients with coronary disease and poor ventricular function, suggests an analysis from a major trial.
The REVIVED-BCIS2 trial recently made waves when it showed no clinical advantage from adding PCI to OMT in stable patients with severe ischemic left ventricular (LV) dysfunction. All the patients had shown viable but dysfunctional myocardium that could potentially be revascularized.
But in a secondary analysis, extent of such hibernating heart muscle was not a good predictor of clinical outcomes, which in the trial meant death from any cause or hospitalization for heart failure (HHF).
Burden of myocardial scar tissue, however, turned out to be a potent predictor of clinical risk regardless of coronary disease severity or even LV ejection fraction (LVEF).
Because myocardial viability tracks poorly with outcomes in patients like those enrolled in the trial, as the new analysis suggests, conventional viability testing isn’t an effective guide for deciding who among them should get PCI, Divaka Perera, MD, said in an interview.
Dr. Perera, of King’s College London and the trial’s principal investigator, presented the REVIVED-BCIS2 secondary results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation..
Viability testing for ischemia, he noted, is often used in practice to aid revascularization decisions. As the extent of myocardial viability can vary, it’s been asked – ever since the trial’s primary publication – whether there could be “a sweet spot or Goldilocks zone of viability that would allow prediction of which patients will do better with PCI compared to medical therapy,” Dr. Perera said. “The trial conclusively shows that is not the case.”
That the extent of hibernating myocardium, which is viable but dysfunctional, didn’t predict clinical outcomes or LV functional recovery “is disruptive of current practice and challenges a view that’s been held for decades.”
The trial’s 700 patients receiving OMT had been randomly assigned to undergo PCI or not, 347 and 353 patients, respectively. About 12% of the total were women.
About 70% of patients underwent baseline and follow-up myocardial viability testing using cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement for estimation of scar burden; the remainder underwent dobutamine-stress echocardiography. All imaging assessments were conducted at independent core laboratories, Dr. Perera reported.
Extent of myocardial viability was defined three ways: volume of hibernating heart muscle, total volume of viable myocardium, and scar burden – all expressed as a percentage of total LV volume.
Every 10% increment in LV volume found to be hibernating related to a hazard ratio of 0.98 (95% confidence interval, 0.93-1.04; P = .56) for all-cause mortality or HHF at a median of 3.3 years. The analysis was adjusted for age, sex, diabetes, previous HHF, chronic renal failure, extent of CAD, type of viability testing, and baseline LVEF.
The adjusted HR for the same percentage increment in total viable myocardium was marginally significantly reduced at 0.93 (95% CI, 0.87-1.00; P = .048).
The correlation with scar burden was stronger. The adjusted composite-endpoint HR per 10% increment in scar burden was significantly increased at 1.18 (95% CI, 1.04-1.33; P = .009).
Extent of myocardial viability by tertiles, regardless of viability definition, did not highlight any group with a reduced risk for death or HHF, or group with better LV functional recovery, from OMT plus PCI, compared with OMT alone.
The findings appear to suggest that scar burden, but not extent of viability as it’s usually measured, may effectively guide PCI decisions in such patients, Dr. Perera said.
“I would say that viability testing as we understand it now, based on the paradigm of hibernating myocardium, is very useful,” he said, “but that is not the only information we can get from a viability test.”
Scar burden can also be determined from the same tests but isn’t typically looked at. “We’re actually collecting this information but not using it,” Dr. Perera said. “When we do, it is really powerfully predictive” of both clinical outcomes and LV functional recovery. “Yet scar burden is not in any of the guidelines for stratifying risk.”
REVIVED-BCIS2 was funded by the National Institute for Health and Care Research Health Technology Assessment Program. Dr. Perera had no disclosures.
A version of this article first appeared on Medscape.com.
There is no magical amount of viable ventricular myocardium that makes percutaneous coronary intervention (PCI) an effective addition to optimal medical therapy (OMT) in stable patients with coronary disease and poor ventricular function, suggests an analysis from a major trial.
The REVIVED-BCIS2 trial recently made waves when it showed no clinical advantage from adding PCI to OMT in stable patients with severe ischemic left ventricular (LV) dysfunction. All the patients had shown viable but dysfunctional myocardium that could potentially be revascularized.
But in a secondary analysis, extent of such hibernating heart muscle was not a good predictor of clinical outcomes, which in the trial meant death from any cause or hospitalization for heart failure (HHF).
Burden of myocardial scar tissue, however, turned out to be a potent predictor of clinical risk regardless of coronary disease severity or even LV ejection fraction (LVEF).
Because myocardial viability tracks poorly with outcomes in patients like those enrolled in the trial, as the new analysis suggests, conventional viability testing isn’t an effective guide for deciding who among them should get PCI, Divaka Perera, MD, said in an interview.
Dr. Perera, of King’s College London and the trial’s principal investigator, presented the REVIVED-BCIS2 secondary results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation..
Viability testing for ischemia, he noted, is often used in practice to aid revascularization decisions. As the extent of myocardial viability can vary, it’s been asked – ever since the trial’s primary publication – whether there could be “a sweet spot or Goldilocks zone of viability that would allow prediction of which patients will do better with PCI compared to medical therapy,” Dr. Perera said. “The trial conclusively shows that is not the case.”
That the extent of hibernating myocardium, which is viable but dysfunctional, didn’t predict clinical outcomes or LV functional recovery “is disruptive of current practice and challenges a view that’s been held for decades.”
The trial’s 700 patients receiving OMT had been randomly assigned to undergo PCI or not, 347 and 353 patients, respectively. About 12% of the total were women.
About 70% of patients underwent baseline and follow-up myocardial viability testing using cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement for estimation of scar burden; the remainder underwent dobutamine-stress echocardiography. All imaging assessments were conducted at independent core laboratories, Dr. Perera reported.
Extent of myocardial viability was defined three ways: volume of hibernating heart muscle, total volume of viable myocardium, and scar burden – all expressed as a percentage of total LV volume.
Every 10% increment in LV volume found to be hibernating related to a hazard ratio of 0.98 (95% confidence interval, 0.93-1.04; P = .56) for all-cause mortality or HHF at a median of 3.3 years. The analysis was adjusted for age, sex, diabetes, previous HHF, chronic renal failure, extent of CAD, type of viability testing, and baseline LVEF.
The adjusted HR for the same percentage increment in total viable myocardium was marginally significantly reduced at 0.93 (95% CI, 0.87-1.00; P = .048).
The correlation with scar burden was stronger. The adjusted composite-endpoint HR per 10% increment in scar burden was significantly increased at 1.18 (95% CI, 1.04-1.33; P = .009).
Extent of myocardial viability by tertiles, regardless of viability definition, did not highlight any group with a reduced risk for death or HHF, or group with better LV functional recovery, from OMT plus PCI, compared with OMT alone.
The findings appear to suggest that scar burden, but not extent of viability as it’s usually measured, may effectively guide PCI decisions in such patients, Dr. Perera said.
“I would say that viability testing as we understand it now, based on the paradigm of hibernating myocardium, is very useful,” he said, “but that is not the only information we can get from a viability test.”
Scar burden can also be determined from the same tests but isn’t typically looked at. “We’re actually collecting this information but not using it,” Dr. Perera said. “When we do, it is really powerfully predictive” of both clinical outcomes and LV functional recovery. “Yet scar burden is not in any of the guidelines for stratifying risk.”
REVIVED-BCIS2 was funded by the National Institute for Health and Care Research Health Technology Assessment Program. Dr. Perera had no disclosures.
A version of this article first appeared on Medscape.com.
There is no magical amount of viable ventricular myocardium that makes percutaneous coronary intervention (PCI) an effective addition to optimal medical therapy (OMT) in stable patients with coronary disease and poor ventricular function, suggests an analysis from a major trial.
The REVIVED-BCIS2 trial recently made waves when it showed no clinical advantage from adding PCI to OMT in stable patients with severe ischemic left ventricular (LV) dysfunction. All the patients had shown viable but dysfunctional myocardium that could potentially be revascularized.
But in a secondary analysis, extent of such hibernating heart muscle was not a good predictor of clinical outcomes, which in the trial meant death from any cause or hospitalization for heart failure (HHF).
Burden of myocardial scar tissue, however, turned out to be a potent predictor of clinical risk regardless of coronary disease severity or even LV ejection fraction (LVEF).
Because myocardial viability tracks poorly with outcomes in patients like those enrolled in the trial, as the new analysis suggests, conventional viability testing isn’t an effective guide for deciding who among them should get PCI, Divaka Perera, MD, said in an interview.
Dr. Perera, of King’s College London and the trial’s principal investigator, presented the REVIVED-BCIS2 secondary results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation..
Viability testing for ischemia, he noted, is often used in practice to aid revascularization decisions. As the extent of myocardial viability can vary, it’s been asked – ever since the trial’s primary publication – whether there could be “a sweet spot or Goldilocks zone of viability that would allow prediction of which patients will do better with PCI compared to medical therapy,” Dr. Perera said. “The trial conclusively shows that is not the case.”
That the extent of hibernating myocardium, which is viable but dysfunctional, didn’t predict clinical outcomes or LV functional recovery “is disruptive of current practice and challenges a view that’s been held for decades.”
The trial’s 700 patients receiving OMT had been randomly assigned to undergo PCI or not, 347 and 353 patients, respectively. About 12% of the total were women.
About 70% of patients underwent baseline and follow-up myocardial viability testing using cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement for estimation of scar burden; the remainder underwent dobutamine-stress echocardiography. All imaging assessments were conducted at independent core laboratories, Dr. Perera reported.
Extent of myocardial viability was defined three ways: volume of hibernating heart muscle, total volume of viable myocardium, and scar burden – all expressed as a percentage of total LV volume.
Every 10% increment in LV volume found to be hibernating related to a hazard ratio of 0.98 (95% confidence interval, 0.93-1.04; P = .56) for all-cause mortality or HHF at a median of 3.3 years. The analysis was adjusted for age, sex, diabetes, previous HHF, chronic renal failure, extent of CAD, type of viability testing, and baseline LVEF.
The adjusted HR for the same percentage increment in total viable myocardium was marginally significantly reduced at 0.93 (95% CI, 0.87-1.00; P = .048).
The correlation with scar burden was stronger. The adjusted composite-endpoint HR per 10% increment in scar burden was significantly increased at 1.18 (95% CI, 1.04-1.33; P = .009).
Extent of myocardial viability by tertiles, regardless of viability definition, did not highlight any group with a reduced risk for death or HHF, or group with better LV functional recovery, from OMT plus PCI, compared with OMT alone.
The findings appear to suggest that scar burden, but not extent of viability as it’s usually measured, may effectively guide PCI decisions in such patients, Dr. Perera said.
“I would say that viability testing as we understand it now, based on the paradigm of hibernating myocardium, is very useful,” he said, “but that is not the only information we can get from a viability test.”
Scar burden can also be determined from the same tests but isn’t typically looked at. “We’re actually collecting this information but not using it,” Dr. Perera said. “When we do, it is really powerfully predictive” of both clinical outcomes and LV functional recovery. “Yet scar burden is not in any of the guidelines for stratifying risk.”
REVIVED-BCIS2 was funded by the National Institute for Health and Care Research Health Technology Assessment Program. Dr. Perera had no disclosures.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Bempedoic acid cuts CV events in statin-intolerant patients: CLEAR Outcomes
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM ACC 2023