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Does new heart transplant method challenge definition of death?
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant. 
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
The relatively recent innovation of heart transplantation after circulatory death of the donor is increasing the number of donor hearts available and leading to many more lives on the heart transplant waiting list being saved. Experts agree it’s a major and very welcome advance in medicine.
However, some of the processes involved in one approach to donation after circulatory death has raised ethical concerns and questions about whether they violate the “dead donor rule” – a principle that requires patients be declared dead before removal of life-sustaining organs for transplant.
Experts in the fields of transplantation and medical ethics have yet to reach consensus, causing problems for the transplant community, who worry that this could cause a loss of confidence in the entire transplant process.
A new pathway for heart transplantation
The traditional approach to transplantation is to retrieve organs from a donor who has been declared brain dead, known as “donation after brain death (DBD).” These patients have usually suffered a catastrophic brain injury but survived to get to intensive care.
As the brain swells because of injury, it becomes evident that all brain function is lost, and the patient is declared brain dead. However, breathing is maintained by the ventilator and the heart is still beating. Because the organs are being oxygenated, there is no immediate rush to retrieve the organs and the heart can be evaluated for its suitability for transplant in a calm and methodical way before it is removed.
However, there is a massive shortage of organs, especially hearts, partially because of the limited number of donors who are declared brain dead in that setting.
In recent years, another pathway for organ transplantation has become available: “donation after circulatory death (DCD).” These patients also have suffered a catastrophic brain injury considered to be nonsurvivable, but unlike the DBD situation, the brain still has some function, so the patient does not meet the criteria for brain death.
Still, because the patient is considered to have no chance of a meaningful recovery, the family often recognizes the futility of treatment and agrees to the withdrawal of life support. When this happens, the heart normally stops beating after a period of time. There is then a “stand-off time” – normally 5 minutes – after which death is declared and the organs can be removed.
The difficulty with this approach, however, is that because the heart has been stopped, it has been deprived of oxygen, potentially causing injury. While DCD has been practiced for several years to retrieve organs such as the kidney, liver, lungs, and pancreas, the heart is more difficult as it is more susceptible to oxygen deprivation. And for the heart to be assessed for transplant suitability, it should ideally be beating, so it has to be reperfused and restarted quickly after death has been declared.
For many years it was thought the oxygen deprivation that occurs after circulatory death would be too much to provide a functional organ. But researchers in the United Kingdom and Australia developed techniques to overcome this problem, and early DCD heart transplants took place in 2014 in Australia, and in 2015 in the United Kingdom.
Heart transplantation after circulatory death has now become a routine part of the transplant program in many countries, including the United States, Spain, Belgium, the Netherlands, and Austria.
In the United States, 348 DCD heart transplants were performed in 2022, with numbers expected to reach 700 to 800 this year as more centers come online.
It is expected that most countries with heart transplant programs will follow suit and the number of donor hearts will increase by up to 30% worldwide because of DCD.
Currently, there are about 8,000 heart transplants worldwide each year and with DCD this could rise to about 10,000, potentially an extra 2,000 lives saved each year, experts estimate.
Two different approaches to DCD heart transplantation have been developed.
The direct procurement approach
The Australian group, based at St. Vincent’s Hospital in Sydney, developed a technique referred to as “direct procurement”: after the standoff period and declaration of circulatory death, the chest is opened, and the heart is removed. New technology, the Organ Care System (OCS) heart box (Transmedics), is then used to reperfuse and restart the heart outside the body so its suitability for transplant can be assessed.
The heart is kept perfused and beating in the OCS box while it is being transported to the recipient. This has enabled longer transit times than the traditional way of transporting the nonbeating heart on ice.
Peter MacDonald, MD, PhD, from the St Vincent’s group that developed this approach, said, “Most people thought a heart from a DCD donor would not survive transport – that the injury to the heart from the combination of life support withdrawal, stand-off time, and cold storage would be too much. But we modeled the process in the lab and were able to show that we were able to get the heart beating again after withdrawal of life support.”
Dr. McDonald noted that “the recipient of their first human DCD heart transplant using this machine in 2014 is still alive and well.” The Australian group has now done 85 of these DCD heart transplants, and they have increased the number of heart transplant procedures at St. Vincent’s Hospital by 25%.
Normothermic regional perfusion (NRP)
The U.K. group, based at the Royal Papworth Hospital in Cambridge, England, developed a different approach to DCD: After the standoff period and the declaration of circulatory death, the donor is connected to a heart/lung machine using extracorporeal membrane oxygenation (ECMO) so that the heart is perfused and starts beating again inside the body. This approach is known as normothermic regional perfusion (NRP).
Marius Berman, MD, surgical lead for Transplantation and Mechanical Circulatory Support at Papworth, explained that the NRP approach allows the heart to be perfused and restarted faster than direct procurement, resulting in a shorter ischemic time. The heart can be evaluated thoroughly for suitability for transplantation in situ before committing to transplantation, and because the heart is less damaged, it can be transported on ice without use of the OCS box.
“DCD is more complicated than DBD, because the heart has stopped and has to be restarted. Retrieval teams have to be very experienced,” Dr. Berman noted. “This is more of an issue for the direct procurement approach, where the chest has to be opened and the heart retrieved as fast as possible. It is a rush. The longer time without the heart being perfused correlates to an increased incidence of primary graft dysfunction. With NRP, we can get the heart started again more quickly, which is crucial.”
Stephen Large, MBBS, another cardiothoracic surgeon with the Papworth team, added that they have reduced ischemic time to about 15 minutes. “That’s considerably shorter than reperfusing the heart outside the body,” he said. “This results in a healthier organ for the recipient.”
The NRP approach is also less expensive than direct procurement as one OCS box costs about $75,000.
He pointed out that the NRP approach can also be used for heart transplants in children and even small babies, while currently the direct procurement technique is not typically suitable for children because the OCS box was not designed for small hearts.
DCD, using either technique, has increased the heart transplant rate by 40% at Papworth, and is being used at all seven transplant centers in the United Kingdom, “a world first,” noted Dr. Large.
The Papworth team recently published its 5-year experience with 25 NRP transplants and 85 direct procurement transplants. Survival in recipients was no different, although there was some suggestion that the NRP hearts may have been in slightly better condition, possibly being more resistant to immunological rejection.
Ethical concerns about NRP
Restarting the circulation during the NRP process has raised ethical concerns.
When the NRP technique was first used in the United States, these ethical questions were raised by several groups, including the American College of Physicians (ACP).
Harry Peled, MD, Providence St. Jude Medical Center, Fullerton, Calif., coauthor of a recent Viewpoint on the issue, is board-certified in both cardiology and critical care, and said he is a supporter of DCD using direct procurement, but he does not believe that NRP is ethical at present. He is not part of the ACP, but said his views align with those of the organization.
There are two ethical problems with NRP, he said. The first is whether by restarting the circulation, the NRP process violates the U.S. definition of death, and retrieval of organs would therefore violate the dead donor rule.
“American law states that death is the irreversible cessation of brain function or of circulatory function. But with NRP, the circulation is artificially restored, so the cessation of circulatory function is not irreversible,” Dr. Peled pointed out.
“I have no problem with DCD using direct procurement as we are not restarting the circulation. But NRP is restarting the circulation and that is a problem for me,” Dr. Peled said. “I would argue that by performing NRP, we are resuscitating the patient.”
The second ethical problem with NRP is concern about whether, during the process, there would be any circulation to the brain, and if so, would this be enough to restore some brain function? Before NRP is started, the main arch vessel arteries to the head are clamped to prevent flow to the brain, but there are worries that some blood flow may still be possible through small collateral vessels.
“We have established that these patients do not have enough brain function for a meaningful life, which is why a decision has been made to remove life support, but they have not been declared brain dead,” Dr. Peled said.
With direct procurement, the circulation is not restarted so there is no chance that any brain function will be restored, he said. “But with NRP, because the arch vessels have to be clamped to prevent brain circulation, that is admitting there is concern that brain function may be restored if circulation to the brain is reestablished, and brain function is compatible with life. As we do not know whether there is any meaningful circulation to the brain via the small collaterals, there is, in effect, a risk of bringing the patient back to life.”
The other major concern for some is whether even a very small amount of circulation to the brain would be enough to support consciousness, and “we don’t know that for certain,” Dr. Peled said.
The argument for NRP
Nader Moazami, MD, professor of cardiovascular surgery, NYU Langone Health, New York, is one of the more vocal proponents of NRP for DCD heart transplantation in the United States, and has coauthored responses to these ethical concerns.
“People are confusing many issues to produce an argument against NRP,” he said.
“Our position is that death has already been declared based on the lack of circulatory function for over 5 minutes and this has been with the full agreement of the family, knowing that the patient has no chance of a meaningful life. No one is thinking of trying to resuscitate the patient. It has already been established that any future efforts to resuscitate are futile. In this case, we are not resuscitating the patient by restarting the circulation. It is just regional perfusion of the organs.”
Dr. Moazami pointed out this concept was accepted for the practice of abdominal DCD when it first started in the United States in the 1990s where cold perfusion was used to preserve the abdominal organs before they were retrieved from the body.
“The new approach of using NRP is similar except that it involves circulating warm blood, which will preserve organs better and result in higher quality organs for the recipient.”
On the issue of concern about possible circulation to the brain, Dr. Moazami said: “The ethical critics of NRP are questioning whether the brain may not be dead. We are arguing that the patient has already been declared dead as they have had a circulatory death. You cannot die twice.”
He maintained that the clamping of the arch vessels to the head will ensure that when the circulation is restarted “the natural process of circulatory death leading to brain death will continue to progress.”
On the concerns about possible collateral flow to the brain, Dr. Moazami said there is no evidence that this occurs. “Prominent neurologists have said it is impossible for collaterals to provide any meaningful blood flow to the brain in this situation. And even if there is small amount of blood flow to the brain, this would be insufficient to maintain any meaningful brain function.”
But Dr. Peled argues that this has not been proved. “Even though we don’t think there is enough circulation to the brain for any function with NRP, we don’t know that with 100% certainty,” he said. “In my view, if there is a possibility of even the smallest amount of brain flow, we are going against the dead donor rule. We are rewriting the rules of death.”
Dr. Moazami countered: “Nothing in life is 100%, particularly in medicine. With that argument can you also prove with 100% certainty to me that there is absolutely no brain function with regular direct procurement DCD? We know that brain death has started, but the question is: Has it been completed? We don’t know the answer to this question with 100% certainty, but that is the case for regular direct procurement DCD as well, and that has been accepted by almost everyone.
“The whole issue revolves around when are we comfortable that death has occurred,” he said. “Those against NRP are concerned that organs are being taken before the patient is dead. But the key point is that the patient has already been declared dead.”
Since there is some concern over the ethics of NRP, why not just stick to DCD with direct procurement?
Dr. Moazami argued that NRP results in healthier organs. “NRP allows more successful heart transplants, liver transplants, lung transplants. It preserves all the organs better,” he said. “This will have a big impact on recipients – they would obviously much prefer a healthier organ. In addition, the process is easier and cheaper, so more centers will be able to do it, therefore more transplants will get done and more lives will be saved if NRP is used.”
He added: “I am a physician taking care of sick patients. I believe I have to respect the wishes of the donor and the donor family; make sure I’m not doing any harm to the donor; and ensure the best quality possible of the organ I am retrieving to best serve the recipient. I am happy I am doing this by using NRP for DCD heart transplantation.”
But Dr. Peled argued that while NRP may have some possible advantages over direct procurement, that does not justify allowing a process to go ahead that is unethical.
“The fact that NRP may result in some benefits doesn’t justify violating the dead donor rule or the possibility, however small, of causing pain to the donor. If it’s unethical, it’s unethical. Full stop,” he said.
“I feel that NRP is not respecting the rights of our patients and that the process does not have adequate transparency. We took it to our local ethics committee, and they decided not to approve NRP in our health care system. I agree with this decision,” Dr. Peled said.
“The trouble is different experts and different countries are not in agreement about this,” he added. “Reasonable, well-informed people are in disagreement. I do not believe we can have a standard of care where there is not consensus.”
Cautious nod
In a 2022 consensus statement, the International Society for Heart and Lung Transplantation (ISHLT) gave a cautious nod toward DCD and NRP, dependent on local recommendations.
The ISHLT conclusion reads: “With appropriate consideration of the ethical principles involved in organ donation, DCD can be undertaken in a morally permissible manner. In all cases, the introduction of DCD programs should be in accordance with local legal regulations. Countries lacking a DCD pathway should be encouraged to develop national ethical, professional, and legal frameworks to address both public and professional concerns.”
The author of a recent editorial on the subject, Ulrich P. Jorde, MD, head of the heart transplant program at Montefiore Medical Center, New York, said, “DCD is a great step forward. People regularly die on the heart transplant waiting list. DCD will increase the supply of donor hearts by 20% to 30%.”
However, he noted that while most societies have agreed on a protocol for organ donation based on brain death, the situation is more complicated with circulatory death.
“Different countries have different definitions of circulatory death. How long do we have to wait after the heart has stopped beating before the patient is declared dead? Most countries have agreed on 5 minutes, but other countries have imposed different periods and as such, different definitions of death.
“The ISHLT statement says that restarting the circulation is acceptable if death has been certified according to prevailing law and surgical interventions are undertaken to preclude any restoration of cerebral circulation. But our problem is that different regional societies have different definitions of circulatory, death which makes the situation confusing.”
Dr. Jorde added: “We also have to weigh the wishes of the donor and their family. If family, advocating what are presumed to be the donor’s wishes, have decided that DCD would be acceptable and they understand the concept and wish to donate the organs after circulatory death, this should be strongly considered under the concept of self-determination, a basic human right.”
Variations in practice around the world
This ethical debate has led to large variations in practice around the world, with some countries, such as Spain, allowing both methods of DCD, while Australia allows direct procurement but not NRP, and Germany currently does not allow DCD at all.
In the United States, things are even more complicated, with some states allowing NRP while others don’t. Even within states, some hospitals and transplant organizations allow NRP, and others don’t.
David A. D’Alessandro, MD, cardiac surgeon at Massachusetts General Hospital, Boston, uses only the direct procurement approach as his region does not allow NRP.
“The direct procurement approach is not controversial and to me that’s a big advantage. I believe we need to agree on the ethics first, and then get into a debate about which technique is better,” he told this news organization.
Dr. D’Alessandro and his group recently published the results of their study, with direct procurement DCD heart transplantation showing similar short-term clinical outcomes to DBD.
“We are only doing direct procurement and we are seeing good results that appear to be comparable to DBD. That is good enough for me,” he said.
Dr. D’Alessandro estimates that in the United States both types of DCD procedures are currently being done about equally.
“Anything we can do to increase the amount of hearts available for transplantation is a big deal,” he said. “At the moment, only the very sickest patients get a heart transplant, and many patients die on the transplant waiting list. Very sadly, many young people die every year from a circulatory death after having life support withdrawn. Before DCD, these beautiful functional organs were not able to be used. Now we have a way of saving lives with these organs.”
Dr. D’Alessandro noted that more and more centers in the United States are starting to perform DCD heart transplants.
“Not every transplant center may join in as the DCD procedures are very resource-intensive and time-consuming. For low-volume transplant centers, it may not be worth the expense and anguish to do DCD heart transplants. But bigger centers will need to engage in DCD to remain competitive. My guess is that 50%-70% of U.S. transplant centers will do DCD in future.”
He said he thinks it is a “medical shortcoming” that agreement cannot be reached on the ethics of NRP. “In an ideal world everyone would be on the same page. It makes me a bit uncomfortable that some people think it’s okay and some people don’t.”
Adam DeVore, MD, a cardiologist at Duke University Medical Center, Durham, N.C., the first U.S. center to perform an adult DCD heart transplant, reported that his institution uses both methods, with the choice sometimes depending on how far the heart must travel.
“If the recipient is near, NRP may be chosen as the heart is transported on ice, but if it needs to go further away we are more likely to choose direct procurement and use of the OCS box,” he said.
“I am really proud of what we’ve been able to do, helping to introduce DCD in the U.S.,” Dr. DeVore said. “This is having a massive benefit in increasing the number of hearts for donation with great outcomes.”
But he acknowledged that the whole concept of DCD is somewhat controversial.
“The idea of brain death really came about for the purpose of heart donation. The two things are very intricately tied. Trying to do heart donation without brain death having been declared is foreign to people. Also, in DCD there is the issue of [this]: When life support is removed, how long do we wait before death can be declared? That could be in conflict with how long the organ needs to remain viable. We are going through the process now of looking at these questions. There is a lot of variation in the U.S. about the withdrawal of care and the declaration of death, which is not completely standardized.
“But the concept of circulatory death itself is accepted after the withdrawal of life support. I think it’s the rush to take the organs out that makes it more difficult.”
Dr. DeVore said the field is moving forward now. “As the process has become more common, people have become more comfortable, probably because of the big difference it will make to saving lives. But we do need to try and standardize best practices.”
A recent Canadian review of the ethics of DCD concluded that the direct procurement approach would be in alignment with current medical guidelines, but that further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
In the United Kingdom, the definition of death is brain-based, and brain death is defined on a neurological basis.
Dr. Stephen Large from Papworth explained that this recognizes the presence of brain-stem death through brain stem reflex testing after the withdrawal of life support, cardiorespiratory arrest and 5 further minutes of ischemia. As long as NRP does not restore intracranial (brainstem) perfusion after death has been confirmed, then it is consistent with laws for death determination and therefore both direct procurement and NRP are permissible.
However, the question over possible collateral flow to the brain has led the United Kingdom to pause the NRP technique as routine practice while this is investigated further. So, at the present time, the vast majority of DCD heart transplants are being conducted using the direct procurement approach.
But the United Kingdom is facing the bigger challenge: national funding that will soon end. “The DCD program in the U.K. has been extremely successful, increasing heart transplant rates by up to 28%,” Dr. Berman said. “Everybody wants it to continue. But at present the DCD program only has national funding in the U.K. until March 2023. We don’t know what will happen after that.”
The current model in the United Kingdom consists of three specialized DCD heart retrieval teams, a national protocol of direct organ procurement and delivery of DCD hearts to all seven transplant programs, both adult and pediatric.
If the national funding is not extended, “we will go back to individual hospitals trying to fund their own programs. That will be a serious threat to the program and could result in a large reduction in heart transplants,” said Dr. Berman.
Definition of death
The crux of the issue with regard to NRP seems to be variations in how death is defined and the interpretation of those definitions.
DCD donors will have had many tests indicating severe brain damage, a neurologist will have declared the prognosis is futile, and relatives will have agreed to withdraw life support, Dr. Jorde said. “The heart stops beating, and the stand-off time means that blood flow to the brain ceases completely for at least 5 minutes before circulatory death is declared. This is enough on its own to stop brain function.”
Dr. Large made the point that by the time the circulation is reestablished with NRP, more time has elapsed, and the brain will have been without perfusion for much longer than 5 minutes, so it would be “physiologically almost impossible” for there to be any blood flow to the brain.
“Because these brains are already very damaged before life support was removed, the intracranial pressure is high, which will further discourage blood flow to the brain,” he said. Then the donor goes through a period of anoxic heart arrest, up to 16 minutes at a minimum of no blood supply, enough on its own to stop meaningful brain function.
“It’s asking an awful lot to believe that there might be any brain function left,” he said. “And if, on reestablishing the circulation with NRP, there is any blood in the collaterals, the pressure of such flow is so low it won’t enter the brain.”
Dr. Large also pointed out that the fact that the United Kingdom requires a neurologic definition for brain-stem death makes the process easier.
In Australia, St. Vincent’s cardiologist Dr. MacDonald noted that death is defined as the irreversible cessation of circulation, so the NRP procedure is not allowed.
“With NRP, there is an ethical dilemma over whether the patient has legally died or not. Different countries have different ways of defining death. Perhaps society will have to review of the definition of death,” he suggested. Death is a process, “but for organ donation, we have to choose a moment in time of that process that satisfies everyone – when there is no prospect of recovery of the donor but the organs can still be utilized without harming the donor.”
Dr. MacDonald said the field is in transition. “I don’t want to argue that one technique is better than the other; I think it’s good to have access to both techniques. Anything that will increase the number of transplants we can do is a good thing.”
Collaborative decision
Everyone seems to agree that there should be an effort to try to define death in a uniform way worldwide, and that international, national and local regulations are aligned with each other.
Dr. Jorde said: “It is of critical importance that local guidelines are streamlined, firstly in any one given country and then globally, and these things must be discussed transparently within society with all stakeholders – doctors, patients, citizens.”
Dr. Peled, from Providence St. Jude in California, concurred: “There is the possibility that we could change the definition of death, but that cannot be a decision based solely on transplant organizations. It has to be a collaborative decision with a large input from groups who do not have an interest in the procurement of organs.”
He added: “The dialogue so far has been civil, and everybody is trying to do the right thing. My hope is that as a civilized society we will figure out a way forward. At present, there is significant controversy about NRP, and families need to know that. My main concern is that if there is any lack of transparency in getting informed consent, then this risks people losing trust in the donation system.”
Dr. Moazami, from NYU Langone, said the controversy has cast a cloud over the practice of NRP throughout the world. “We need to get it sorted out.”
He said he believes the way forward is to settle the question of whether there is any meaningful blood flow to the brain with the NRP technique.
“This is where the research has to focus. I believe this concern is hypothetical, but I am happy to do the studies to confirm that. Then, the issue should come to a rest. I think that is the right way forward – to do the studies rather than enforcing a moratorium on the practice because of a hypothetical concern.”
These studies on blood flow to the brain are now getting started in both the United Kingdom and the United States.
The U.K. study is being run by Antonio Rubino, MD, consultant in cardiothoracic anesthesia and intensive care at Papworth Hospital NHS Foundation and clinical lead, organ donation. Dr. Rubino explained that the study will assess cerebral blood flow using CT angiography of the brain. “We hypothesize that this will provide evidence to indicate that brain blood flow is not present during NRP and promote trust in the use of NRP in routine practice,” he said.
Dr. Large said: “Rather than having these tortured arguments, we will do the measurements. For the sake of society in this situation, I think it’s good to stop and take a breath. We must measure this, and we are doing just that.”
If there is any blood flow at all, Dr. Large said they will then have to seek expert guidance. “Say we find there is 50 mL of blood flow and normal blood flow is 1,500 mL/min. We will need expert guidance on whether it is remotely possible to be sentient on that. I would say it would be extraordinarily unlikely.”
Dr. Berman summarized the situation: “DCD is increasing the availability of hearts for transplant. This is saving lives, reducing the number of patients on the waiting list, and reducing hospital stays for patients unable to leave the hospital without a transplant. It is definitely here to stay. It is crucial that it gets funded properly, and it is also crucial that we resolve the NRP ethical issues as soon as possible.”
He is hopeful that some of these issues will be resolved this year.
Dr. MacDonald reported he has received “in-kind” support from Transmedics through provision of research modules for preclinical research studies. Dr. D’Alessandro reported he is on the speakers bureau for Abiomed, not relevant to this article. No other relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
Oral PCSK9 inhibitor shows encouraging LDL lowering
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
A new oral formulation of a PCSK9-inhibiting, cholesterol-lowering drug in development by Merck has shown encouraging results in a phase 2 study.
The study was presented by Christie Ballantyne, MD, Baylor College of Medicine, Houston, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“In this diverse population of hypercholesterolemic patients, all doses of MK-0616 showed superior reduction of LDL vs. placebo up to a 60.9% placebo-adjusted reduction from baseline to week 8, which was consistent across subgroups,” Dr. Ballantyne reported.
“Reduction in ApoB and non-HDL cholesterol were consistent with that of LDL cholesterol, with up to a 51.8% reduction in ApoB and a 55.8% reduction in non-HDL,” he noted.
He added that the drug was well tolerated with no difference in adverse events across the treatment groups, compared with placebo.
“These data support the further development of MK-0616, an oral PCSK9 inhibitor that may improve access to effective LDL-cholesterol lowering therapies and improve attainment of guideline-recommended LDL goals aimed at reducing cardiovascular risk,” Dr. Ballantyne concluded. “The results are encouraging for a phase 3 program that is now being designed.”
He explained that elevated LDL is a primary causative factor for atherosclerotic cardiovascular disease (ASCVD), and despite effective treatments (statins), a large proportion of patients fail to achieve guideline-recommended LDL levels. Injectable treatments targeting PCSK9 have demonstrated large reductions in LDL and decreased risk of ASCVD events, but access barriers and need for repeat injections have led to poor adoption. An oral PCSK9 inhibitor may widen access and improve attainment of guideline-recommended treatment goals.
Dr. Ballantyne described the new drug, MK-0616, as a “macrocyclic peptide that can bind PCSK9 with monoclonal antibody-like affinity at 1/100th of the molecular weight.”
The current phase 2 study included 381 adult patients (49% female; median age 62 years) with a wide range of ASCVD risk. Average LDL-C level was 119.5 mg/dL at baseline. Around 40% of patients were not taking statins, 35% were on low- to moderate-intensity statin therapy, and 26% were on high-intensity statin therapy.
They were randomly assigned to four different doses of MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo.
Results showed that all doses of MK-0616 demonstrated statistically significant differences in percentage change in LDL-C from baseline to week 8 vs. placebo: –41.2% (6 mg), –55.7% (12 mg), –59.1% (18 mg), and –60.9% (30 mg).
The mean percentage changes in ApoB from baseline vs. placebo were –32.8%, –45.8%, –48.7%, and 51.8% for the four escalating doses of the drug. And non-HDL cholesterol changes were –35.9%, –50.5%, –53.2%, and –55.8% respectively.
The proportion of participants at protocol-defined goals for LDL reduction was 80.5%, 85.5%, 90.8%, and 90.8% with MK-0616 at the 6-mg, 12-mg, 18-mg, and 30-mg doses, compared with 9.3% with placebo.
Dr. Ballantyne reported that the efficacy looked similar in all subgroups, and regardless of baseline therapy.
“This was a dose-finding study, which will help select a dose to be taken forward in larger studies, and it looks from these results as though you get most of the efficacy by 12 mg,” he added.
Adverse events occurred in a proportion of participants in the MK-0616 groups (39.5% to 43.4%) similar to that of placebo (44.0%), and discontinuations as a result of adverse events occurred in two or fewer participants in any treatment group.
‘Super exciting’
Putting the results of his study into perspective at an ACC press conference, Rhonda Cooper-DeHoff, PharmD, associate professor in the department of pharmacotherapy and translational research at the University of Florida in Gainesville, commented.
“For the last quarter of a century we have had statins available to treat elevated LDL and atherosclerosis and despite that we have many patients who refuse to take statins or are afraid to take statins,” she said. “This is not about cost as the statins are all available generically now. But many patients claim to be intolerant or unresponsive.”
She noted that in 2015/2016 the first injectable PCSK9 inhibitors became available “which really were very exciting molecules, but they have a high cost and access issues, and patients often do not like injections so there are still a lot of issues.”
Dr. Cooper-DeHoff pointed out that this oral PCSK9 inhibitor seems to be as effective at lowering LDL as the injectable products regardless of whether statins are on board or not, which she said was “super exciting.”
She added: “We are all going to be waiting excitedly for the outcome data with this oral PCSK9 inhibitor.”
She also noted that another study (CLEAR Outcomes) presented at the ACC meeting showed good lipid-lowering results and a reduction in cardiovascular outcomes in statin-intolerant patients with another oral lipid lowering drug, bempedoic acid (Nexletol).
She said the two oral drugs promised a “very bright for the future for LDL lowering and the treatment of atherosclerosis in our patients,” adding that “we are now really chipping away at the barriers to achieving the holy grail of guideline-directed LDL lowering to prevent hard outcomes.”
The results were published online in the Journal of the American College of Cardiology at the time of presentation.
This study was funded by Merck. Dr. Ballantyne has received grant/research support through his institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostics and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Roche Diagnostics.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Endurance exercise tied to more coronary atherosclerosis
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.
The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.
“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.
The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.
Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”
The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.
“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.
“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”
On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”
In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”
He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”
However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”
Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”
He noted that the Master@Heart study as an “important contribution” to the field.
“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”
It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”
He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”
However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”
Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.
But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.
“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”
In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.
He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.
The Master@Heart study aimed to look at this question in a more comprehensive way.
The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.
Maximal oxygen uptake (VO2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO2max than nonathletes (159 vs. 155 vs. 122).
There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).
The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.
Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).
In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:
- More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
- More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
- More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
- More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
- More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
- More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
- More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)
In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.
Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).
In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.
“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.
“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Encouraging 3-year data for TAVR in low-risk patients: EVOLUT
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
Three-year results from the Evolut trial seem to provide more reassurance on the use of transcatheter aortic valve replacement (TAVR) in low-surgical-risk patients.
The 3-year results show that low-surgical-risk patients undergoing aortic valve replacement continue to show lower rates of all-cause mortality and disabling stroke with TAVR, compared with surgery.
The rates of all-cause mortality or disabling stroke (the primary endpoint) at 3 years were 7.4% with TAVR and 10.4% with surgery.
Rates of new pacemaker implantation continued to be higher after TAVR and the frequency of new onset atrial fibrillation was more common after surgery.
“At 3 years, the rate of all-cause mortality or disabling stroke after TAVR with the Evolut valve compared very favorably to surgery. The absolute difference between treatment arms remained consistent with a 30% relative reduction in the hazard of death or disabling stroke, with a P value that just missed statistical significance,” said Evolut investigator John Forrest, MD, Yale University School of Medicine, New Haven, Conn.
“The Kaplan-Meier curves show what we’ve come to expect – an early separation of the curves – but what’s unique here, and seen for the first time, is that the early separation is maintained at year 1 and year 2, and between years 2 and 3 the curve didn’t start to come together, but, if anything, separated a little,” Dr. Forrest commented.
“Both components of the primary endpoint – all cause mortality and disabling stroke – numerically favor TAVR. The separation of the curves for stroke are maintained, and if anything, we see a further slight separation of the curves as we go forward out to 3 years in terms of all-cause mortality,” he added.
Dr. Forrest presented the 3-year results from the Evolut trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. They were simultaneously published online in the Journal of the American College of Cardiology.
Dr. Forrest also reported that TAVR patients continued to have better valve hemodynamics at 3 years and very low rates of valve thrombosis; moreover, rates of moderate or greater paravalvular regurgitation and paravalvular leak (factors that can affect valve durability) were also low, although mild paravalvular regurgitation was higher with TAVR.
“In these low-risk patients, the durability of the valve is going to be critically important,” Dr. Forrest commented. “The excellent valve performance and durable outcomes out to 3 years in low-risk patients affirms the role of TAVR in this population,” he concluded.
On how these results may affect clinical practice, Dr. Forrest said: “I think in the U.S. these results reaffirm what we are doing. It gives us confidence to continue treating low-risk patients and being comfortable with that.”
He added: “Outside the U.S., the guidelines are a little different. Maybe we should reconsider some of these guidelines based on these data.”
David Moliterno, MD, Gill Heart and Vascular Institute, Lexington, Ky., who is not involved in the TAVR studies, said: “The results provide a little more reassurance ... that will go a little way further.”
“Uncertainty remains regarding long-term durability of the transcatheter valve in low-risk patients who are generally younger and likely more active than higher-risk cohorts,” he added. “The current 3-year results provide more confidence as the outcome curves for death and disabling stroke are trending in the right direction for TAVR versus surgery.”
Dr. Moliterno pointed out that while rates of paravalvular regurgitation and permanent pacemaker placement are decreasing with newer generation Evolut devices and implantation techniques, he noted that according to the U.S. Social Security Administration, patients aged 74 years as enrolled in this low-risk cohort have an additional life expectancy of approximately 12 years. “So, we have more device durability (and coronary access feasibility) to prove.”
In his presentation, Dr. Forrest explained that TAVR is now approved in the United States for all patients with aortic stenosis regardless of surgical risk and has become the dominant form of aortic valve replacement. Current ACC/AHA guidelines recommend that heart teams utilize a shared decision-making process when discussing aortic valve replacement with patients aged 65-80 years. In younger, lower-risk patients, the faster recovery and short-term benefits after TAVR must be balanced with long-term durability; however, only limited intermediate and long-term data exist to guide such discussions in this patient population.
The Evolut Low Risk trial randomly assigned 1,414 patients in need of aortic valve replacement to TAVR with a self-expanding, supra-annular valve or surgery. Results at 1 and 2 years have shown a similar benefit in the primary endpoint of all-cause mortality/disabling stroke for the less invasive TAVR procedure.
The current 3-year results suggest the benefit appears to be maintained out for another year.
The main results show that the rate of death or disabling stroke was 7.4% in the TAVR group versus 10.4% in the surgery group, giving a hazard ratio of 0.70 (P = .051).
In the JACC paper, the authors report that the absolute difference between treatment arms for all-cause mortality or disabling stroke remained broadly consistent over time: –1.8% at year 1; –2.0% at year 2; and –2.9% at year 3.
Other key results on valve durability show that mild paravalvular regurgitation was increased in the TAVR group (20.3%) versus 2.5% with surgery. However, rates of moderate or greater paravalvular regurgitation for both groups were below 1% and not significantly different between groups.
Patients who underwent TAVR had significantly improved valve hemodynamics (mean gradient 9.1 mm Hg TAVR vs. 12.1 mm Hg surgery; P < .001) at 3 years.
However, pacemaker placement was much higher in the TAVR group (23.2%), compared with 9.1% in the surgery group.
On the other hand, the surgery group had a greater incidence of atrial fibrillation (40%) versus 13% with TAVR.
Quality-of-life results looked good in both groups.
“As we’ve come to expect, patients recover more quickly after TAVR, so at 30 days their quality of life is better than those who have undergone surgery,” Dr. Forrest commented. “But by 1 year, both groups are doing exceptionally well and, remarkably, here by 3 years both groups have greater than a 20-point increase in their KCCQ score, showing a very large improvement in quality of life.”
Discussant of these latest results at the ACC late-breaking trials session, James Hermiller, MD, St. Vincent Ascension Heart Center, Indianapolis, said: “This 3-year data continues to demonstrate that the gift of TAVR keeps giving.”
Noting that the divergence in the effect curves was primarily driven by mortality rather than stroke, he asked whether this was cardiac or noncardiac mortality that was reduced.
Dr. Forrest responded: “It was a fairly equal contribution – a little bit more cardiac death. We have to remember that although the average age in this study was 74, there were some patients over 80 who were still low-surgical-risk included so we are going to see noncardiac death as well.”
Dr. Hermiller drew attention to the high pacemaker rate in the TAVR group and asked how these patients fared in comparison to those who didn’t need a pacemaker.
Dr. Forrest replied: “I think it’s fair to say that putting in a pacemaker is not a benign procedure. Patients who got a pacemaker did slightly worse than those who didn’t get a pacemaker, so we need to try to drive that rate down.”
He added that the number of patients needing a pacemaker after TAVR has come down with new implantation techniques and new generation valves.
“We realize that using a cusp overlap technique can significantly reduce the need for a pacemaker, and we see from registry data that with the use of this new technique the need for a pacemaker has dropped down to 8%-9%, significantly less than seen in this study,” Dr. Forrest commented.
Dr. Hermiller also asked about how TAVR affects future access for catheterization or percutaneous coronary intervention.
Dr. Forrest noted that 24 patients in the TAVR group required PCI in first 3 years, and all the PCI procedures had been successful. He noted that operators reported the procedure to be easy or moderately easy in about 75%-80% of cases and difficult in about 20% of patients. “So, it is slightly more challenging to engage the coronaries and have to go through the frame, but it is very feasible.”
Dr. Forrest concluded that: “These results provide patients and heart teams important data to aid in the shared decision-making process.”
But he acknowledged that longer term data are still needed. “And the potential impact that hemodynamics, valve design, new pacemakers, and other secondary endpoints have on long-term outcomes will be important to follow in this group of low-risk patients.”
The Evolut Low Risk trial was funded by Medtronic. Dr. Forrest has received grant support/research contracts and consultant fees/honoraria/speakers bureau fees from Edwards Lifesciences and Medtronic.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
‘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
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
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
New AHA statement urges focus on CV risk before pregnancy
Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.
“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.
Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.
“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.
“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.
The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.
Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
Prepregnancy window
Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.
Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.
The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.
“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
Critical research gap
Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.
“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”
She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”
She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”
Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”
A version of this article first appeared on Medscape.com.
Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.
“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.
Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.
“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.
“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.
The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.
Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
Prepregnancy window
Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.
Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.
The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.
“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
Critical research gap
Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.
“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”
She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”
She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”
Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”
A version of this article first appeared on Medscape.com.
Increased public health and research efforts to optimize prepregnancy cardiovascular health are needed, particularly among those in under-represented racial and ethnic groups, according to a new scientific statement from the American Heart Association.
“We have released this statement at this time because there is a maternal health crisis in the U.S. with rising maternal morbidity and mortality rates, which are the highest among high-income countries,” chair of the scientific statement writing group, Sadiya S. Khan, MD, told this news organization.
Cardiovascular disease (CVD) is the leading cause of death during pregnancy and the postpartum period and represents 26.5% of pregnancy-related deaths, the statement reports.
“While there is a lot of emphasis in trying to reduce cardiovascular risk during the period of actual pregnancy, much of that risk has often already developed and the women have been living with it for some time, so interventions during pregnancy may be too late,” Dr. Khan, assistant professor of medicine and preventive medicine at Northwestern University, Chicago, said.
“We wanted to try and emphasize the importance of starting to reduce cardiovascular risk earlier before pregnancy. In terms of improving cardiovascular health, this should have benefits both for the mother and the child,” she added.
The statement, “Optimizing Prepregnancy Cardiovascular Health to Improve Outcomes in Pregnant and Postpartum Individuals and Offspring” was published online in a “Go Red For Women” spotlight issue of the AHA publication Circulation.
Currently, nearly one in five births are complicated by such an adverse pregnancy outcome, and there is a strong association between these complications and risk for subsequent cardiovascular disease.
Prepregnancy window
Over the past decade, rates of adverse pregnancy outcomes have increased significantly in the United States, with a near doubling in rates of hypertensive disorders of pregnancy, and there are persistent disparities, with Black individuals significantly more likely to experience adverse pregnancy outcomes, the statement notes.
Emerging data suggest that these complications have, at least in part, prepregnancy origins. Thus, the prepregnancy period may be a critical window during which interventions have a great potential for benefit in both women and their offspring, it says.
The authors suggest a life-course approach to measure, modify, and monitor prepregnancy cardiovascular health, with all clinicians who interact with pregnancy-capable individuals emphasizing optimization of cardiovascular health beginning early in childhood.
“Leveraging these opportunities to target cardiovascular health has the potential to improve health across the life course and for subsequent generations,” they add.
Critical research gap
Despite the evidence linking an individual’s prepregnancy health to their offspring’s health, there are no large trials to test whether improving overall cardiovascular health before pregnancy will reduce pregnancy complications, pregnancy-related cardiovascular death, or cardiovascular risk for offspring. The statement authors suggest that such a trial should be considered.
“This would be a big undertaking, but it could be feasible and could be really impactful,” Dr. Khan said. “Of course it would be challenging to recruit women who are planning a pregnancy and to follow them to see if they do get pregnant and consider interventions and outcomes, but given the importance of the need, we think this is something that should be invested in.”
She pointed out that the main way to improve the cardiovascular health of this cohort would be through behavioral counseling on physical activity and diet. “We need to develop strategies tailored to this age group – young women and those who may already have young children – and often the last thing they are thinking about is themselves and their own health.”
She explained that while it is presumed that controlling cardiovascular risk factors will be beneficial, the bigger question is how that can be achieved. “Behavioral interventions are difficult to achieve and often have low adherence, so the focus of the trials should be on strategies on how to deliver behavioral counseling to achieve better cardiovascular health in this population.”
Dr. Khan stressed that any approaches to improving prepregnancy cardiovascular health must address the current racial disparities that are present. “We must make sure that our policies are successful not just in improving cardiovascular health but to ensure it is done equitably. We must find ways to ensure all individuals can access care.”
A version of this article first appeared on Medscape.com.
FROM CIRCULATION
Similar effect of early, late BP reduction in stroke: CATIS-2
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
in the CATIS-2 trial.
The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.
But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.
Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”
But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”
Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.
“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.
In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.
In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.
Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.
The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.
Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).
The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.
BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).
At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).
The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).
There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).
There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.
Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.
Dr. Liu has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ISC 2023
Thrombolysis not necessary in mild nondisabling stroke: ARAMIS
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
in the ARAMIS trial.
The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.
“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.
In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.
Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”
She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”
Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.
A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.
This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.
In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.
In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.
The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.
The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).
The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.
In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).
“Therefore, this was a positive trial,” Dr. Nguyen stated.
About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.
Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.
In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.
Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).
Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.
Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.
In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.
“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.
“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.
In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”
But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”
The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.
A version of this article first appeared on Medscape.com.
FROM ISC 2023