Cardiothoracic

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

A version of this article first appeared on Medscape.com.

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

A version of this article first appeared on Medscape.com.

In a first-of-its-kind in utero surgery, researchers have successfully repaired a cerebrovascular malformation, which often leads to heart failure, severe brain injury, or possibly death soon after birth.
 

The team from Boston Children’s Hospital and Brigham and Women’s Hospital used ultrasound guidance to repair the vein of Galen malformation, which causes excessively high blood flow, resulting in both neurologic and cardiac complications. 

The surgery was performed in a fetus at 34 weeks’ gestational age, with remarkable results. Since birth, the baby girl, who was identified in utero as being at high risk of suffering serious complications of the malformation, has required no medication to treat heart failure and no postnatal surgery.

Repeated echocardiograms after birth displayed marked improvement in cardiac output, and brain MRI showed no brain injury and a normal neurologic exam.

“This is incredibly exciting. The hope is that this baby, and others with this condition who receive this in utero surgery in future, will go on to have a normal life,” lead researcher Darren B. Orbach, MD, PhD, said in an interview.

“We were thrilled to see that the aggressive decline usually seen after birth simply did not appear. We are pleased to report that at 6 weeks, the infant is progressing remarkably well, on no medications, eating normally, gaining weight and is back home. There are no signs of any negative effects on the brain,” he added.

Dr. Orbach, codirector of the Cerebrovascular Surgery & Interventions Center at Boston Children’s Hospital, and colleagues described this first case report of the in utero vein of Galen malformation repair in a research letter, published online in the journal Stroke.
 

Vein of Galen malformation

Dr. Orbach explained that vein of Galen malformation, which occurs in around 1 in every 60,000 births, is a cerebrovascular anomaly in which the arterial system is directly connected to the venous system rather than to capillaries that are necessary to slow blood flow and deliver oxygen to surrounding brain tissue.

“The arterial and venous systems are fundamentally very different. The arterial system is high pressure, high flow; while the venous system is low pressure, low flow. They shouldn’t be directly connected,” he noted.

The vein of Galen malformation is the most extreme version of such an anomaly. Developing in early gestation, it is associated with a large increase in blood flow through the brain which grows over time and can sometimes result in twice the total cardiac output of the body or even more, Dr. Orbach said.

The placenta is believed to be protective as most babies don’t have overt physiologic problems in utero, but they can run into crisis after birth, with the abnormally high blood flow causing an immense stress to the heart.

Babies typically present with heart failure as their first major symptom soon after birth, Dr. Orbach said. “Although the anatomical problem is in the brain, the clinical manifestation is high-output heart failure. The heart is trying to do double its normal work, pumping the blood to the malformation and immediately back to the heart and that blood is not performing any useful function.

“These newborns can get very sick. They need multiple medications to support their cardiovascular system and we need to do procedures to try and reduce the blood flow,” he explained. 

Brain injury is also a common problem. “The brain circulation is very abnormal. The blood is being shunted through the malformation rather than circulating through the brain tissue which can become ischemic,” Dr. Orbach commented.

“The babies who get sick would have a very high mortality (up to 90%) without expert care. Even those who do receive expert care at a specialty center have a mortality rate of 30% to 40% and those who survive have a high risk of neurologic and cognitive impairment,” he added.

The current treatment for babies born with the condition involves transarterial embolization, by which a catheter is inserted into the arterial system to enable the malformation to be occluded by various techniques. 

But Dr. Orbach pointed out that some babies are born too sick to have the postnatal intervention. “The heart failure and brain injury is so overwhelming that no matter what we do, we cannot reverse it, and these babies normally do not survive. What we are doing with the fetal surgery is trying to help those babies who cannot be treated with the current postnatal approach,” he said.

The first stage of this research involved trying to identify these very-high-risk babies in utero, and the researchers found that on fetal MRI a particular measurement of one of the venous sinuses that drains the main malformation was a good predictor of how the baby would fare after birth. The babies predicted to do poorly from this test are the targets for the fetal surgery.

The technique used for the postnatal intervention is too technically challenging to perform in utero. “So we have developed a different approach for the in utero surgery that involves navigating into the accepting vein in the malformation with a needle under ultrasound guidance, and then packing the vein with metal coils to dramatically reduce the blood flow,” Dr. Orbach explained.

This procedure was performed in this first patient on March 15. The surgery was part of a clinical trial that is planned to include 20 cases in total.

“The immediate goal is to see whether we can transform those fetuses who are at very high risk of getting sick after birth into babies who do well in the [neonatal] ICU and are able to be sent home for elective treatment at a few months of age,” Dr. Orbach noted. “The study is continuing as it is vital that we continue and show efficacy and safety in other patients as well,” he added.

Dr. Orbach said the results of this first case were extremely encouraging. “Each stage was exciting – the technical success of the procedure, and then seeing the [blood] flow diminish on the ultrasound right there during the procedure; then the next day we did a fetal echocardiogram, and we could see that the abnormal cardiac output was dramatically reduced, and a fetal MRI scan also showed the malformation was already coming down in size.”

The baby was born prematurely 2 days after the procedure because of ruptured membranes with a birth weight of 1.9 kg (4.2 lb). She has not required any cardiovascular support or postnatal embolization.

“We were waiting with bated breath until the baby was born to see how she did clinically. I was trying to be conservative in my expectations, but it was quickly apparent that she was going to do great,” he said. Now at home, she has some oxygen treatment for the first few weeks, “but right now her neurological status is completely intact and essentially she looks like any other baby,” Dr. Orbach commented.

It is not yet known whether the infant will need any additional procedures. “We will follow her closely and make a decision on whether further treatment is needed based on whether the malformation is growing or not,” Dr. Orbach said. Longer term follow-up will also assess secondary problems sometimes seen, such as learning problems and seizures.

Although other fetal surgeries are now routinely performed, this is believed to be the first in utero surgery aimed at the cerebrovascular system.

“There were a lot of uncertainties,” Dr. Orbach said. “We didn’t even know if we would be able to see our instruments on ultrasound.” To model the procedure, the researchers had a phantom fetal skull and brain constructed with a vein of Galen malformation, which was key to obtaining Food and Drug Administration approval for the study.

If the study shows success in the other patients too, the technique could be rolled out to other centers. “There definitely needs to be fetal surgery and neurointerventional teams familiar with vein of Galen malformation in place, and ready to manage complications after delivery regardless of outcome. But we are not the only center with those capabilities, so if our trial pans out, yes, the hope is that other teams in specialist children’s hospitals around the world could do this too,” he added.
 

Pioneering work

Commenting on the case report in an American Heart Association press release, Colin Derdeyn, MD, a neurointerventional radiologist at University of Iowa Health Care, Iowa City, who performs vein of Galen malformation embolizations on neonates, said: “The key advance here is to intervene before the physiologic events of birth can cause life-threatening heart failure.”

Dr. Derdeyn, who is a past chair of the American Heart Association’s Stroke Council, cautioned that one successful case is not enough experience to conclude that the risks of this procedure are worth the benefits.

But, he added: “The positive hemodynamic changes that they observed in utero and after birth – reduction in flow, reduction in size of the draining vein, reversal of the abnormal reversed flow in the aorta – are really encouraging. These are some of the most exciting and surprising aspects of this case report. This is pioneering work being done in a very careful and responsible way.”

The study was funded by a grant from the Sage Schermerhorn Chair for Image-Guided Therapy.

A version of this article first appeared on Medscape.com.

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Prediction models that incorporate more than just treatment status could rank order heart transplant candidates by urgency more effectively than the current system, a modeling study suggests.

Since 2018, the U.S. heart transplant allocation system has ranked heart candidates according to six treatment-based “statuses” (up from three used previously), ignoring many objective patient characteristics, the authors write.

Their study showed no significant difference in survival between statuses four and six, and status five had lower survival than status four.

“We expected multivariable prediction models to outperform the six-status system when it comes to rank ordering patients by how likely they are to die on the wait list (medical urgency),” William F. Parker, MD, MS, PhD, of the University of Chicago, told this news organization.

“However, we were surprised to see that the statuses were out of order,” he said. “Status five patients are more urgent than status three or status four patients,” mainly because most are in renal failure and listed for multiorgan transplantation with a kidney.

Objective physiologic measurements, such as glomerular filtration rate (GFR), had high variable importance, offering a minimally invasive measurement with predictive power in assessing medical urgency. Therefore, including GFR and other variables such as extracorporeal membrane oxygenation (ECMO) could improve the accuracy of the allocation system in identifying the most medically urgent candidates, Dr. Parker and colleagues suggest.

The study was published online in JACC: Heart Failure.
 

‘Moderate ability’ to rank order

The investigators assessed the effectiveness of the standard six-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates. The primary outcome was death before receipt of a heart transplant.

The final data set contained 32,294 candidates (mean age, 53 years; 74%, men); 27,200 made up the prepolicy training set and 5,094 were included in the postpolicy test set.

The team evaluated the accuracy of the six-status system using Harrell’s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed after the policy change (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set.

They then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). Predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing.

They found that the six-status ranking at listing has had “moderate ability” to rank order candidates.

As Dr. Parker indicated, statuses four and six had no significant difference in survival, and status five had lower survival than status four.

The investigators’ multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the six-status rankings. Objective physiologic measurements, such as GFR and ECMO, were identified as having significant importance with regard to ranking by urgency.

“The novel prediction models we developed … could be implemented by the Organ Procurement and Transplantation Network (OPTN) as allocation policy and would be better than the status quo,” Dr. Parker said. “However, I think we could do even better using the newer data collected after 2018.” 
 

Modifications underway

The OPTN Heart Transplantation Committee is currently working on developing a new framework for allocating deceased donor hearts called Continuous Distribution.

“The six-tiered system works well, and it better stratifies the most medically urgent candidates than the previous allocation framework,” the leadership of the United Network for Organ Sharing Heart Transplantation Committee, including Chair Richard C. Daly, MD, Mayo Clinic; Vice-Chair Jondavid Menteer, MD, University of Southern California, Los Angeles; and former Chair Shelley Hall, MD, Baylor University Medical Center, told this news organization.

“That said, it is always appropriate to review and adjust variables that affect the medical urgency attribute for heart allocation.”

The new framework will change how patients are prioritized, they said. “Continuous distribution will consider all patient factors, including medical urgency, together to determine the order of an organ offer, and no single factor will decide an organ match.

“The goal is to increase fairness by moving to a points-based allocation framework that allows candidates to be compared using a single score composed of multiple factors.

“Furthermore,” they added, “continuous distribution provides a framework that will allow modifications of the criteria defining medical urgency (and other attributes of allocation) to a finer degree than the current policy. … Once continuous distribution is in place and the OPTN has policy monitoring data, the committee may consider and model different ways of defining medical urgency.”

Kiran K. Khush, MD, of Stanford (Calif.) University School of Medicine, coauthor of a related commentary, elaborated. “The composite allocation score (CAS) will consist of a ‘points-based system,’ in which candidates will be assigned points based on (1) medical urgency, (2) anticipated posttransplant survival, (3) candidate biology (eg., special characteristics that may result in higher prioritization, such as blood type O and allosensitization), (4) access (eg., prior living donor, pediatric patient), and (5) placement efficacy (travel, proximity).”

Candidates will be assigned points based on these categories, and will be rank ordered for each donor offer.

Dr. Khush and colleagues propose that a multivariable model – such as the ones described in the study – would be the best way to assign points for medical urgency.

“This system will be more equitable than the current system,” Dr. Khush said, “because it will better prioritize the sickest candidates while improving access for patients who are currently at a disadvantage [for example, blood O, highly sensitized patients], and will also remove artificial geographic boundaries [for example, the current 500-mile rule for heart allocation].”
 

Going further

Jesse D. Schold, PhD, of the University of Colorado at Denver, Aurora, raises concerns about other aspects of the heart allocation system in another related commentary.

“One big issue with our data in transplantation … is that, while it is very comprehensive for capturing transplant candidates and recipients, there is no data collection for patients and processes of care for patients prior to wait list placement,” he told this news organization. This phase of care is subject to wide variation in practice, he said, “and is likely as important as any to patients – the ability to be referred, evaluated, and placed on a waiting list.”

Report cards that measure quality of care after wait list placement ignore key phases prior to wait list placement, he said. “This may have the unintended consequences of limiting access to care and to the waiting list for patients perceived to be at higher risk, or the use of higher-risk donors, despite their potential survival advantage.

“In contrast,” he said, “quality report cards that incentivize treatment for all patients who may benefit would likely have a greater beneficial impact on patients with end-organ disease.”

There is also significant risk of underlying differences in patient populations between centers, despite the use of multivariable models, he added. This heterogeneity “may not be reflected accurately in the report cards [which] have significant impact for regulatory review, private payer contracting, and center reputation.”

Some of these concerns may be addressed in the new OPTN Modernization Initiative, according to David Bowman, a public affairs specialist at the Health Resources and Services Administration. One of the goals of the initiative “is to ensure that the OPTN Board of Directors is high functioning, has greater independence, and represents the diversity of communities served by the OPTN,” he told this news organization. “Strengthened governance will lead to effective policy development and implementation, and enhanced transparency and accountability of the process.”

Addressing another concern about the system, Savitri Fedson, MD, of the Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, wonders in a related editorial whether organ donors and recipients should know more about each other, and if so, could that reverse the ongoing downward trend in organ acceptance?

Although some organizations are in favor of sharing more information, Dr. Fedson notes that “less information may have the greater benefit.” She writes, “We might realize that the simplest approach is often the best: a fulsome thank you for the donor’s gift that is willingly given to a stranger without expectation of payment, and on the recipient side, the knowledge that an organ is of good quality.

“The transplant patient can be comforted with the understanding that the risk of disease transmission, while not zero, is low, and that their survival following acceptance of an organ is better than languishing on a waiting list.”

The study received no commercial funding. Dr. Parker, Dr. Khush, Dr. Schold, and Dr. Fedson report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

FROM AACR 2023

Systemic therapy prior to surgery has been slow to catch on in the treatment of patients with resectable non–small cell lung cancer (NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.

That may change, however, in light of new data from the phase 3 AEGEAN trial.

AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.

The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.

“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.

In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.

“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”

For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.

After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.

At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).

The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.

The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.

The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.

Are these data practice changing?

Dr. Herbst gave a “resounding ‘Yes.’ “

But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.

Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.

“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.

It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.

Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
 

A version of this article first appeared on Medscape.com.

FROM AACR 2023

Systemic therapy prior to surgery has been slow to catch on in the treatment of patients with resectable non–small cell lung cancer (NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.

That may change, however, in light of new data from the phase 3 AEGEAN trial.

AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.

The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.

“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.

In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.

“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”

For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.

After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.

At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).

The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.

The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.

The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.

Are these data practice changing?

Dr. Herbst gave a “resounding ‘Yes.’ “

But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.

Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.

“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.

It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.

Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
 

A version of this article first appeared on Medscape.com.

FROM AACR 2023

Systemic therapy prior to surgery has been slow to catch on in the treatment of patients with resectable non–small cell lung cancer (NSCLC), primarily out of concern that neoadjuvant therapy could delay surgery or render patients ineligible for resection.

That may change, however, in light of new data from the phase 3 AEGEAN trial.

AEGEAN showed that neoadjuvant immunotherapy with durvalumab (Imfinzi) and chemotherapy followed by adjuvant durvalumab was associated with significant improvements in pathologic complete response rates and event-free survival, compared with neoadjuvant placebo plus chemotherapy followed by adjuvant placebo, and it did not affect patients’ ability to undergo surgery.

The event-free survival benefit among patients who received durvalumab translated to a 32% reduction in the risk of recurrence, recurrence precluding definitive surgery, or death, John V. Heymach, MD, reported in an oral abstract session at the annual meeting of the American Association for Cancer Research.

“Perioperative durvalumab plus neoadjuvant chemotherapy is a potential new treatment for patients with resectable non–small cell lung cancer,” said Dr. Heymach, chair of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

The AEGEAN findings confirm the benefits of neoadjuvant immunotherapy that were first seen on a large scale in the Checkmate 816 study, which was reported at last year’s AACR annual meeting.

In Checkmate 816, adding the immune checkpoint inhibitor nivolumab to chemotherapy in the neoadjuvant setting resulted in significantly longer event-free survival and a 14-fold greater likelihood of a pathologic complete response compared with chemotherapy alone.

“I’m impressed by the fact that we now have a second study that shows the benefits of immunotherapy in the neoadjuvant setting, along with several adjuvant studies,” the invited discussant, Roy S. Herbst, MD, PhD, deputy director of the Yale Cancer Center, New Haven, Conn., said in an interview. “There’s no doubt that in early lung cancer, resectable disease, immunotherapy is part of the equation.”

For the current study, Dr. Heymach and colleagues recruited 802 patients from 222 sites in North and South America, Europe, and Asia. The patients had NSCLC and were treatment-naive, regardless of programmed cell death–ligand-1 (PD-L1) expression.

After excluding patients with targetable EGFR/ALK alterations, the team randomly allocated 740 patients who had good performance status (ECOG 0 or 1) to receive either neoadjuvant chemoimmunotherapy plus adjuvant immunotherapy or neoadjuvant chemotherapy alone. Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.

At the trial’s first planned interim analysis, for patients assigned to preoperative durvalumab plus platinum-based chemotherapy and postoperative durvalumab, the 12-month event-free survival rate was 73.4%, compared with 64.5% for patients who received chemotherapy alone before and placebo after surgery (stratified P = .003902).

The other endpoint, pathologic complete response, was observed in 17.2% of patients in the durvalumab arm, vs. 4.3% in the control arm – a 13% difference (P = .000036). Major pathologic responses, a secondary efficacy endpoint, were seen in 33.3% and 12.3% of patients, respectively.

The benefits of durvalumab were consistent across all subgroups, including those based on age at randomization, sex, performance status, race, smoking, histology (squamous vs. nonsquamous), disease stage, baseline PD-L1 expression, and planned neoadjuvant agent.

The safety profile of durvalumab plus chemotherapy was manageable, and the addition of durvalumab did not affect patients’ ability to complete four cycles of neoadjuvant chemotherapy, Dr. Heymach said.

Are these data practice changing?

Dr. Herbst gave a “resounding ‘Yes.’ “

But while the AEGEAN protocol represents a new standard of care, it can’t yet be labeled the standard of care, Dr. Herbst explained.

Dr. Herbst emphasized that, because this regimen was not compared against the current standard of care, it’s “impossible to determine” whether this is indeed the new standard.

“The data are early, and additional maturity is needed to better understand the benefit of the extra adjuvant therapy, and we’ll await the survival results,” he said.

It will also be important to analyze why some patients have only minor responses with the addition of durvalumab and whether there are resistance mechanisms at play for these patients. That would be a great setting “to start to test new therapies in a personalized way,” Dr. Herbst said.

Dr. Heymach and Dr. Herbst disclosed ties to AstraZeneca, which funded the study.
 

A version of this article first appeared on Medscape.com.

A new analysis suggests that the initial target of therapy – lung or brain – doesn’t affect overall survival rates in patients with non–small cell lung cancer that has spread to the brain.

“The findings of our study highlight the importance of adopting a personalized, case-based approach when treating each patient” instead of always treating the brain or lung first, lead author Arvind Kumar, a medical student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

The study was released at European Lung Cancer Congress 2023.

According to the author, current guidelines recommend treating the brain first in patients with non–small cell lung cancer and a tumor that has spread to the brain.

“Determining whether the brain or body gets treated first depends on where the symptoms are coming from, how severe the symptoms are, how bulky the disease is, and how long the treatment to each is expected to take,” radiation oncologist Henry S. Park, MD, MPH, chief of the thoracic radiotherapy program at Yale University, New Haven, Conn., said in an interview. “Often the brain is treated first since surgery is used for both diagnosis of metastatic disease as well as removal of the brain metastasis, especially if it is causing symptoms. The radiosurgery that follows tends to occur within a day or a few days.”

However, he said, “if the brain disease is small and not causing symptoms, and the lung disease is more problematic, then we will often treat the body first and fit in the brain treatment later.”

For the new study, researchers identified 1,044 patients in the National Cancer Database with non–small cell lung cancer and brain metastases who received systemic therapy plus surgery, brain stereotactic radiosurgery, or lung radiation. All were treated from 2010 to 2019; 79.0% received brain treatment first, and the other 21.0% received lung treatment first.

There was no statistically significant difference in overall survival between those whose brains were treated first and those whose lungs were treated first (hazard ratio, 1.24, 95% confidence interval [CI], 0.91-1.70, P = .17). A propensity score–matched analysis turned up no difference in 5-year survival (38.2% of those whose brains were treated first, 95% CI, 27.5-34.4, vs. 38.0% of those whose lungs were treated first, 95% CI, 29.9-44.7, P = .32.)

“These results were consistent regardless of which combination of treatment modalities the patient received – neurosurgery versus brain stereotactic radiosurgery, thoracic surgery versus thoracic radiation,” the author said.

He cautioned that “our study only included patients who were considered candidates for either surgery or radiation to both the brain and lung. The results of our study should therefore be cautiously interpreted for patients who may have contraindications to such treatment.”

Dr. Park, who didn’t take part in the study, said “the results are consistent with what I would generally expect.”

He added: “The take-home message for clinicians should be that there is no one correct answer in how to manage non–small cell lung cancer with synchronous limited metastatic disease in only the brain. If the brain disease is bulky and/or causes symptoms while the body disease isn’t – or if a biopsy or surgery is required to prove that the patient in fact has metastatic disease – then the brain disease should be treated first. On the other hand, if the body disease is bulky and/or causing symptoms while the brain disease isn’t – and there is no need for surgery but rather only a biopsy of the brain – then the body disease can be treated first.”

No funding was reported. The study authors and Dr. Park reported no financial conflicts or other disclosures.

A new analysis suggests that the initial target of therapy – lung or brain – doesn’t affect overall survival rates in patients with non–small cell lung cancer that has spread to the brain.

“The findings of our study highlight the importance of adopting a personalized, case-based approach when treating each patient” instead of always treating the brain or lung first, lead author Arvind Kumar, a medical student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

The study was released at European Lung Cancer Congress 2023.

According to the author, current guidelines recommend treating the brain first in patients with non–small cell lung cancer and a tumor that has spread to the brain.

“Determining whether the brain or body gets treated first depends on where the symptoms are coming from, how severe the symptoms are, how bulky the disease is, and how long the treatment to each is expected to take,” radiation oncologist Henry S. Park, MD, MPH, chief of the thoracic radiotherapy program at Yale University, New Haven, Conn., said in an interview. “Often the brain is treated first since surgery is used for both diagnosis of metastatic disease as well as removal of the brain metastasis, especially if it is causing symptoms. The radiosurgery that follows tends to occur within a day or a few days.”

However, he said, “if the brain disease is small and not causing symptoms, and the lung disease is more problematic, then we will often treat the body first and fit in the brain treatment later.”

For the new study, researchers identified 1,044 patients in the National Cancer Database with non–small cell lung cancer and brain metastases who received systemic therapy plus surgery, brain stereotactic radiosurgery, or lung radiation. All were treated from 2010 to 2019; 79.0% received brain treatment first, and the other 21.0% received lung treatment first.

There was no statistically significant difference in overall survival between those whose brains were treated first and those whose lungs were treated first (hazard ratio, 1.24, 95% confidence interval [CI], 0.91-1.70, P = .17). A propensity score–matched analysis turned up no difference in 5-year survival (38.2% of those whose brains were treated first, 95% CI, 27.5-34.4, vs. 38.0% of those whose lungs were treated first, 95% CI, 29.9-44.7, P = .32.)

“These results were consistent regardless of which combination of treatment modalities the patient received – neurosurgery versus brain stereotactic radiosurgery, thoracic surgery versus thoracic radiation,” the author said.

He cautioned that “our study only included patients who were considered candidates for either surgery or radiation to both the brain and lung. The results of our study should therefore be cautiously interpreted for patients who may have contraindications to such treatment.”

Dr. Park, who didn’t take part in the study, said “the results are consistent with what I would generally expect.”

He added: “The take-home message for clinicians should be that there is no one correct answer in how to manage non–small cell lung cancer with synchronous limited metastatic disease in only the brain. If the brain disease is bulky and/or causes symptoms while the body disease isn’t – or if a biopsy or surgery is required to prove that the patient in fact has metastatic disease – then the brain disease should be treated first. On the other hand, if the body disease is bulky and/or causing symptoms while the brain disease isn’t – and there is no need for surgery but rather only a biopsy of the brain – then the body disease can be treated first.”

No funding was reported. The study authors and Dr. Park reported no financial conflicts or other disclosures.

A new analysis suggests that the initial target of therapy – lung or brain – doesn’t affect overall survival rates in patients with non–small cell lung cancer that has spread to the brain.

“The findings of our study highlight the importance of adopting a personalized, case-based approach when treating each patient” instead of always treating the brain or lung first, lead author Arvind Kumar, a medical student at Icahn School of Medicine at Mount Sinai, New York, said in an interview.

The study was released at European Lung Cancer Congress 2023.

According to the author, current guidelines recommend treating the brain first in patients with non–small cell lung cancer and a tumor that has spread to the brain.

“Determining whether the brain or body gets treated first depends on where the symptoms are coming from, how severe the symptoms are, how bulky the disease is, and how long the treatment to each is expected to take,” radiation oncologist Henry S. Park, MD, MPH, chief of the thoracic radiotherapy program at Yale University, New Haven, Conn., said in an interview. “Often the brain is treated first since surgery is used for both diagnosis of metastatic disease as well as removal of the brain metastasis, especially if it is causing symptoms. The radiosurgery that follows tends to occur within a day or a few days.”

However, he said, “if the brain disease is small and not causing symptoms, and the lung disease is more problematic, then we will often treat the body first and fit in the brain treatment later.”

For the new study, researchers identified 1,044 patients in the National Cancer Database with non–small cell lung cancer and brain metastases who received systemic therapy plus surgery, brain stereotactic radiosurgery, or lung radiation. All were treated from 2010 to 2019; 79.0% received brain treatment first, and the other 21.0% received lung treatment first.

There was no statistically significant difference in overall survival between those whose brains were treated first and those whose lungs were treated first (hazard ratio, 1.24, 95% confidence interval [CI], 0.91-1.70, P = .17). A propensity score–matched analysis turned up no difference in 5-year survival (38.2% of those whose brains were treated first, 95% CI, 27.5-34.4, vs. 38.0% of those whose lungs were treated first, 95% CI, 29.9-44.7, P = .32.)

“These results were consistent regardless of which combination of treatment modalities the patient received – neurosurgery versus brain stereotactic radiosurgery, thoracic surgery versus thoracic radiation,” the author said.

He cautioned that “our study only included patients who were considered candidates for either surgery or radiation to both the brain and lung. The results of our study should therefore be cautiously interpreted for patients who may have contraindications to such treatment.”

Dr. Park, who didn’t take part in the study, said “the results are consistent with what I would generally expect.”

He added: “The take-home message for clinicians should be that there is no one correct answer in how to manage non–small cell lung cancer with synchronous limited metastatic disease in only the brain. If the brain disease is bulky and/or causes symptoms while the body disease isn’t – or if a biopsy or surgery is required to prove that the patient in fact has metastatic disease – then the brain disease should be treated first. On the other hand, if the body disease is bulky and/or causing symptoms while the brain disease isn’t – and there is no need for surgery but rather only a biopsy of the brain – then the body disease can be treated first.”

No funding was reported. The study authors and Dr. Park reported no financial conflicts or other disclosures.

At a single robotic-assisted pulmonary lobectomy center, patients with public insurance or combined public and private insurance fared worse than those with private insurance, according to a new retrospective analysis.

The study used public insurance status as a marker for low socioeconomic status (SES) and suggests that patients with combined insurance may constitute a separate population that deserves more attention.

Lower SES has been linked to later stage diagnoses and worse outcomes in NSCLC. Private insurance is a generally-accepted indicator of higher SES, while public insurance like Medicare or Medicaid, alone or in combination with private supplementary insurance, is an indicator of lower SES.

Although previous studies have found associations between patients having public health insurance and experiencing later-stage diagnoses and worse overall survival, there have been few studies of surgical outcomes, and almost no research has examined combination health insurance, according to Allison O. Dumitriu Carcoana, who presented the research during a poster session at the European Lung Cancer Congress 2023.

“This is an important insurance subgroup for us because the majority of our patients fall into this subgroup by being over 65 years old and thus qualifying for Medicare while also paying for a private supplement,” said Ms. Dumitriu Carcoana, who is a medical student at University of South Florida Health Morsani College of Medicine, Tampa.

A previous analysis by the group found an association between private insurance status and better discharge status, as well as higher 5-year overall survival. After accumulating an additional 278 patients, the researchers examined 10-year survival outcomes.

In the new analysis, 52% of 711 participants had combination insurance, while 28% had private insurance, and 20% had public insurance. The subgroups all had similar demographic and histological characteristics. The study was unique in that it found no between-group differences in higher stage at diagnosis, whereas previous studies have found a greater risk of higher stage diagnosis among individuals with public insurance. As expected, patients in the combined insurance group had a higher mean age (P less than .0001) and higher Charlson comorbidity index scores (P = .0014), which in turn was associated with lower 10-year survival. The group also had the highest percentage of former smokers, while the public insurance group had the highest percentage of current smokers (P = .0003).

At both 5 and 10 years, the private insurance group had better OS than the group with public (P less than .001) and the combination insurance group (P = .08). Public health insurance was associated with worse OS at 5 years (hazard ratio, 1.83; P less than .005) but not at 10 years (HR, 1.18; P = .51), while combination insurance was associated with worse OS at 10 years (HR, 1.72; P = .02).

“We think that patients with public health insurance having the worst 5-year overall survival, despite their lower ages and fewer comorbid conditions, compared with patients with combination insurance, highlights the impact of lower socioeconomic status on health outcomes. These patients had the same tumor characteristics, BMI, sex, and race as our patients in the other two insurance groups. The only other significant risk factor [the group had besides having a higher proportion of patients with lower socioeconomic status was that it had a higher proportion of current smokers]. But the multivariate analyses showed that insurance status was an independent predictor of survival, regardless of smoking status or other comorbidities,” said Ms. Dumitriu Carcoana.

“At 10 years post-operatively, the survival curves have shifted and the combination patients had the worst 10-year overall survival. We attribute this to their higher number of comorbid conditions and increased age. In practice, [this means that] the group of patients with public insurance type, but no supplement, should be identified clinically, and the clinical team can initiate a discussion,” Ms. Dumitriu Carcoana said.

“Do these patients feel that they can make follow-up appointments, keep up with medication costs, and make the right lifestyle decisions postoperatively on their current insurance plan? If not, can they afford a private supplement? In our cohort specifically, it may also be important to do more preoperative counseling on the importance of smoking cessation,” she added.

The study is interesting, but it has some important limitations, according to Raja Flores, MD, who was not involved with the study. The authors stated that there was no difference between the insurance groups with respect to mortality or cancer stage, which is the most important predictor of survival. However, the poster didn't include details of the authors' analysis, making it difficult to interpret, Dr. Flores said.

The fact that the study includes a single surgeon has some disadvantages in terms of broader applicability, but it also controls for surgical technique. “Different surgeons have different ways of doing things, so if you had the same surgeon doing it the same way every time, you can look at other variables like insurance (status) and stage,” said Dr. Flores.

The results may also provide an argument against using robotic surgery in patients who do not have insurance, especially since they have not been proven to be better than standard minimally invasive surgery with no robotic assistance. With uninsured patients, “you’re using taxpayer money for a more expensive procedure that isn’t proving to be any better,” Dr. Flores explained.

The study was performed at a single center and cannot prove causation due to its retrospective nature.

Ms. Dumitriu Carcoana and Dr. Flores have no relevant financial disclosures.

*This article was updated on 4/13/2023.

At a single robotic-assisted pulmonary lobectomy center, patients with public insurance or combined public and private insurance fared worse than those with private insurance, according to a new retrospective analysis.

The study used public insurance status as a marker for low socioeconomic status (SES) and suggests that patients with combined insurance may constitute a separate population that deserves more attention.

Lower SES has been linked to later stage diagnoses and worse outcomes in NSCLC. Private insurance is a generally-accepted indicator of higher SES, while public insurance like Medicare or Medicaid, alone or in combination with private supplementary insurance, is an indicator of lower SES.

Although previous studies have found associations between patients having public health insurance and experiencing later-stage diagnoses and worse overall survival, there have been few studies of surgical outcomes, and almost no research has examined combination health insurance, according to Allison O. Dumitriu Carcoana, who presented the research during a poster session at the European Lung Cancer Congress 2023.

“This is an important insurance subgroup for us because the majority of our patients fall into this subgroup by being over 65 years old and thus qualifying for Medicare while also paying for a private supplement,” said Ms. Dumitriu Carcoana, who is a medical student at University of South Florida Health Morsani College of Medicine, Tampa.

A previous analysis by the group found an association between private insurance status and better discharge status, as well as higher 5-year overall survival. After accumulating an additional 278 patients, the researchers examined 10-year survival outcomes.

In the new analysis, 52% of 711 participants had combination insurance, while 28% had private insurance, and 20% had public insurance. The subgroups all had similar demographic and histological characteristics. The study was unique in that it found no between-group differences in higher stage at diagnosis, whereas previous studies have found a greater risk of higher stage diagnosis among individuals with public insurance. As expected, patients in the combined insurance group had a higher mean age (P less than .0001) and higher Charlson comorbidity index scores (P = .0014), which in turn was associated with lower 10-year survival. The group also had the highest percentage of former smokers, while the public insurance group had the highest percentage of current smokers (P = .0003).

At both 5 and 10 years, the private insurance group had better OS than the group with public (P less than .001) and the combination insurance group (P = .08). Public health insurance was associated with worse OS at 5 years (hazard ratio, 1.83; P less than .005) but not at 10 years (HR, 1.18; P = .51), while combination insurance was associated with worse OS at 10 years (HR, 1.72; P = .02).

“We think that patients with public health insurance having the worst 5-year overall survival, despite their lower ages and fewer comorbid conditions, compared with patients with combination insurance, highlights the impact of lower socioeconomic status on health outcomes. These patients had the same tumor characteristics, BMI, sex, and race as our patients in the other two insurance groups. The only other significant risk factor [the group had besides having a higher proportion of patients with lower socioeconomic status was that it had a higher proportion of current smokers]. But the multivariate analyses showed that insurance status was an independent predictor of survival, regardless of smoking status or other comorbidities,” said Ms. Dumitriu Carcoana.

“At 10 years post-operatively, the survival curves have shifted and the combination patients had the worst 10-year overall survival. We attribute this to their higher number of comorbid conditions and increased age. In practice, [this means that] the group of patients with public insurance type, but no supplement, should be identified clinically, and the clinical team can initiate a discussion,” Ms. Dumitriu Carcoana said.

“Do these patients feel that they can make follow-up appointments, keep up with medication costs, and make the right lifestyle decisions postoperatively on their current insurance plan? If not, can they afford a private supplement? In our cohort specifically, it may also be important to do more preoperative counseling on the importance of smoking cessation,” she added.

The study is interesting, but it has some important limitations, according to Raja Flores, MD, who was not involved with the study. The authors stated that there was no difference between the insurance groups with respect to mortality or cancer stage, which is the most important predictor of survival. However, the poster didn't include details of the authors' analysis, making it difficult to interpret, Dr. Flores said.

The fact that the study includes a single surgeon has some disadvantages in terms of broader applicability, but it also controls for surgical technique. “Different surgeons have different ways of doing things, so if you had the same surgeon doing it the same way every time, you can look at other variables like insurance (status) and stage,” said Dr. Flores.

The results may also provide an argument against using robotic surgery in patients who do not have insurance, especially since they have not been proven to be better than standard minimally invasive surgery with no robotic assistance. With uninsured patients, “you’re using taxpayer money for a more expensive procedure that isn’t proving to be any better,” Dr. Flores explained.

The study was performed at a single center and cannot prove causation due to its retrospective nature.

Ms. Dumitriu Carcoana and Dr. Flores have no relevant financial disclosures.

*This article was updated on 4/13/2023.

At a single robotic-assisted pulmonary lobectomy center, patients with public insurance or combined public and private insurance fared worse than those with private insurance, according to a new retrospective analysis.

The study used public insurance status as a marker for low socioeconomic status (SES) and suggests that patients with combined insurance may constitute a separate population that deserves more attention.

Lower SES has been linked to later stage diagnoses and worse outcomes in NSCLC. Private insurance is a generally-accepted indicator of higher SES, while public insurance like Medicare or Medicaid, alone or in combination with private supplementary insurance, is an indicator of lower SES.

Although previous studies have found associations between patients having public health insurance and experiencing later-stage diagnoses and worse overall survival, there have been few studies of surgical outcomes, and almost no research has examined combination health insurance, according to Allison O. Dumitriu Carcoana, who presented the research during a poster session at the European Lung Cancer Congress 2023.

“This is an important insurance subgroup for us because the majority of our patients fall into this subgroup by being over 65 years old and thus qualifying for Medicare while also paying for a private supplement,” said Ms. Dumitriu Carcoana, who is a medical student at University of South Florida Health Morsani College of Medicine, Tampa.

A previous analysis by the group found an association between private insurance status and better discharge status, as well as higher 5-year overall survival. After accumulating an additional 278 patients, the researchers examined 10-year survival outcomes.

In the new analysis, 52% of 711 participants had combination insurance, while 28% had private insurance, and 20% had public insurance. The subgroups all had similar demographic and histological characteristics. The study was unique in that it found no between-group differences in higher stage at diagnosis, whereas previous studies have found a greater risk of higher stage diagnosis among individuals with public insurance. As expected, patients in the combined insurance group had a higher mean age (P less than .0001) and higher Charlson comorbidity index scores (P = .0014), which in turn was associated with lower 10-year survival. The group also had the highest percentage of former smokers, while the public insurance group had the highest percentage of current smokers (P = .0003).

At both 5 and 10 years, the private insurance group had better OS than the group with public (P less than .001) and the combination insurance group (P = .08). Public health insurance was associated with worse OS at 5 years (hazard ratio, 1.83; P less than .005) but not at 10 years (HR, 1.18; P = .51), while combination insurance was associated with worse OS at 10 years (HR, 1.72; P = .02).

“We think that patients with public health insurance having the worst 5-year overall survival, despite their lower ages and fewer comorbid conditions, compared with patients with combination insurance, highlights the impact of lower socioeconomic status on health outcomes. These patients had the same tumor characteristics, BMI, sex, and race as our patients in the other two insurance groups. The only other significant risk factor [the group had besides having a higher proportion of patients with lower socioeconomic status was that it had a higher proportion of current smokers]. But the multivariate analyses showed that insurance status was an independent predictor of survival, regardless of smoking status or other comorbidities,” said Ms. Dumitriu Carcoana.

“At 10 years post-operatively, the survival curves have shifted and the combination patients had the worst 10-year overall survival. We attribute this to their higher number of comorbid conditions and increased age. In practice, [this means that] the group of patients with public insurance type, but no supplement, should be identified clinically, and the clinical team can initiate a discussion,” Ms. Dumitriu Carcoana said.

“Do these patients feel that they can make follow-up appointments, keep up with medication costs, and make the right lifestyle decisions postoperatively on their current insurance plan? If not, can they afford a private supplement? In our cohort specifically, it may also be important to do more preoperative counseling on the importance of smoking cessation,” she added.

The study is interesting, but it has some important limitations, according to Raja Flores, MD, who was not involved with the study. The authors stated that there was no difference between the insurance groups with respect to mortality or cancer stage, which is the most important predictor of survival. However, the poster didn't include details of the authors' analysis, making it difficult to interpret, Dr. Flores said.

The fact that the study includes a single surgeon has some disadvantages in terms of broader applicability, but it also controls for surgical technique. “Different surgeons have different ways of doing things, so if you had the same surgeon doing it the same way every time, you can look at other variables like insurance (status) and stage,” said Dr. Flores.

The results may also provide an argument against using robotic surgery in patients who do not have insurance, especially since they have not been proven to be better than standard minimally invasive surgery with no robotic assistance. With uninsured patients, “you’re using taxpayer money for a more expensive procedure that isn’t proving to be any better,” Dr. Flores explained.

The study was performed at a single center and cannot prove causation due to its retrospective nature.

Ms. Dumitriu Carcoana and Dr. Flores have no relevant financial disclosures.

*This article was updated on 4/13/2023.

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.  

Rasi Bhadramani/iStock/Getty Images

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.  

Rasi Bhadramani/iStock/Getty Images

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.  

Rasi Bhadramani/iStock/Getty Images

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.

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

A version of this article first appeared on Medscape.com.

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

A version of this article first appeared on Medscape.com.

Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.

The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.

The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.

Wikimedia Commons/FitzColinGerald/Creative Commons License

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.

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.

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

A version of this article first appeared on Medscape.com.

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

A version of this article first appeared on Medscape.com.

Patients with degenerative mitral valve (MV) regurgitation that calls for surgery may, for the most part, safely choose either a standard procedure requiring a midline sternotomy or one performed through a minithoracotomy, suggests a randomized comparison of the two techniques.

Still, the minimally invasive approach showed some advantages in the study. Patients’ quality of recovery was about the same with both procedures at 12 weeks, but those who had the minimally invasive thoracoscopy-guided surgery had shown greater improvement 6 weeks earlier.

Also in the UK Mini Mitral Trial, hospital length of stay (LOS) was significantly shorter for patients who underwent the mini-thoracotomy procedure, and that group spent fewer days in the hospital over the following months.

But neither procedure had an edge in terms of postoperative clinical risk in the study. Rates of clinical events, such as death or hospitalization for heart failure (HHF), were about the same over 1 year.

Patients in this trial had been deemed suitable for either of the two surgeries, which were always performed by surgeons specially chosen by the steering committee for their experience and expertise.

This first randomized head-to-head comparison of the two approaches in such patients should make both patients and clinicians more confident about choosing the minimally invasive surgery for degenerative MV disease, said Enoch Akowuah, MD, Newcastle (England) University, United Kingdom.

Dr. Akowuah presented the UK Mini-Mitral Trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

A “main takeaway” for clinical practice from the trial would be that minithoracotomy MV repair “is as safe and effective as conventional sternotomy for degenerative mitral regurgitation,” said discussant Amy E. Simone, PA-C, following Dr. Akowuah’s presentation.

“I think this study is unique in that its focus is on delivering high-quality, cost-efficient care for mitral regurgitation, but also with an emphasis on patients’ goals and wishes,” said Ms. Simone, who directs the Marcus Heart Valve Center of the Piedmont Heart Institute, Atlanta.

Cardiac surgeon Thomas MacGillivray, MD, another discussant, agreed that the data presented from at least this study suggest neither the minithoracotomy nor sternotomy approach is better than the other. But he questioned whether that would hold true if applied to broader clinical practice.

Dr. MacGillivray, of MedStar Washington Hospital Center, Washington, observed that only 330 patients were randomly assigned among a total of 1,167 candidates for candidates for MV repair surgery.

Indeed, he noted, more than 200 declined and about 600 were declared ineligible for the study, “even though it had seemed as if all were appropriate for mitral valve repair. That could be viewed as a significant limitation in terms of scalability in the real world.”

Some of those patients weren’t randomly assigned because they ultimately were not considered appropriate for both procedures, and some expressed a preference for one or the other approach, Dr. Akowuah replied. Those were the most common reasons. Many others did not enter the study, he said, because their mitral regurgitation was functional, not degenerative.

The two randomization groups fared similarly for the primary endpoint reflecting recovery from surgery, so the trial was actually “negative,” Dr. Akowuah said in an interview. However, “I see it as very much a win for minithoracotomy. The outstanding questions for clinicians and patients have been about the clinical efficacy and safety of the technique. And we’ve shown in this trial that minithoracotomy is safe and effective.”

If the minithoracotomy procedure is available, he continued, “and it’s just as clinically effective and safe – and we weren’t sure that was the case until we did this trial – and the repair is almost as durable, then why have a sternotomy?”

The researchers assigned 330 patients with degenerative MV disease who were deemed suitable for either type of surgery to undergo the standard operation via sternotomy or the minithoracotomy procedure at 10 centers in the United Kingdom. The steering committee had hand-selected its 28 experienced surgeons, each of whom performed only one of the two surgeries consistently for the trial’s patients.

The technically more demanding minithoracotomy procedure took longer to perform by a mean of 44 minutes,  it prolonged cross-clamp time by 11 minutes, and it required 30 minutes more cardiopulmonary bypass support, Dr. Akowuah reported.

The two patient groups showed no significant differences in the primary endpoint of physical function and ability to return to usual activity levels at 12 weeks, as assessed by scores on the 36-Item Short Form Survey and wrist-worn accelerometer monitoring. At 6 weeks, however, the mini-thoracotomy patients had shown a significant early but temporary advantage for those recovery measures.

The minithoracotomy group clearly fared better, however, on some secondary endpoints. For example, their median hospital LOS was 5 days, compared with 6 days for the sternotomy group (P = .003), and 33.1% of the mini-thoracotomy patients were discharged within 4 days of the surgery, compared with only 15.3% of patients who had the standard procedure (P < .001).

The minithoracotomy group also had marginally more days alive out of the hospital at both 30 days (23.6 days vs. 22.4 days in the sternotomy group) and 90 days (82.7 days and 80.5 days, respectively) after the surgery (P = .03 for both differences).

Safety outcomes at 12 weeks were similar, with no significant differences in rate of death, strokes, MI, or renal impairment, or in ICU length of stay or need for more than 48 hours of mechanical ventilation, Dr. Akowuah reported.

Safety outcomes at 1 year were also similar. Mortality by then was 2.4% for the minithoracotomy patients and 2.5% for the sternotomy group, nor were there significant differences in HHF rates or need for repeat MV surgical repair.

Dr. Akowuah said the patients will be followed for up to 5 years for the primary outcomes, echocardiographic changes, and clinical events.

The minithoracotomy surgery’s longer operative times and specialized equipment make it more a expensive procedure than the standard surgery, he said. “So we need to work out in a cost-effectiveness analysis whether that is offset by the benefits,” such as shorter hospital stays or perhaps fewer transfusions or readmissions.

The study was funded by the United Kingdom’s National Institute for Health and Care Research. Dr. Akowuah reported no relevant financial relationships with industry.

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.

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.