Liam Davenport

Oncologists commonly suffer “professional grief” when a patient dies – in fact, it is a “familiar, daily reality for the oncology clinician,” says one – but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.

The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.  

Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.

The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.

Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.

One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.

“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.

“I love this idea,” she said. “The most important thing is to commemorate that person.”
 

Amplified during pandemic

Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.

This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.

If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.

The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.

“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”

Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
 

Teamwork intervention

The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.

The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.

Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.

It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.

After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.

The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.

They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.

Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.

So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.

They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.

The second was time-consuming electronic health record tasks.

Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.

“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”

“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.

“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
 

Tackling burnout

The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.

Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.

Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.

Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”

Initiatives such as virtual happy hours and game nights may be helpful, she suggested.

A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”

Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.

She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”

No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.

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

Oncologists commonly suffer “professional grief” when a patient dies – in fact, it is a “familiar, daily reality for the oncology clinician,” says one – but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.

The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.  

Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.

The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.

Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.

One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.

“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.

“I love this idea,” she said. “The most important thing is to commemorate that person.”
 

Amplified during pandemic

Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.

This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.

If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.

The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.

“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”

Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
 

Teamwork intervention

The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.

The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.

Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.

It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.

After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.

The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.

They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.

Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.

So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.

They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.

The second was time-consuming electronic health record tasks.

Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.

“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”

“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.

“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
 

Tackling burnout

The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.

Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.

Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.

Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”

Initiatives such as virtual happy hours and game nights may be helpful, she suggested.

A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”

Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.

She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”

No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.

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

Oncologists commonly suffer “professional grief” when a patient dies – in fact, it is a “familiar, daily reality for the oncology clinician,” says one – but when it is also accompanied by a sense of emotional isolation, it can lead to reduced well-being and burnout.

The issue was discussed at a special session at the annual meeting of the American Society of Clinical Oncology, and several speakers offered solutions.  

Laurie Jean Lyckholm, MD, professor, Hematology/Oncology, West Virginia University School of Medicine, Morgantown, polled the audience to ask how they deal with patient-related loss and grief.

The responses showed that 44.4% said they talk with their colleagues, 16.7% said they talk about it with family and friends, but 22.2% said that they simply move on to the next patient.

Dr. Lyckholm noted that there are positive and negative ways of dealing with grief.

One example of a positive way comes from an oncologist who attended one of her talks and shared with her how his practice deals with the issue.

“At the end of every fourth Friday, he closes his community practice office early and all the oncologists, everyone, stays for a while, and they have a list of the people who have died,” Dr. Lyckholm explained. As a group, they go through the list and reminisce about the patients who died, recalling funny incidents or things that person had said.

“I love this idea,” she said. “The most important thing is to commemorate that person.”
 

Amplified during pandemic

Like many other issues, the problem of how to deal with “professional grief” was amplified during the COVID-19 pandemic. Many people were unable to see their dying relatives because of the restricted access to sealed-off, dedicated COVID-19 units. One oncologist who had developed a friendly relationship with a patient while treating them for cancer over several years was unable to visit the patient once they were ill with the disease and was left to communicate via an iPad. “It was the only way I could say ‘goodbye’ before she died. ... It still haunts me today, 2 years later,” the clinician recalled.

This anecdote illustrates “disenfranchised grief,” which occurs when an individual experiences a “significant loss and the resultant grief is not openly acknowledged, socially validated, or publicly mourned,” Dr. Lyckholm explained.

If this goes unrecognized, it can lead to shame, guilt, and organizational mistrust, resulting in reduced well-being and clinician burnout, she warned.

The pandemic also had an impact on clinicians directly. Dr. Lyckholm quoted one nurse practitioner who talked about coming back to a new “lonely normal” when returning to a Veterans Affairs hospital.

“I am still getting used to calling colleagues, and paging colleagues, and realizing that they just aren’t there,” the nurse practitioner said. “They aren’t there because they either left or died. I just didn’t expect that.”

Dr. Lyckholm said, “I don’t think we can ever stop acknowledging COVID, because it just had such a terrible impact on all of us.”
 

Teamwork intervention

The next speaker also polled the audience. Christopher Ryan Friese, PhD, RN, AOCN, Elizabeth Tone Hosmer Professor of Nursing, University of Michigan, Ann Arbor, asked the audience what strategy they would prioritize to reduce burnout, from the perspective of the entire cancer care team.

The response indicated that many (43.6%) would like to see team-based grief and bereavement sessions, while 31.1% thought it best to tackle low-value administrative work.

Dr. Friese drew on a teamwork intervention that researchers at the Dana-Farber Cancer Institute, Boston, with support from the National Cancer Institute, implemented to help identify opportunities to improve cancer care delivery services.

It began with a focus group of nurses who were invited to identify practice pain points, then six 2-hour sessions with all members of the clinical team to identify and develop service expectations and commitments across the various roles.

After these sessions, the researchers saw a decrease in missing orders from 30% to 2%, while patient satisfaction increased from 93% to 97% as a result. Interestingly, there was also a reported rise in efficiency, practice quality and safety, and respectful professional behaviors.

The pilot was then rolled out across the whole institution, and Dr. Friese and colleagues also implemented a version of the program at their community medical oncology practice.

They had a huge response from patients and clinicians alike (with participation rates of 90% and 78%, respectively), and the survey results led to changes in workflow and the standardization of communications.

Importantly for Dr. Friese, the clinicians who took part wanted to repeat the survey to evaluate any practice changes, which was not part of the study protocol and had not been envisaged by the researchers.

So they developed a survey for clinicians, using as an inspiration the Choosing Wisely campaign by the American Board of Internal Medicine Foundation to identify the best treatments to improve patient outcomes and those to deprioritize.

They used the survey on 373 clinicians at the University of Michigan Health System and found that “the number one thing was getting rid of the administrative work” – that it doesn’t have to be done specifically by physicians or other providers and that other people can do it.

The second was time-consuming electronic health record tasks.

Both of these have since been the focus of an elimination and reduction process to give clinicians more time to do what matters most to them and their patients.

“We have the opportunity to do this in a different way,” Dr. Friese said, “and I think it’s a really powerful opportunity.”

“We can retrofit the solution, which is the pizza parties, and the yoga apps, and the T-shirts ... [or] we could actually redesign the work that we’re asking clinicians to do on a daily basis,” he commented.

“We could make the work easier to do so that you have more time with patients and less time with administrative work and have more time to process grief or to celebrate successes,” he concluded.
 

Tackling burnout

The final speaker, Vicki A. Jackson, MD, MPH, chief of palliative care, Massachusetts General Hospital, emphasized that the recognition of grief by a cancer care provider is “imperative” for physician well-being and pointed out that that interventions to help “do exist,” including ASCO’s SafeHaven collection of physician well-being resources.

Oncology inherently carries with it “threats” to well-being, including uncertainty and doubt, isolation, fears over one’s usefulness, exhaustion, the witnessing of suffering, and moral distress, she noted.

Things that are necessary for well-being, in contrast, include a sense of connection and community, having boundaries between work and personal life, self-awareness, compassion, and empowerment, among others.

Dr. Jackson believes that in the current era community building within oncology must be “intentional” and not just based around “water cooler moments,” as the sense of isolation experienced by clinicians is “not fluff; this is critical.”

Initiatives such as virtual happy hours and game nights may be helpful, she suggested.

A colleague of hers likes to send out the dad joke of the day, “which made everybody groan, but let me tell you, it changed the affective tone before they started seeing all these really hard, sad patients.”

Setting boundaries, which was the topic of another session at ASCO 2023, is also an important way to address the “emotionally powerful” work of oncology, Dr. Jackson commented.

She underlined the need to channel or be “fully present when you are in the room” but emphasized the need to detach at the end of the day, commenting that “when you leave, you leave.”

No funding was declared. Dr. Friese reported relationships with Merck, NCCN/Pfizer, National Cancer Institute, Patient-Centered Outcomes Research Institute, and the Simms/Mann Foundation. No other speakers reported relevant financial relationships.

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

CHICAGO – Oncologists need to learn how to set boundaries in their professional lives and how to address their fear of saying “no” to sometimes illusory career opportunities in order to protect their well-being and reduce their risk of burnout.

This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).

Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.

Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.

“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.

“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
 

A calling, not a job

However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.

“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.

But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.

Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”

“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.

“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
 

Communicating with patients

Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”

The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”

“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”

“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”

She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”

On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”

But this can also cause problems when patients become “demanding for certain treatments,” she said.
 

Limits to ethical care?

Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”

He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”

This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.

Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?

Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.

He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.

In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.

Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”

When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
 

Goldilocks situation

Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.

Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.

Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”

“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.

In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.

“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”

“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.

Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”

Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
 

Wearing several hats

The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.

These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”

Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.

“The question is: What are all the other competing priorities that a person faces?”

For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.

He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”

“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
 

Fear of saying no

One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.

He gave an example from his own life – when he was at a soccer game and received  a call on his cell from a patient who has seen test results before he has had a chance to review them.

Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”

“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”

“So this is really a bit of an [out of] left field request, and how does this person address this?”

Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.

The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”

But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”

“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”

This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”

“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”

Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”

“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”

Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.

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

CHICAGO – Oncologists need to learn how to set boundaries in their professional lives and how to address their fear of saying “no” to sometimes illusory career opportunities in order to protect their well-being and reduce their risk of burnout.

This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).

Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.

Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.

“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.

“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
 

A calling, not a job

However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.

“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.

But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.

Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”

“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.

“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
 

Communicating with patients

Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”

The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”

“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”

“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”

She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”

On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”

But this can also cause problems when patients become “demanding for certain treatments,” she said.
 

Limits to ethical care?

Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”

He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”

This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.

Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?

Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.

He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.

In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.

Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”

When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
 

Goldilocks situation

Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.

Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.

Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”

“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.

In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.

“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”

“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.

Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”

Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
 

Wearing several hats

The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.

These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”

Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.

“The question is: What are all the other competing priorities that a person faces?”

For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.

He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”

“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
 

Fear of saying no

One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.

He gave an example from his own life – when he was at a soccer game and received  a call on his cell from a patient who has seen test results before he has had a chance to review them.

Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”

“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”

“So this is really a bit of an [out of] left field request, and how does this person address this?”

Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.

The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”

But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”

“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”

This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”

“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”

Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”

“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”

Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.

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

CHICAGO – Oncologists need to learn how to set boundaries in their professional lives and how to address their fear of saying “no” to sometimes illusory career opportunities in order to protect their well-being and reduce their risk of burnout.

This was the message from speakers at a special session on “Setting Boundaries” during the annual meeting of the American Society of Clinical Oncology (ASCO).

Monica Sheila Chatwal, MD, a medical oncologist at Moffitt Cancer Center and Research Institute, Tampa, Fla., suggested that, like a painting in a museum, physicians should have “some level of guardrail” to protect their knowledge and expertise, and also their ability to be able to continue to care for patients.

Having set boundaries “provides more emotional and cognitive flexibility, and less uncertainty, in the relationships that we have with our colleagues, with our patients, with everyone around us,” she argued.

“More importantly, boundaries acknowledge that, as humans, we are multifaceted, multidimensional people,” and that “we have lives outside of medicine, much as we may or may not want to admit that.

“It’s great to be devoted to what we do, but there are so many other aspects of ourselves that make us who we are, and that is wonderful,” she said.
 

A calling, not a job

However, the idea of demarcating one’s professional and personal life can go against the still-persistent idea that being a doctor is a calling rather than a job.

“I don’t think it matters whether you call it a job or a calling,” commented another speaker at the session, Jonathan M. Marron, MD, MPH, Dana-Farber/Boston Children’s Cancer.

But even if it is a calling, which implies that “you are supposed to devote all of yourself to the work and not to anything else,” there is still a need for setting boundaries, he argued. Saying “no” and allowing “yourself to be yourself” are important measures, Dr. Marron emphasized, as taking time out can make you a better clinician.

Crucial to that is being able to communicate with colleagues and share a degree of “vulnerability,” added Dr. Chatwal. “Showing that you’re vulnerable not only to your trainees, but also to your staff and to your patients really normalizes everything.”

“I have nurses who are feeling like they have to work 24/7 and manage their inbox to answer all of their messages, because they feel like they have to keep up.

“But it’s nice for me to be able to model that and say: ‘Listen, I want you to know it’s not urgent, please take 24 hours and we’ll come back to it.’ ”
 

Communicating with patients

Dr. Chatwal noted that, while there are clear boundaries related to sexual or physical relationships between doctors and patients and around not treating family members or friends, the boundaries pertaining to communication, and “how frequently [patients] have access to us ... are not so clearly defined.”

The advent of telemedicine has added to that, she believes, as it offers a “patient portal that can allow access 24/7.”

“Does that mean we as physicians or providers also give that level of access? Are we supposed to check messages at all periods of time?”

“More and more people are becoming more cognizant of this,” she commented, noting that the issue has taken on greater import with the rise of social media and the “ability for our patients to request us as friends.”

She pointed out that former president of the American College of Physicians Wayne J. Riley, MD, MPH, MBA, suggested doctors should maintain an air of detachment with their patients, as “it allows us to protect ourselves and continue to provide that great level of care.”

On the other hand, she noted that there has been a sea change in how patients see doctors. Whereas in the past, medicine “was very paternalistic” with doctors seen as the “be all and end all,” now patients tend to be more knowledgeable and Dr. Google “makes them much more engaged in their care.”

But this can also cause problems when patients become “demanding for certain treatments,” she said.
 

Limits to ethical care?

Dr. Marron posed the question: “Is there a limit to my ethical obligations to ethical care?”

He described a hypothetical scenario where a patient has found their doctor’s email address online and they now sends “frequent emails, despite very clear instructions to use the on-call paging system for something that’s urgent, and the electronic health record messaging system otherwise.”

This patient’s behavior is “causing a huge amount of stress” for the doctor, and this is affecting their care of other patients, as well as their academic work and home life.

Dr. Marron asked the audience: Would it be ethically acceptable to stop seeing such a patient?

Taking a quick straw poll of the audience, Dr. Marron noted that there were “not a lot of hands” raised in favor.

He suggested this is because the notion of nonabandonment comes into play, in which there is an obligation to not let patients go without providing adequate time for them to find an alternative clinician.

In this scenario, for example, the doctor could find “several local oncologists who are willing to accept the patient,” as well as talk the situation through with a trusted colleagues, and only then “compassionately but resolutely” tell the patient that they will be transferred.

Dr. Marron acknowledged that this may seem at odds with the theme of this year’s ASCO annual meeting, which emphasizes “partnering with patients.” But he argued that “it doesn’t have to be.”

When thoughtfully done, setting boundaries “can ethically allow us to give more to, and partner more with, our patients, while supporting our well-being, sense of purpose, and job satisfaction,” he argued.
 

Goldilocks situation

Speaking more broadly, Dr. Marron said that boundaries might be considered on a spectrum.

Too few boundaries can lead to conflicts of interest, loss of balance in the patient-physician relationship, and overengagement, while too many boundaries may result in insufficient connection with patients, thus reducing the “human element” and increasing a sense of disengagement.

Either way, “we run the risk of having decreased satisfaction what with what we’re doing, and decreasing the quality of patient care.”

“It’s a little bit of a Goldilocks situation: You want to find just the right balance, somewhere in the middle,” he said.

In the past, issues around having too few boundaries related to conflicts of interest. This reduced trust in the medical profession, he commented, which may have affected patient outcomes, and certainly increased the risk of reduced well-being and burnout.

“Today, we probably still lie on the end of the spectrum with too few boundaries,” Dr. Marron said, “but in a very different way, as we worry about limited work-life balance, and always being connected.”

“I don’t think there’s anybody in the room who doesn’t have some kind of electronic device, either in their hand or not too far from their hand,” he continued.

Moreover, “the patients that we’re taking care of have a greater amount of complexity than they’ve ever had before ... [with] greater numbers of needs than ever before,” and as a result, they require “a greater amount of our time as clinicians.”

Just as with the lack of boundaries in the past, this “runs the risk of us having decreased well-being and an increased risk of burnout,” he suggested.
 

Wearing several hats

The third speaker, Arif Kamal, MD, MBA, MHS, associate professor of medicine and population health, Duke University, Durham, N.C., and chief patient officer at the American Cancer Society, said that every oncologist wears several “hats” in addition to being a clinician.

These may include, in his case, being “a father, a husband, and a brother, and a soccer coach, and a lot of different things.”

Dr. Kamal underlined that recognizing these various roles is “really important,” especially when it comes to the “moment of comparison with others,” as there is a temptation to see one’s own complexity but not that of a colleague.

“The question is: What are all the other competing priorities that a person faces?”

For example, a person’s tally of publications is “just one of many metrics” when it comes to measuring the “success of a career, and, frankly, I’m not sure that’s one of the good ones,” Dr. Kamal said.

He recalled how a mentor of his when he was at the Mayo Clinic had a “remarkable dip” in the number of publications at a certain point in his career, and he explained to Dr. Kamal that this was the time “when my kids needed me the most.”

“That was really important,” Dr. Kamal said, “because it taught me a lesson about having mentors in your life that are not only focused on your career and academic success, but also those who are very interested in the other hats that you wear.”
 

Fear of saying no

One way of setting boundaries is saying no to certain requests, Dr. Kamal commented.

He gave an example from his own life – when he was at a soccer game and received  a call on his cell from a patient who has seen test results before he has had a chance to review them.

Dr. Kamal also painted a hypothetical scenario, where a doctor on junior faculty, staffing a GI oncology clinic 4 days a week, is also volunteering to collect and organize new cases for the tumor board, and is writing several letters of intent for pharmaceutical trials. They are saying “yes” to 90% of the requests for their time, he said, and the result is they go home “most days feeling like their tank is on empty.”

“Then this person gets asked by the division chief to serve on the hospital’s pain committee,” he said, “regardless of the fact that this is not necessarily in their clinical or research interests.”

“So this is really a bit of an [out of] left field request, and how does this person address this?”

Dr. Kamal said that a useful concept to consider is something commonly ascribed to teenagers, that of the fear of missing out, or FOMO.

The problem is that, “due to this concept of FOMO, when opportunities come your way, saying ‘no’ to them gives rise to the question: What if the opportunity never comes back?”

But Dr. Kamal also reminded the audience that “without being able to say no to things ... your capacity will go down.”

“That’s really important to recognize, because for a long time, healing professions have been thought of as [having] people that can continue to expand and expand and expand, without calling out this concept of inflation.”

This is really about “being true to yourself,” and acknowledging that “no one is going to set boundaries for you.”

“That was a tough lesson I learned in my career,” Dr. Kamal commented, and when he looked for guidance, he found that “everyone is struggling with this.”

Setting boundaries, he emphasized, requires “a certain amount of looking inward ... and it requires some bravery.”

“You just have to ask yourself: Is the only reason you’re going to do something because of FOMO?” Dr. Kamal commented. “Maybe that’s okay, but you have to acknowledge that’s the case.”

Dr. Chatwal reported a relationship with Merck. Dr. Marron reported relationships with Genzyme, Partner Therapeutics, ROM Technologies, Arnett, Draper, & Hagood, and Trentalange & Kelley. Dr. Kamal reported relationships with Acclivity Health, Prepped Health, Private Diagnostic Clinic, AstraZeneca, Care4ward, Compassus, HERON, Janssen Oncology, Medtronic, New Century Health, UnitedHealth Group, and Janssen Oncology.

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

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

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

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

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

MUNICH – Patients undergoing carotid artery stenting (CAS) may have fewer ischemic lesions and a lower lesion burden if they are given the reversible P2Y12 receptor antagonist ticagrelor rather than clopidogrel, another P2Y12 inhibitor, prior to the procedure, secondary endpoint results of the PRECISE-MRI trial suggest.

More than 200 patients with carotid artery stenosis underwent MRI and were randomized to ticagrelor or clopidogrel before undergoing CAS. They then had two follow-up MRIs to assess the presence of emergent ischemic lesions.

Although the trial, which was stopped early, failed to show a difference between the two treatments in the primary endpoint – occurrence of at least one ischemic lesion – it did show that ticagrelor was associated with significant reductions in secondary endpoints including the total number and total volume of new lesions.

There were also significantly fewer cases of a composite of adverse clinical events with ticagrelor versus clopidogrel, but no difference in rates of hemorrhagic bleeds.

The research was presented at the annual European Stroke Organisation Conference .

Highlighting the failure of the trial to meet its primary endpoint, study presenter Leo Bonati, MD, head of the Stroke Center, Rena Rheinfelden, University Hospital Basel (Switzerland), pointed out that the proportion of patients with one or more ischemic brain lesions was “much higher than expected.”

Based on the secondary outcomes, the study nevertheless indicates that, “compared with clopidogrel, ticagrelor reduces the total burden of ischemic brain lesions occurring during CAS,” he said.

Ticagrelor is therefore a “safe alternative to clopidogrel as an add-on to aspirin to cover carotid artery stent procedures.”

Dr. Bonati cautioned, however, that the findings are preliminary.
 

‘Promising’ results

Session cochair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the stroke unit, department of neurology, Oslo University Hospital, called the results “interesting” and “promising.”

She said in an interview that they “also provide us with an additional option” in the management of patients undergoing CAS.

Dr. Sandset suggested that “it may have been a little bit hard to prove the primary endpoint” chosen for the trial, but believes that the secondary endpoint results “are very interesting.”

“Of course, we would need more data and further trials to provide some reassurance that we can use ticagrelor in this fashion,” she said.
 

Major complication

Dr. Bonati began by noting that the major procedural complication of CAS is embolic stroke, but this may be prevented with optimized antiplatelet therapy.

Previous studies have shown that ticagrelor is superior to clopidogrel as an add-on to aspirin in reducing rates of major adverse cardiovascular events in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Adding the drug to aspirin is also superior to aspirin alone in preventing recurrent stroke in patients with minor stroke or transient ischemic attack, Dr. Bonati said.

To examine whether ticagrelor is superior to clopidogrel as an add-on to aspirin in preventing ischemic brain lesions during CAS, the team conducted a randomized, open, active-controlled trial.

They recruited patients with ≥ 50% symptomatic or asymptomatic carotid stenosis undergoing CAS in line with local guidelines and performed a baseline MRI scan and clinical examination.

The patients were then randomized to ticagrelor or clopidogrel plus aspirin 1-3 days before undergoing CAS. A second MRI and clinical examination, as well as an ultrasound scan, was performed at 1 to 3 days post-CAS, with a third set of examinations performed at 28-32 days after the procedure.

The study included 14 sites in Belgium, Germany, Italy, the Netherlands, Switzerland, and the United Kingdom. Enrollment was stopped after 209 of the originally planned 370 patients, “due to slow recruitment and a lack of further funding,” Dr. Bonati said.

Of those, 207 patients were included in the intention-to-treat safety analysis, and 172 in the per-protocol efficacy analysis.

The mean age of the patients was 69.0-69.5 years in the two treatment groups, and 67%-71% were male. Dr. Bonati noted that 52%-55% of the patients had symptomatic stenosis, and that in 83%-88% the stenosis was severe.

The majority (79%-82%) of patients had hypertension, alongside hypercholesterolemia, at 76% in both treatment groups.

Dr. Bonati showed that there was no significant difference in the primary efficacy outcome of the presence of at least new ischemic brain lesion on the second or third MRI, at 74.7% for patients given ticagrelor versus 79.8% with clopidogrel, or a relative risk of 0.94 (95% confidence interval, 0.79-1.10; P = .43).

However, there was a significant reduction in the number of new ischemic lesions, at a median of 2 (interquartile range, 0.5-5.5) with ticagrelor versus 3 with clopidogrel (IQR, 1-8), or an exponential beta value of 0.63 (95% CI, 0.42-0.95; P = .027).

Ticagrelor was also associated with a significant reduction in the total volume of lesions, at a median of 66 mcL (IQR, 2.5-2.19) versus 91 mcL (IQR, 25-394) for clopidogrel, or an exponential beta value of 0.30 (95% CI, 0.10-0.92; P = .030).

Patients assigned to ticagrelor also had a significantly lower rate of the primary clinical safety outcome, a composite of stroke, myocardial infarction, major bleeding, or cardiovascular death, at 2.9% versus 7.8% (relative risk, 0.36; 95% CI, 0.08-1.20). This was driven by a reduction in rates of post-CAS stroke.

Dr. Bonati noted that there was no significant difference in the presence of at least one hemorrhagic lesion after CAS, at 42.7% with ticagrelor and 47.6% in the clopidogrel group (RR, 0.90; 95% CI, 0.63-1.26).

There was also a similar rate of microbleeds between the two treatment groups, at 36.6% in patients given ticagrelor and 47.6% in those assigned to clopidogrel.

The study was investigator initiated and funded by an unrestricted research grant from AstraZeneca. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Patients with high lipoprotein(a) (Lp[a]) levels not only have an almost twofold higher coronary plaque burden than those with low levels but also a faster rate of plaque progression, an observational imaging study shows.

This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.

The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.

At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.

Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.

Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.

He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.

He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”

Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”

However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.

“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
 

Plaque burden

Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.

Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.

“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.

But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.

Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”

It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”

Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.

These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”

Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”

For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”

Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”

What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.

To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.

In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.

After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.

The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).

The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).

Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.

Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).

High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)

Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).

No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.

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

MANNHEIM, GERMANY – Patients with high lipoprotein(a) (Lp[a]) levels not only have an almost twofold higher coronary plaque burden than those with low levels but also a faster rate of plaque progression, an observational imaging study shows.

This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.

The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.

At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.

Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.

Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.

He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.

He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”

Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”

However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.

“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
 

Plaque burden

Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.

Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.

“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.

But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.

Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”

It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”

Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.

These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”

Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”

For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”

Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”

What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.

To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.

In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.

After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.

The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).

The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).

Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.

Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).

High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)

Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).

No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.

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

MANNHEIM, GERMANY – Patients with high lipoprotein(a) (Lp[a]) levels not only have an almost twofold higher coronary plaque burden than those with low levels but also a faster rate of plaque progression, an observational imaging study shows.

This could explain the greater risk for major adverse cardiovascular events seen in patients with high Lp(a) levels, suggests the research, presented during the annual European Atherosclerosis Society Congress.

The team performed follow-up coronary CT angiography (CCTA) on almost 275 patients who had undergone imaging approximately 10 years earlier, finding that almost one-third had high Lp(a) levels.

At baseline, per cent plaque volumes were 1.8 times greater in high Lp(a) patients versus those with low levels of the protein. After 10 years, plaque volumes were 3.3 times larger in patients with high Lp(a) levels.

Over this period, the rate of increase of plaque volume was 1.9 times greater in patients with high Lp(a) levels.

Study presenter Nick S. Nurmohamed, MD, PhD candidate, department of vascular medicine, Amsterdam University Medical Centers, also showed that high Lp(a) levels were associated with a 2.1-fold increase in rates of MACE.

He said in an interview that this finding could be related to Lp(a) increasing inflammatory signaling in the plaque, “making it more prone to rupture, and we saw that on the CCTA scans,” where high Lp(a) levels were associated with the presence of more high-risk plaques.

He added that in the absence of drugs that target Lp(a) levels directly, the results underline the need to focus on other means of lipid-lowering, as well as “creating awareness that Lp(a) is associated with plaque formation.”

Dr. Nurmohamed said that “for the moment, we have to treat patients with high Lp(a) with other risk-lowering therapies, such as low-density lipoprotein [LDL] cholesterol–lowering drugs, and the management of other risk factors.”

However, he noted that “there are a couple of Lp(a)-lowering medications in trials,” with results expected in the next 2-3 years.

“Then we will have the means to treat those patients, and with CCTA we can identify the patients with the biggest risk,” Dr. Nurmohamed added.
 

Plaque burden

Philippe Moulin, MD, PhD, head of endocrinology and professor of human nutrition at Faculté Lyon Est, Claude Bernard Lyon (France) 1 University, said that the association between Lp(a) and plaque burden has been seen previously in the literature in a very similar study but with only 1-year follow-up.

Similarly, registry data have suggested that Lp(a) is associated with worsening plaque progression over time.

“Here, with 10-year follow-up, [the study] is much more interesting,” due to its greater statistical power, he said in an interview. It is also “well-documented” and uses an “appropriate” methodology.

But Dr. Moulin underlined that the number of patients with high Lp(a) levels included in the study is relatively small.

Consequently, the researchers were not able to look at the level and rate of progression of atherosclerosis between different quartiles of Lp(a), “so you have no dose-response analysis.”

It also does not “establish causality,” as it remains an observational study, despite being longitudinal, “well done, and so on.”

Dr. Moulin added that the study nevertheless adds “one more stone” to the construct of the idea of high risk around high Lp(a) levels, and “prepares the ground” for the availability of two drugs to decrease Lp(a) levels, expected in 2026 and 2027.

These are expected to substantially reduce Lp(a) levels and achieve a reduction in cardiovascular risk of around 20%-40%, “which would be interesting,” especially as “we have patients who have Lp(a) levels four times above the upper normal value.”

Crucially, they may already have normal LDL cholesterol levels, meaning that, for some patients, “there is clearly a need for such treatment, as long as it is proven that it will decrease cardiovascular risk.”

For the moment, however, the strategy for managing patients with high Lp(a) remains to increase the dose of statin and to have more stringent targets, although Dr. Moulin pointed out that, “when you give statins, you raise slightly Lp(a) levels.”

Dr. Nurmohamed said in an interview that “we know from largely genetic and observational studies that Lp(a) is causally associated with atherosclerotic cardiovascular disease.”

What is less clear is the exact underlying mechanism, he said, noting that there have been several imaging studies in high and low Lp(a) patients that have yielded conflicting results in terms of the relationship with plaque burden.

To investigate the impact of Lp(a) levels on long-term coronary plaque progression, the team invited patients who had taken part in a previous CCTA study to undergo repeat CCTA, regardless of their underlying symptoms.

In all, 299 patients underwent follow-up imaging a median of 10.2 years after their original scan. Plaque volumes were quantified and adjusted for vessel volumes, and the patients were classified as having high (≥ 70 nmol/L) or low (< 70 nmol/L) Lp(a) levels.

After excluding patients who had undergone coronary artery bypass grafting, the team analyzed 274 patients with a mean age at baseline of 57 years. Of these, 159 (58%) were men. High Lp(a) levels were identified in 87 (32%) patients.

The team found that at baseline, patients with high Lp(a) levels had significantly larger percent atheroma volumes than those with low levels, at 3.92% versus 2.17%, or an absolute difference of 1.75% (P = .013).

The difference between the two groups was even greater at the follow-up, when percent atheroma volumes reached 8.75% in patients with high Lp(a) levels versus 3.90% for those with low levels, or an absolute difference of 4.85% (P = .005).

Similar findings were seen when looking separately at percentage of noncalcified and calcified plaque volumes as well as when analyzing for the presence of low-density plaques.

Multivariate analysis taking into account clinical risk factors, statin use, and CT tube voltage found that high Lp(a) levels were associated with a greater percent atheroma volume at baseline, at an odds ratio versus low Lp(a) of 1.83 (95% confidence interval, 0.12-3.54; P = .037).

High Lp(a) levels were also linked to a larger percent atheroma volume on follow-up imaging, at an odds ratio of 3.25 (95% CI, 0.80-5.71; P = .010), and a significantly greater change in atheroma volume from baseline to follow-up imaging, at an odds ratio of 1.86 (95% CI, 0.59-3.14; P = .005)

Finally, the team showed that, after adjusting for clinical risk factors, high baseline Lp(a) levels were associated with an increased risk of MACE during the follow-up period, at a hazard ratio versus low Lp(a) levels of 2.10 (95% CI, 1.01-4.29, P = .048).

No funding was declared. Dr. Nurmohamed is cofounder of Lipid Tools. Other authors declare relationships with Amgen, Novartis, Esperion, Sanofi-Regeneron, Ackee, Cleerly, GW Heart and Vascular Institute, Siemens Healthineers, and HeartFlow.

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

CHICAGO – New results in the treatment of advanced ovarian cancer have been welcomed by an expert not involved in the trial, even though the study showed only an improvement in progression-free survival (PFS), not yet overall survival.

The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.

A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.

This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.

Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”

She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.

Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”

She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”

Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”

“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”

Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
 

Access to treatment and testing

When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.

They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”

She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.

Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”

She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”

“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.

Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”

“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
 

Study details

Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.

“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.

While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.

The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.

Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.

After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:

• Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)

In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.

Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.

Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).

In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.

While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”

She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.

The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.

Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.

The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).

Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
 

Tackling underserved patient populations

Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.

Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.

Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.

The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.

The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.

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

CHICAGO – New results in the treatment of advanced ovarian cancer have been welcomed by an expert not involved in the trial, even though the study showed only an improvement in progression-free survival (PFS), not yet overall survival.

The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.

A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.

This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.

Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”

She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.

Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”

She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”

Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”

“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”

Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
 

Access to treatment and testing

When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.

They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”

She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.

Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”

She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”

“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.

Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”

“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
 

Study details

Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.

“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.

While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.

The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.

Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.

After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:

• Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)

In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.

Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.

Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).

In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.

While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”

She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.

The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.

Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.

The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).

Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
 

Tackling underserved patient populations

Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.

Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.

Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.

The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.

The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.

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

CHICAGO – New results in the treatment of advanced ovarian cancer have been welcomed by an expert not involved in the trial, even though the study showed only an improvement in progression-free survival (PFS), not yet overall survival.

The results come from the DUO-O trial, in which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) and immunotherapy with the anti–PD-L1 antibody durvalumab (Imfinzi) were added on to standard of care with paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin) in patients with newly diagnosed,non–BRCA-mutated advanced ovarian cancer.

A preplanned interim analysis revealed that the addition of durvalumab and olaparib was associated with a 37% improvement of PFS, compared with the standard of care of chemotherapy plus bevacizumab alone.

This improvement increased to 51% in patients who had tumors positive for homologous recombination deficiency (HRD), which indicates the inability to effectively repair double-stranded DNA breaks, a defect that is present in approximately 70% of ovarian cancers.

Coprincipal investigator Carol Aghajanian, MD, chief of the gynecologic medical oncology service at Memorial Sloan Kettering Cancer Center, New York, described the benefit seen with the novel combination therapy as both “statistically significant and clinically meaningful.”

She was speaking at a press briefing held ahead of the annual meeting of the American Society of Clinical Oncology, where the results were presented.

Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at University of Florida Health, Gainesville, said the results represents a “huge step forward.”

She added the rate of progress it represents may not be “quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies that are important, like this one, really means so much to that individual patient in that exam room.”

Dr. Markham underlined that around 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage. “They know what they are facing,” she said. “The vast majority” of them will have a recurrence “at some point.”

“So while progression-free survival may not necessarily mean their overall survival, there will be hope it does. And I’m very excited to see where this study heads in that direction.” Dr. Markham added that PFS is “very important to our patients,” and the study does represent progress. “We are chipping away at improving outcomes for advanced ovarian cancer.”

Moreover, “women are often disappointed when their tumor doesn’t have a BRCA mutation because they know that that may limit some of their treatment options,” and so the current study suggests that there are “options for all-comers” and “there is still hope.”
 

Access to treatment and testing

When asked whether there could be any access issues for patients clinically eligible for the novel combination, Dr. Aghajanian said that all of the drugs have been approved by the Food and Drug Administration for indications that cover this usage.

They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to co-pay assistance programs and the like.”

She said that patients can then “be counseled on their expected benefit,” based on their BRCA and HRD testing.

Dr. Markham, on the other hand, said she is “a little less optimistic” about access, explaining that she practices in the southern United States, and “our populations [and] insurance coverages are a bit different.”

She noted that, at her institution, a “fair number of patients are underinsured,” and they “ran into a lot of issues with people not being able to afford their copays,” which can be “prohibitive.”

“A large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity, that that individual patient may experience and the need for copay assistance programs or other support mechanisms,” Markham said.

Dr. Aghajanian added that “financial toxicity and the access issue comes even prior to the treatment, in getting those BRCA1/2 tests and the HRD testing done, so patients have the information they need to make informed decisions.”

“We do have disparities with genetic testing and genomic testing that need to be solved,” she said.
 

Study details

Previous studies, including SOLO1 and PAOLA-1, have shown that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.

“However, there still remains unmet need, especially in some patient subgroups without a BRCA mutation,” Dr. Aghajanian said.

While the addition of immunotherapy to standard of care has yet to show a clinical benefit in this setting in phase 3 trials, the phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in nongermline, BRCA-mutated, platinum-sensitive relapsed cancer.

The phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as a maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without a tumor BRCA1/2 mutation.

Patients were required to have had no prior systemic therapy for ovarian cancer, and be naive to both PARP inhibition and immunotherapy. They also had to have completed up-front primary debulking surgery, or be scheduled to undergo the procedure.

After an initial cycle of paclitaxel/carboplatin chemotherapy, the patients were randomly assigned to one of three regimens:

• Standard of care treatment, comprising chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib-placebo (arm 2)
• Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab, and olaparib (arm 3)

In the maintenance phase, bevacizumab was to be given for a total of 15 months, while durvalumab and olaparib, or their equivalent placebos, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or another discontinuation criteria was met.

Dr. Aghajanian presented results from a preplanned interim analysis, with a date cutoff of Dec. 5, 2022.

Among HRD-positive patients, those in arm 3 had a significantly longer PFS than those in arm 1, at a median of 37.3 months versus 23 months, or a hazard ratio of 0.49 (P < .0001).

In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS over arm 1, at 24.2 months versus 19.3 months, or an HR of 0.63 (P < .0001), indicating that the trial met both of its primary endpoints.

While there was a numerical difference in median PFS between arm 2 and arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means that relative contribution of adding durvalumab alone is not clear, Dr. Aghajanian commented, and said that this comparison “will be reassessed at the time of the final PFS analysis.”

She added that a “PFS effect was observed across all subgroups for the arm 3 versus arm 1 comparison,” including in the HRD-negative subgroup, at a median of 20.9 months versus 17.4 months, or an HR of 0.68.

The safety and tolerability of the regimens were generally consistent with what is known for the individual agents, she commented.

Serious adverse events were reported in 34%, 43%, and 39% of patients in arms 1, 2, and 3, respectively.

The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of those in arm 2, and 31% of those in arm 3) followed by anemia (in 8%, 8%, and 24%, respectively).

Dose modifications were required in 72% of arm 1 patients, 80% of those in arm 2, and 85% of arm 3 patients. Treatment discontinuation was recorded in 20%, 26%, and 35%, respectively.
 

Tackling underserved patient populations

Discussing the results, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the department of surgery and cancer, Imperial College London, said that, while the regimen may seem new, the treatments involved are “veterans,” and that they are nevertheless tackling previously underserved patient populations.

Dr. Fotopoulou, who was not involved in the study, noted that the results were highly anticipated, and the study has delivered a “breakthrough in ovarian cancer.” She nevertheless questioned the choice of the control arm, and pointed out that the hazard ratio in favor of the combination therapy is “relatively modest” considering that it involves three drugs.

Dr. Fotopoulou highlighted, however, that one of the most important results was in the HRD-negative patients, which she characterized as the equivalent of the clinicians going to “the dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she underlined that the results are from an interim analysis.

The key question that remains, Dr. Fotopoulou asked, is “why? What is making the difference?” She noted that, unfortunately, the trial design does not allow the identification of the relative contribution of olaparib and durvalumab.

The study was sponsored by AstraZeneca, and conducted in collaboration with the European Network of Gynaecological Oncological Trial Groups, GOG Foundation, and Myriad Genetic Laboratories. Dr. Aghajanian declared relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche. Dr. Markham declared relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, Lilly, Tesaro, Novartis, VBL Therapeutics, AstraZeneca, and Merck.

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

CHICAGO – Many patients with locally advanced rectal cancer who do not have high-risk disease can skip radiotherapy to the pelvic area, and instead be treated with chemotherapy alone and then surgery, say researchers reporting results from the PROSPECT trial.

“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.

“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”

Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”

“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”

Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.

She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”

Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”

The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
 

Chemoradiation is standard approach

Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.

She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.

“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”

However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.

This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”

Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”

The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”

The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.

They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.

All patients then underwent surgery, with low anterior resection with total mesorectal excision.

The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.

The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.

Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).

Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.

Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.

FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.

She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.

“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.

She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
 

Trial results

After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).

The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.

Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.

Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.

The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).

In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).

However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).

At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).

“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.

“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.

The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.

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

CHICAGO – Many patients with locally advanced rectal cancer who do not have high-risk disease can skip radiotherapy to the pelvic area, and instead be treated with chemotherapy alone and then surgery, say researchers reporting results from the PROSPECT trial.

“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.

“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”

Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”

“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”

Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.

She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”

Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”

The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
 

Chemoradiation is standard approach

Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.

She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.

“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”

However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.

This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”

Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”

The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”

The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.

They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.

All patients then underwent surgery, with low anterior resection with total mesorectal excision.

The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.

The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.

Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).

Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.

Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.

FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.

She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.

“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.

She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
 

Trial results

After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).

The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.

Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.

Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.

The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).

In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).

However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).

At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).

“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.

“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.

The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.

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

CHICAGO – Many patients with locally advanced rectal cancer who do not have high-risk disease can skip radiotherapy to the pelvic area, and instead be treated with chemotherapy alone and then surgery, say researchers reporting results from the PROSPECT trial.

“This study establishes preoperative therapy with FOLFOX and only selective use of chemoradiation for patients with locally advanced rectal cancer,” commented principal investigator Deborah Schrag, MD, MPH, gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center, New York.

“Having this option is important for several reasons,” she said. “First, in many parts of the world, radiation therapy is not readily accessible. An all-chemotherapy approach may make curative intent treatment accessible for patients in these resource-constrained settings. Additionally, given the rising rates of colorectal cancer in young patients, this provides an option for patients who wish to preserve fertility or avoid early menopause.”

Reacting to the findings, Pamela Kunz, MD, leader of the gastrointestinal cancers program at Yale Cancer Center, New Haven, Conn., commented: “What’s important here is that radiation can be safely omitted in many patients with clinically advanced rectal cancer – this is really ‘less is more.’ ”

“We can spare select patients from receiving radiation without compromising efficacy,” she said. “This leads to improved quality of life, and reduced side effects, including things like early menopause and infertility.”

Dr. Kunz spoke at a press briefing where the results were highlighted prior to being presented at a plenary session at the annual meeting of the American Society of Clinical Oncology.

She said the trial was “practice changing, and it aligns incredibly well with the theme at this year’s annual meeting around de-escalation of therapy and partnering with patients.”

Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, added that the theme may be de-escalation, but in this case it is “really more accurately optimization, because you were able to de-escalate in 91%, but you found the 9% who really needed that escalation, if you will.”

The efficacy results were published simultaneously in the New England Journal of Medicine, while the patient-reported outcomes were published in the Journal of Clinical Oncology.
 

Chemoradiation is standard approach

Presenting the findings, Dr. Schrag began by noting that approximately half of all new rectal cancer diagnoses have locally advanced disease, which in the United States represents 48,000 cases per year.

She explained that the “standard approach” to treatment is 5½ weeks of daily chemoradiation, comprising radiation to the pelvis alongside sensitizing chemotherapy with a fluoropyrimidine, followed by surgery, and then approximately 16 weeks of adjuvant chemotherapy.

“This way, we have achieved very good outcomes,” Dr. Schrag noted, with the inclusion of radiation in the 1980s a “critically important advance” in slowing rates of recurrence, which is a “cause of enormous suffering.”

However, the treatment is “long and hard,” and the pelvic radiation causes “real toxicities,” she said. These can include impaired bowel, bladder, and sexual function, and an increase in late effects, such as increased risk of pelvic fractures and secondary cancers, as well as infertility and early menopause, and impaired bone marrow function.

This depressed bone marrow function can “become a problem for people going into chemotherapy into the future,” while infertility and early menopause are “a big deal because we’re seeing increasing diagnosis of rectal cancer in people before the age of 50 years.”

Dr. Schrag said that, since chemoradiotherapy became the standard of care, there has been “so much progress,” with better chemotherapy, better surgical techniques, and more screening, so we’re finding more tumors when they are smaller and easier to treat.”

The impetus for the PROSPECT trial, Dr. Schrag said, was therefore: “Could we use radiotherapy more selectively, and only give it to people who don’t respond to chemotherapy rather than giving [it] to everybody?”

The trial enrolled 1,128 patients with rectal cancer with clinically staged T2 node–positive, T3 node–negative, or T3 node–positive disease and who were candidates for sphincter-sparing surgery.

They were randomly assigned to receive either a modified chemotherapy regimen (n = 585) or standard chemoradiation (n = 543). The mean age of the patients was 57 years; 34.5% were female. The majority (85%) were White.

All patients then underwent surgery, with low anterior resection with total mesorectal excision.

The standard chemoradiotherapy consisted of pelvic radiotherapy at 50.4 Gy over 28 fractions alongside sensitizing chemotherapy with either fluorouracil or capecitabine.

The modified chemotherapy regimen consisted of mFOLFOX6, which included modified oxaliplatin with l-leucovorin, and bolus/continuous infusion of 5-fluorouracil.

Patients in the mFOLFOX6 group whose primary tumor decreased in size by at least 20% after the six cycles proceeded straight to surgery, while were rest given the chemoradiotherapy before surgery (9% ended up receiving chemoradiotherapy).

Postoperative adjuvant chemotherapy with six cycles in the mFOLFOX6 group, or eight cycles in the chemoradiotherapy group, was suggested but not mandated.

Dr. Schrag said in an interview that the team chose to use mFOLFOX6 because of their long experience in using it.

FOLFOX first became available in 2002, and randomized controlled trials showed that it was more effective than 5-fluorouracil alone in colon cancer trials.

She explained that locally advanced rectal cancer patients were “never included” in those trials because they were already receiving chemoradiotherapy, but that its use in metastatic rectal cancer, coupled with the data in colon cancer, led them to try it in the current setting.

“It’s also quite tolerable, it’s given every 2 weeks, and it’s familiar to oncologists everywhere,” Dr. Schrag added.

She noted that it’s “not risk free,” with an increased risk of neuropathy, “which is not a great side effect, but we’re able to modulate that.”
 

Trial results

After a median follow-up of 58 months, mFOLFOX6 was found to be noninferior to chemoradiotherapy for disease-free survival, at a hazard ratio for disease recurrence or death of 0.92 (P = .005 for noninferiority).

The 5-year disease-free survival was 80.8% in the mFOLFOX6 group and 78.6% among patients assigned to chemoradiotherapy, while 5-year overall survival was 89.5% versus 90.2%, at a nonsignificant HR for death of 1.04.

Rates of local recurrence at 5 years were low, at 1.8% with mFOLFOX6 and 1.6% with chemoradiotherapy.

Grade 3 or higher adverse effects were twice as common in the mFOLFOX6 group than among patients who received chemoradiotherapy, at 41% versus 22.8%, although the researchers noted that the treatment period was also twice as long in the chemotherapy arm.

The most common grade 3 or higher adverse effects with mFOLFOX6 were neutropenia (20.3%), pain (3.1%), and hypertension (2.9%), while those with chemoradiotherapy were lymphopenia (8.3%), diarrhea (6.4%), and hypertension (1.7%).

In terms of patient reported outcomes, patients receiving mFOLFOX6 reported lower rates of diarrhea and better overall bowel function during the neoadjuvant phase than those given chemoradiotherapy (P < .05 for all).

However, those assigned to chemoradiotherapy experienced lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting during treatment (P < .05 for all).

At 12-month postoperative follow-up, however, those differences had disappeared, and patients originally assigned to mFOLFOX6 had lower rates of fatigue and neuropathy, and better sexual function, than those given chemoradiotherapy (P < .05 for all).

“During the treatment itself, multiple symptoms were worse with chemotherapy, but a year after treatment ended, those symptoms resolved and the pattern flipped so that patients who received radiation exhibited lingering symptoms,” said coinvestigator Ethan Basch, MD, MSc, chief of medical oncology, and director of the cancer outcomes research program at University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill.

“Patients ideally will understand the potential impact of treatments on how they feel and function when making choices, so as oncologists we need to talk with our patients about their options and the consequences of those options,” he said in a statement.

The study was funded by the National Cancer Institute of the National Institutes of Health. Dr. Schrag reported relationships with Merck, JAMA, the American Association for Cancer Research, and Grail. Dr. Basch reported relationships with AstraZeneca, Navigating Cancer, Resilience Care, SIVAN Innovation, ASCO, Centers for Medicare & Medicaid Services, JAMA, the National Cancer Institute, and the Patient-Centered Outcomes Research Institute. Dr. Kunz reported relationships with Novartis, Genentech/Roche, Amgen, Crinetics Pharmaceuticals, Natera, HUTCHMED, and Isotope Technologies Munich. Dr. Gralow reported relationships with Genentech/Roche.

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

Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MANNHEIM, Germany – Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.

The research was presented May 23 at the 91st European Atherosclerosis Society Congress.

Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.

It was approved in December 2012 by the U.S. Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.

The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein cholesterol of almost 54%, with nearly 42% reaching target levels.

The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
 

Early diagnosis ‘imperative’

The findings show that the “early diagnosis and treatment of HoFH is imperative,” said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at Sant Joan de Reus University Hospital, Tarragona, Spain.

“I think that, with these results, we are bringing a new hope for this group of patients,” he continued. “I also think we will increase the quality of life, not just of the patients but also all the families involved in [managing] this problem.”

Session co-chair Andreas Zirlik, MD, PhD, head of the department of cardiology and chairman of the University Heart Center Graz, LKH-University Hospital, and Medical University of Graz (Austria), was more circumspect in his appraisal of the results.

He told this news organization that it is “always very difficult to establish therapy in pediatrics,” and believes that the drug “will give us an additional option” in managing HoFH.

However, Dr. Zirlik warned that he is a “little bit concerned” about lomitapide’s adverse event profile, and “would need to see a little bit deeper into the safety data.”

Highlighting the elevations in liver enzymes of around 25%, he asked: “What does it mean?” And how will it “play out in the long run?”

Beyond lomitapide, Dr. Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. “So, let’s see how they pan out,” he said.
 

Life-limiting condition

HoFH is an “ultra-rare, life-limiting condition,” with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Dr. Masana said during his presentation.

Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.

To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.

“As you can imagine,” Dr. Masana said, “we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary.”

Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, then a follow-up period.

For the current presentation, Dr. Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.

Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).

This meant that 41.9% of patients achieved their EAS LDL cholesterol target of less than 135 mg/dL at some point during the 24-week treatment period.

Stratifying by age, the reduction between baseline and week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.

Dr. Masana explained that the results were “a little bit better in the younger group because they were receiving less treatment at this stage of the disease” than the older group.

He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).

Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event but no deaths.

He said that, despite these figures, the adverse events were “mostly mild or moderate.”

The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, “in general, associated with a lack of adherence to the low-fat diet.”

Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Dr. Masana as “moderate.”

The study was sponsored by Amryt Pharma. Dr. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Intensive systolic blood pressure (SBP) management in the 24 hours after successful recanalization with intra-arterial thrombectomy (IAT) substantially increases the risk of a poor outcome at 3 months, suggests results from the OPTIMAL-BP trial.

The research, presented at the annual European Stroke Organisation Conference, supports the latest U.S. and European guidelines, which recommend a relatively high upper SBP limit.

For the trial, which was halted early, more than 300 patients who successfully underwent IAT for acute ischemic stroke were randomly assigned to intensive or conventional BP management within 2 hours of recanalization.

Patients in the intensive group were 44% less likely than those assigned to conventional management to have a favorable outcome of a modified Rankin Scale (mRS) score of 0-2 at 3 months, while having similar rates of adverse outcomes.

The results suggest that intensive BP lowering in the 24 hours after recanalization leads to an increased risk of disability without decreasing the risk of intracerebral hemorrhage (ICH) or death, said study presenter Hyo Suk Nam, MD, PhD, department of neurology, Yonsei (South Korea) University.

Consequently, the trial “does not support intensive blood pressure management” in that early post-IAT period, although the “optimal blood pressure range remains unclear and requires more investigation,” he said.

Dr. Nam added that the results suggest, “despite recanalization, some areas in the ischemic brain may have already been damaged,” or that surrounding areas continue to have reduced blood circulation.

He believes that these areas may have reduced capacity for autoregulation and so “may not effectively counteract sudden drops in blood pressure.

“Thus, intensive blood pressure lowering may further reduce blood flow ... and exacerbate ischemic injury.”

On the other hand, the conventional group confirmed prior studies indicating that high SBP is associated with poor outcomes.

Dr. Nam suggested that increased BP “may be a physiological response to the acute stress of stroke,” but that the adverse outcomes in some patients “might reflect stroke severity rather than being a direct effect of raised blood pressure.”

Session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics at Vall d’Hebron Hospital, Barcelona, commented that “it’s very important to remember that the guidances are endorsed by the results of this study.

He said in an interview that “intensive blood pressure lowering harms the brain, especially just after reperfusion.

“So, the results are in line with the previous concept that we need to be careful, as intensive blood pressure lowering is associated with clinical deterioration and poor outcomes.”

He agreed with Dr. Nam that, with high BP also being harmful, the optimal range is currently unclear.

Dr. Molina underlined, however, that, in the absence of further studies, “we have to stick to the guidelines.”

Dr. Nam pointed out that, while high BP can result in reperfusion injury or ICH, “too low blood pressure can worsen cerebral ischemia.”

Yet the management of BP after successful recanalization with IAT is “largely unknown.”

He noted that, while both the European Stroke Organisation and American Heart Association/American Stroke Association guidelines recommend that BP should be kept below 180/105 mm Hg in patients who have undergone successful recanalization, the evidence class for this recommendation is “weak.”

Furthermore, observational studies have indicated that higher maximum or average SBP is associated with poor outcomes, but two multicenter clinical trials of intensive BP lowering after IAT, BP-TARGET and ENCHANTED2/MT, had conflicting results.

The researchers therefore investigated whether intensive BP management would result in better clinical outcomes in the 24 hours after successful recanalization with IAT.

They conducted a multicenter, open-label trial in which patients aged 20 years and older who underwent IAT for acute ischemic stroke with large cerebrovascular occlusion and had an SBP of at least 140 mm Hg were recruited from 19 centers in South Korea between June 2020 and November 2022.

The patients were randomly assigned within 2 hours of successful recanalization to intensive BP management, targeting an SBP less than 140 mm Hg, or conventional management, targeting an SBP of 140-180 mm Hg.

Clinicians could use local treatment protocols based on available intravenous BP-lowering drugs. BP was measured every 15 minutes for the first hour after randomization and then hourly for 24 hours.

The trial was terminated early because of safety concerns after the ENCHANTED2/MT trial revealed a negative impact on mRS scores at 3 months with intensive BP management.

Of 1,606 potentially eligible patients with acute ischemic stroke treated with IAT, 306 were randomly assigned, with 155 in the intensive group and 150 in the conventional group included in the primary analysis.

The mean age was 73.1 years, and 40.3% were women. The average National Institutes of Health Stroke Scale (NIHSS) score prior to IAT was 13. The mean time from stroke onset to randomization was 480 minutes (interquartile range, 320-820 minutes).

At 24 hours, the mean SBP in the intensive group was 129.2 mm Hg versus 138.0 mm Hg in the conventional group, for a between-group difference of 9.6 mm Hg (95% confidence interval, –12.2 to –6.9, P < .001).

Patients in the intensive group spent 80.3% of the first 24 hours with SBP less than 140 mm Hg versus 54.2% in the conventional group (P < .001). In contrast, conventional group patients spent 42.1% of the first 24 hours with SBP 140-180 mm Hg versus 14.2% in the intensive group.

Crucially, Dr. Nam showed that patients in the intensive BP-lowering group were significantly less likely than those in the conventional group to have a favorable outcome, defined as an mRS score of 0-2, at 3 months, at 39.4% versus 54.4%, or an adjusted odds ratio of 0.56 (95% CI, 0.33-0.96, P = .034).

Moreover, a poor outcome was 1.84 (95% CI, 1.17-2.91) times more common in the intervention group than the conventional group, Dr. Nam reported, with a number needed to harm of 6.6.

In terms of safety, there was no significant difference in rates of symptomatic ICH between the groups, at 9% in the intensive versus 8.1% in the conventional groups, or an aOR of 1.10 (95% CI, 0.48-2.53, P = .816).

There was also no difference in the rate of death related to the index stroke within 90 days, at 7.7% versus 5.4% (AOR, 1.73; 95% CI, 0.61-4.92, P = .307).

There were also no significant differences between the groups in key secondary outcomes, such as NIHSS score at 24 hours, recanalization at 24 hours, favorable outcome on the mRS at 1 month, and the EQ-5D-3L quality of life score.

However, patients in the intensive group were substantially more likely to experience malignant brain edema, at 7.7% versus 1.3% in the conventional group (aOR, 7.88; 95% CI, 1.57-39.39, P = .012).

Restricted cubic spline regression analysis indicated that there was a U-shaped relationship between mean SBP during the 24 hours following IAT and the odds ratio of a poor outcome, in which both a low and a high BPe were unfavorable.

Dr. Nam cautioned that, when interpreting the results, the early termination of the study may have reduced its statistical power and increased the likelihood of random and exaggerated treatment effects.

He also noted that the study was conducted in South Korea, and so the results may not be generalizable to other populations.

The study received a grant from the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health and Welfare. No relevant financial relationships were declared.

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