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Hematology is in the Brodsky family’s blood
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
FROM ASH 2023
ASH 2023: Equity, Sickle Cell, and Real-Life Outcomes
Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.
“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”
As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.
In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”
Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”
Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.
Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.
She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”
ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.
AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”
Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”
Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.
He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”
Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.
“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”
As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.
In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”
Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”
Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.
Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.
She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”
ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.
AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”
Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”
Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.
He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”
Cynthia E. Dunbar, MD, chief of the Translational Stem Cell Biology Branch at the National Heart, Lung, and Blood Institute and secretary of ASH, added that insight into actual patient experiences also will be a major theme at ASH 2023.
“There is a huge growth in research on outcomes and focusing on using real-world data and how important that is,” Dr. Dunbar said. “Academic research and hematology is really focusing on patient-reported outcomes and how care is delivered in a real-world setting – actually looking at what matters to patients. Are they alive in a certain number of years? And how are they feeling?”
As an example, Dr. Dunbar pointed to an abstract that examined clinical databases in Canada and found that real-world outcomes in multiple myeloma treatments were much worse than those in the original clinical trials for the therapies. Patients reached relapse 44% faster and their overall survival was 75% worse.
In the media briefing, ASH chair of communications Mikkael A. Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami, noted that patients in these types of clinical trials “are just these pristine specimens of human beings except for the cancer that’s being treated.”
Dr. Dunbar agreed, noting that “patients who are able to enroll in clinical trials are more likely to be able to show up at the treatment center at the right time and for every dose, have transportation, and afford drugs to prevent side effects. They might stay on the drug for longer, or they have nurses who are always encouraging them of how to make it through a toxicity.”
Hematologists and patients should consider randomized controlled trials to be “the best possible outcome, and perhaps adjust their thinking if an individual patient is older, sicker, or less able to follow a regimen exactly,” she said.
Another highlighted study linked worse outcomes in African-Americans with pediatric acute myeloid leukemia to genetic traits that are more common in that population. The traits “likely explain at least in part the worst outcomes in Black patients in prior studies and on some regimens,” Dr. Dunbar said.
She added that the findings emphasize how testing for genetic variants and biomarkers that impact outcomes should be performed “instead of assuming that a certain dose should be given simply based on perceived or reported race or ethnicity.”
ASH President Robert A. Brodsky, MD, of Johns Hopkins University School of Medicine, Baltimore, highlighted an abstract that reported on the use of AI as a clinical decision support tool to differentiate two easily confused conditions — prefibrotic primary myelofibrosis and essential thrombocythemia.
AI “is a tool that’s going to help pathologists make more accurate and faster diagnoses,” he said. He also spotlighted an abstract about the use of “social media listening” to understand the experiences of patients with SCD and their caregivers. “There can be a lot of misuse and waste of time with social media, but they used this in a way to try and gain insight as to what’s really important to the patients and the caregiver.”
Also, in regard to SCD, Dr. Dunbar pointed to a study that reports on outcomes in patients who received lovotibeglogene autotemcel (lovo-cel) gene therapy for up to 60 months. Both this treatment and a CRISPR-based therapy called exa-cel “appear to result in comparable very impressive efficacy in terms of pain crises and organ dysfunction,” she said. “The hurdle is going to be figuring out how to deliver what will be very expensive and complicated therapies — but likely curative — therapies to patients.”
Another study to be presented at ASH — coauthored by Dr. Brodsky — shows promising results from reduced-intensity haploidentical bone marrow transplantation in adults with severe SCD. Results were similar to those seen with bone marrow from matched siblings, Dr. Sekeres said.
He added that more clarity is needed about new treatment options for SCD, perhaps through a “randomized trial where patients upfront get a haploidentical bone marrow transplant or fully matched bone marrow transplant. Then other patients are randomized to some of these other, newer technology therapies, and we follow them over time. We’re looking not only for overall survival but complications of the therapy itself and how many patients relapse from the treatment.”
AT ASH 2023
FDA approves first tx for rare, deadly clotting disorder
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Congenital TTP affects fewer than 1,000 people in the United States and is caused by a mutation in the ADAMTS13 gene, which makes an enzyme that regulates blood clotting. Patients with the congenital TTP typically receive prophylactic plasma-based therapy to replenish the ADAMTS13 enzyme and reduce the risk for clotting and bleeding. The condition, however, can be fatal if left untreated.
The new agent is a purified recombinant form of the ADAMTS13 enzyme that works by replacing low levels of the deficient enzyme in patients with congenital TTP. Adzynma is given prophylactically to reduce the risk for disease symptoms and on demand when a patient is experiencing an acute event, according to the FDA approval announcement.
The approval was based on a global randomized phase 3 study comparing the product with plasma-based therapies in 46 patients with congenital TTP. Patients in the trial were randomized to receive 6 months of treatment with either intravenous Adzynma — given once every other week as prophylactic enzyme replacement therapy or once daily as on-demand enzyme replacement therapy — or plasma-based therapies. The patients then crossed over to the other treatment for 6 months.
Interim findings from the study showed that Adzynma reduced the incidence of thrombocytopenia — the most common symptom of congenital TTP — by 60% compared with plasma-based therapy (rate ratio, 0.40). No patients experienced an acute TTP event during Adzynma prophylaxis, Takeda said.
Significantly more patients receiving plasma-based therapies experienced treatment-emergent adverse events compared with those receiving the biologic.
The most common side effects associated with the biologic were headache (31.3%), diarrhea (16.7%), migraine (14.6%), abdominal pain (12.5%), nausea (12.5%), upper respiratory tract infection (12.5%), dizziness (10.4%), and vomiting (10.4%). No treatment-related adverse events, including allergic reactions, were observed during administration.
“The FDA remains deeply committed in our efforts to help facilitate the development and approval of safe and effective therapies for patients with rare diseases,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, stated. The “approval reflects important progress in the development of much-needed treatment options for patients affected by this life-threatening disorder.”
A version of this article first appeared on Medscape.com.
Pregnancy in rheumatic disease quadruples risk of cardiovascular events
SAN DIEGO – Pregnant individuals with autoimmune rheumatic diseases (ARDs) are at least four times more likely to experience an acute cardiovascular event (CVE) than are pregnant individuals without these conditions, according to new research presented at the annual meeting of the American College of Rheumatology. Pregnant individuals with primary antiphospholipid syndrome (APS) had a 15-fold increase in CVE risk.
Patients who experienced CVEs were also more likely to experience preterm birth and other adverse pregnancy outcomes (APOs).
Rashmi Dhital, MD, a rheumatology fellow at the University of California, San Diego, and colleagues examined the medical records of pregnant individuals in California who had delivered singleton live-born infants from 2005 to 2020. Using data from the Study of Outcomes in Mothers and Infants (SOMI) database, an administrative population-based birth cohort in California, they identified more than 7 million individuals, 19,340 with ARDs and 7,758 with APS.
They then analyzed how many patients experienced an acute CVE during pregnancy and up to 6 weeks after giving birth.
CVEs occurred in 2.0% of patients with ARDs, 6.9% of individuals with APS, and 0.4% of women without these conditions. CVE risk was four times higher in the ARDs group (adjusted relative risk, 4.1; 95% confidence interval, 3.7-4.5) and nearly 15 times higher in the APS group (aRR, 14.7; 95% CI, 13.5-16.0) than in the comparison group. Patients with systemic lupus erythematosus (SLE) had a sixfold higher risk of CVE, which was further exacerbated by concomitant APS (18-fold higher risk) or lupus nephritis (15-fold higher risk).
Dr. Dhital also classified CVEs as either venous thromboembolism and non-VTE events. Pregnant patients with APS had a high risk for VTE-only CVE (40-fold greater) and a 3.7-fold higher risk of non-VTE events, compared with pregnant patients without these conditions. Patients with SLE along with lupus nephritis had a 20-fold increased risk of VTE-only CVE and an 11-fold higher risk of non-VTE CVE.
Although the study grouped rheumatic diseases together, “lupus is generally driving these results,” Sharon Kolasinski, MD, of the University of Pennsylvania, Philadelphia, noted in an interview. She moderated the plenary session where the research was presented. “If you take out lupus, then what is the risk? That would be an interesting question.”
Between 25% and 30% of all CVEs occurred in the postpartum period, highlighting the importance of close monitoring of cardiovascular risks and events in women with ARDs or APS both during pregnancy and postpartum, Dr. Dhital noted.
Recognizing these risks “can sometimes be challenging due to a lower suspicion of CVE in younger patients, and also symptoms overlap with normal pregnancy,” Dr. Dhital said during her plenary presentation. Working with other clinical teams could help physicians detect these risks in patients.
“It’s important for us to remember that there’s increased risk of cardiovascular events in pregnancy in our patients. It’s uncommon, but it’s not zero,” added Dr. Kolasinski, and this study highlighted when physicians should be more focused about that risk.
Dr. Dhital noted there were some limitations to the study that are inherent in using administrative databases for research that relies on ICD codes, including “the availability of information on disease activity, medications, and labs, which may restrict clinical interpretation.”
SOMI data reinforced by National Inpatient Sample study
The findings were complemented by a study using the National Inpatient Sample database to explore CVE risk in pregnant individuals with various rheumatic diseases. Lead author Karun Shrestha, MD, a resident physician at St. Barnabas Hospital in New York, and colleagues identified delivery hospitalizations from 2016 to 2019 for individuals with SLE, RA, and systemic vasculitis and looked for CVEs including preeclampsia, peripartum cardiomyopathy (PPCM), heart failure, stroke, cardiac arrhythmias, and VTE.
Out of over 3.4 million delivery hospitalizations, researchers identified 5,900 individuals with SLE, 4,895 with RA, and 325 with vasculitis. After adjusting for confounding factors such as race, age, insurance, and other comorbidities, SLE was identified as an independent risk factor for preeclampsia (odds ratio, 1.5; 95% CI, 1.1-2.1), arrhythmia (OR, 3.17; 95% CI, 1.73-5.79), and venous thrombosis (OR, 8.4; 95% CI, 2.9-22.1). Vasculitis was tied to increased risk for preeclampsia (OR, 4.7; 95% CI, 2-11.3), stroke (OR, 513.3; 95% CI, 114-2,284), heart failure (OR, 24.17; 95% CI, 4.68-124.6), and PPCM (OR, 66.7; 95% CI, 8.7-509.4). RA was tied to an increased risk for preeclampsia (OR, 1.5; 95% CI, 1.05-2.1).
Patients with SLE or vasculitis had longer, more costly hospital stays, compared with those without these conditions, and they experienced higher rates of in-hospital mortality. While previous research has demonstrated that patients with SLE have higher risk of cardiac events, there is less literature on CVE risk in pregnancies for vasculitis, Dr. Shrestha said in an interview.
“It’s something to work on,” he said.
Adverse pregnancy outcomes higher with ARDs, APS
In a second abstract also led by Dr. Dhital using SOMI data, researchers found that pregnant individuals with ARDs or APS had a higher risk of experiencing an APO – preterm birth or small-for-gestational age – than individuals without these conditions. CVEs exacerbated that risk, regardless of underlying chronic health conditions.
Over half of patients with an ARD and a CVE during pregnancy experienced an APO – most commonly preterm birth. More than one in four pregnant individuals without ARD or APS who experienced a CVE also had an APO.
After differentiating CVEs as either VTE and non-VTE events, patients with ARD and a non-VTE CVE had a fivefold greater risk of early preterm birth (< 32 weeks) and a threefold higher risk of moderate preterm birth (32 to < 34 weeks).
“These findings highlight the need for close monitoring and management of pregnant women, not only for adverse outcomes, but also for cardiovascular risks and events, in order to identify those at the highest risk for adverse outcomes,” the authors wrote. “This need is particularly significant for individuals with ARDs, as 53.4% of our population with an ARD and CVE in pregnancy experienced an APO.”
Dr. Dhital, Dr. Kolasinski, and Dr. Shrestha disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO – Pregnant individuals with autoimmune rheumatic diseases (ARDs) are at least four times more likely to experience an acute cardiovascular event (CVE) than are pregnant individuals without these conditions, according to new research presented at the annual meeting of the American College of Rheumatology. Pregnant individuals with primary antiphospholipid syndrome (APS) had a 15-fold increase in CVE risk.
Patients who experienced CVEs were also more likely to experience preterm birth and other adverse pregnancy outcomes (APOs).
Rashmi Dhital, MD, a rheumatology fellow at the University of California, San Diego, and colleagues examined the medical records of pregnant individuals in California who had delivered singleton live-born infants from 2005 to 2020. Using data from the Study of Outcomes in Mothers and Infants (SOMI) database, an administrative population-based birth cohort in California, they identified more than 7 million individuals, 19,340 with ARDs and 7,758 with APS.
They then analyzed how many patients experienced an acute CVE during pregnancy and up to 6 weeks after giving birth.
CVEs occurred in 2.0% of patients with ARDs, 6.9% of individuals with APS, and 0.4% of women without these conditions. CVE risk was four times higher in the ARDs group (adjusted relative risk, 4.1; 95% confidence interval, 3.7-4.5) and nearly 15 times higher in the APS group (aRR, 14.7; 95% CI, 13.5-16.0) than in the comparison group. Patients with systemic lupus erythematosus (SLE) had a sixfold higher risk of CVE, which was further exacerbated by concomitant APS (18-fold higher risk) or lupus nephritis (15-fold higher risk).
Dr. Dhital also classified CVEs as either venous thromboembolism and non-VTE events. Pregnant patients with APS had a high risk for VTE-only CVE (40-fold greater) and a 3.7-fold higher risk of non-VTE events, compared with pregnant patients without these conditions. Patients with SLE along with lupus nephritis had a 20-fold increased risk of VTE-only CVE and an 11-fold higher risk of non-VTE CVE.
Although the study grouped rheumatic diseases together, “lupus is generally driving these results,” Sharon Kolasinski, MD, of the University of Pennsylvania, Philadelphia, noted in an interview. She moderated the plenary session where the research was presented. “If you take out lupus, then what is the risk? That would be an interesting question.”
Between 25% and 30% of all CVEs occurred in the postpartum period, highlighting the importance of close monitoring of cardiovascular risks and events in women with ARDs or APS both during pregnancy and postpartum, Dr. Dhital noted.
Recognizing these risks “can sometimes be challenging due to a lower suspicion of CVE in younger patients, and also symptoms overlap with normal pregnancy,” Dr. Dhital said during her plenary presentation. Working with other clinical teams could help physicians detect these risks in patients.
“It’s important for us to remember that there’s increased risk of cardiovascular events in pregnancy in our patients. It’s uncommon, but it’s not zero,” added Dr. Kolasinski, and this study highlighted when physicians should be more focused about that risk.
Dr. Dhital noted there were some limitations to the study that are inherent in using administrative databases for research that relies on ICD codes, including “the availability of information on disease activity, medications, and labs, which may restrict clinical interpretation.”
SOMI data reinforced by National Inpatient Sample study
The findings were complemented by a study using the National Inpatient Sample database to explore CVE risk in pregnant individuals with various rheumatic diseases. Lead author Karun Shrestha, MD, a resident physician at St. Barnabas Hospital in New York, and colleagues identified delivery hospitalizations from 2016 to 2019 for individuals with SLE, RA, and systemic vasculitis and looked for CVEs including preeclampsia, peripartum cardiomyopathy (PPCM), heart failure, stroke, cardiac arrhythmias, and VTE.
Out of over 3.4 million delivery hospitalizations, researchers identified 5,900 individuals with SLE, 4,895 with RA, and 325 with vasculitis. After adjusting for confounding factors such as race, age, insurance, and other comorbidities, SLE was identified as an independent risk factor for preeclampsia (odds ratio, 1.5; 95% CI, 1.1-2.1), arrhythmia (OR, 3.17; 95% CI, 1.73-5.79), and venous thrombosis (OR, 8.4; 95% CI, 2.9-22.1). Vasculitis was tied to increased risk for preeclampsia (OR, 4.7; 95% CI, 2-11.3), stroke (OR, 513.3; 95% CI, 114-2,284), heart failure (OR, 24.17; 95% CI, 4.68-124.6), and PPCM (OR, 66.7; 95% CI, 8.7-509.4). RA was tied to an increased risk for preeclampsia (OR, 1.5; 95% CI, 1.05-2.1).
Patients with SLE or vasculitis had longer, more costly hospital stays, compared with those without these conditions, and they experienced higher rates of in-hospital mortality. While previous research has demonstrated that patients with SLE have higher risk of cardiac events, there is less literature on CVE risk in pregnancies for vasculitis, Dr. Shrestha said in an interview.
“It’s something to work on,” he said.
Adverse pregnancy outcomes higher with ARDs, APS
In a second abstract also led by Dr. Dhital using SOMI data, researchers found that pregnant individuals with ARDs or APS had a higher risk of experiencing an APO – preterm birth or small-for-gestational age – than individuals without these conditions. CVEs exacerbated that risk, regardless of underlying chronic health conditions.
Over half of patients with an ARD and a CVE during pregnancy experienced an APO – most commonly preterm birth. More than one in four pregnant individuals without ARD or APS who experienced a CVE also had an APO.
After differentiating CVEs as either VTE and non-VTE events, patients with ARD and a non-VTE CVE had a fivefold greater risk of early preterm birth (< 32 weeks) and a threefold higher risk of moderate preterm birth (32 to < 34 weeks).
“These findings highlight the need for close monitoring and management of pregnant women, not only for adverse outcomes, but also for cardiovascular risks and events, in order to identify those at the highest risk for adverse outcomes,” the authors wrote. “This need is particularly significant for individuals with ARDs, as 53.4% of our population with an ARD and CVE in pregnancy experienced an APO.”
Dr. Dhital, Dr. Kolasinski, and Dr. Shrestha disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
SAN DIEGO – Pregnant individuals with autoimmune rheumatic diseases (ARDs) are at least four times more likely to experience an acute cardiovascular event (CVE) than are pregnant individuals without these conditions, according to new research presented at the annual meeting of the American College of Rheumatology. Pregnant individuals with primary antiphospholipid syndrome (APS) had a 15-fold increase in CVE risk.
Patients who experienced CVEs were also more likely to experience preterm birth and other adverse pregnancy outcomes (APOs).
Rashmi Dhital, MD, a rheumatology fellow at the University of California, San Diego, and colleagues examined the medical records of pregnant individuals in California who had delivered singleton live-born infants from 2005 to 2020. Using data from the Study of Outcomes in Mothers and Infants (SOMI) database, an administrative population-based birth cohort in California, they identified more than 7 million individuals, 19,340 with ARDs and 7,758 with APS.
They then analyzed how many patients experienced an acute CVE during pregnancy and up to 6 weeks after giving birth.
CVEs occurred in 2.0% of patients with ARDs, 6.9% of individuals with APS, and 0.4% of women without these conditions. CVE risk was four times higher in the ARDs group (adjusted relative risk, 4.1; 95% confidence interval, 3.7-4.5) and nearly 15 times higher in the APS group (aRR, 14.7; 95% CI, 13.5-16.0) than in the comparison group. Patients with systemic lupus erythematosus (SLE) had a sixfold higher risk of CVE, which was further exacerbated by concomitant APS (18-fold higher risk) or lupus nephritis (15-fold higher risk).
Dr. Dhital also classified CVEs as either venous thromboembolism and non-VTE events. Pregnant patients with APS had a high risk for VTE-only CVE (40-fold greater) and a 3.7-fold higher risk of non-VTE events, compared with pregnant patients without these conditions. Patients with SLE along with lupus nephritis had a 20-fold increased risk of VTE-only CVE and an 11-fold higher risk of non-VTE CVE.
Although the study grouped rheumatic diseases together, “lupus is generally driving these results,” Sharon Kolasinski, MD, of the University of Pennsylvania, Philadelphia, noted in an interview. She moderated the plenary session where the research was presented. “If you take out lupus, then what is the risk? That would be an interesting question.”
Between 25% and 30% of all CVEs occurred in the postpartum period, highlighting the importance of close monitoring of cardiovascular risks and events in women with ARDs or APS both during pregnancy and postpartum, Dr. Dhital noted.
Recognizing these risks “can sometimes be challenging due to a lower suspicion of CVE in younger patients, and also symptoms overlap with normal pregnancy,” Dr. Dhital said during her plenary presentation. Working with other clinical teams could help physicians detect these risks in patients.
“It’s important for us to remember that there’s increased risk of cardiovascular events in pregnancy in our patients. It’s uncommon, but it’s not zero,” added Dr. Kolasinski, and this study highlighted when physicians should be more focused about that risk.
Dr. Dhital noted there were some limitations to the study that are inherent in using administrative databases for research that relies on ICD codes, including “the availability of information on disease activity, medications, and labs, which may restrict clinical interpretation.”
SOMI data reinforced by National Inpatient Sample study
The findings were complemented by a study using the National Inpatient Sample database to explore CVE risk in pregnant individuals with various rheumatic diseases. Lead author Karun Shrestha, MD, a resident physician at St. Barnabas Hospital in New York, and colleagues identified delivery hospitalizations from 2016 to 2019 for individuals with SLE, RA, and systemic vasculitis and looked for CVEs including preeclampsia, peripartum cardiomyopathy (PPCM), heart failure, stroke, cardiac arrhythmias, and VTE.
Out of over 3.4 million delivery hospitalizations, researchers identified 5,900 individuals with SLE, 4,895 with RA, and 325 with vasculitis. After adjusting for confounding factors such as race, age, insurance, and other comorbidities, SLE was identified as an independent risk factor for preeclampsia (odds ratio, 1.5; 95% CI, 1.1-2.1), arrhythmia (OR, 3.17; 95% CI, 1.73-5.79), and venous thrombosis (OR, 8.4; 95% CI, 2.9-22.1). Vasculitis was tied to increased risk for preeclampsia (OR, 4.7; 95% CI, 2-11.3), stroke (OR, 513.3; 95% CI, 114-2,284), heart failure (OR, 24.17; 95% CI, 4.68-124.6), and PPCM (OR, 66.7; 95% CI, 8.7-509.4). RA was tied to an increased risk for preeclampsia (OR, 1.5; 95% CI, 1.05-2.1).
Patients with SLE or vasculitis had longer, more costly hospital stays, compared with those without these conditions, and they experienced higher rates of in-hospital mortality. While previous research has demonstrated that patients with SLE have higher risk of cardiac events, there is less literature on CVE risk in pregnancies for vasculitis, Dr. Shrestha said in an interview.
“It’s something to work on,” he said.
Adverse pregnancy outcomes higher with ARDs, APS
In a second abstract also led by Dr. Dhital using SOMI data, researchers found that pregnant individuals with ARDs or APS had a higher risk of experiencing an APO – preterm birth or small-for-gestational age – than individuals without these conditions. CVEs exacerbated that risk, regardless of underlying chronic health conditions.
Over half of patients with an ARD and a CVE during pregnancy experienced an APO – most commonly preterm birth. More than one in four pregnant individuals without ARD or APS who experienced a CVE also had an APO.
After differentiating CVEs as either VTE and non-VTE events, patients with ARD and a non-VTE CVE had a fivefold greater risk of early preterm birth (< 32 weeks) and a threefold higher risk of moderate preterm birth (32 to < 34 weeks).
“These findings highlight the need for close monitoring and management of pregnant women, not only for adverse outcomes, but also for cardiovascular risks and events, in order to identify those at the highest risk for adverse outcomes,” the authors wrote. “This need is particularly significant for individuals with ARDs, as 53.4% of our population with an ARD and CVE in pregnancy experienced an APO.”
Dr. Dhital, Dr. Kolasinski, and Dr. Shrestha disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ACR 2023
Review finds no CV or VTE risk signal with use of JAK inhibitors for skin indications
, results from a systematic literature review, and meta-analysis showed.
“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .
For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.
The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).
The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).
In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.
The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”
Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.
“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”
However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.
Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.
, results from a systematic literature review, and meta-analysis showed.
“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .
For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.
The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).
The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).
In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.
The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”
Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.
“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”
However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.
Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.
, results from a systematic literature review, and meta-analysis showed.
“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .
For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.
The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).
The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).
In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.
The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”
Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.
“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”
However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.
Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.
FROM JAMA DERMATOLOGY
Longer edoxaban may benefit cancer patients with distal DVT
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
Patients with active cancer and newly diagnosed isolated distal deep vein thrombosis (DVT) who received 12 months of edoxaban (Savaysa) had fewer thrombotic events at 1 year than those who received 3 months of treatment, without significantly increased bleeding, in the ONCO-DVT trial.
However, lead author Yugo Yamashita, MD, of Kyoto University noted that caution is needed when determining anticoagulation strategies in individual patients with distal DVT, especially those with high risk for bleeding.
Dr. Yamashita presented the results at the annual congress of the European Society of Cardiology, and the trial was simultaneously published in the journal Circulation.
“This is the first and only randomized trial to show the superiority of longer duration over shorter duration of anticoagulation therapy for reducing thrombotic events in cancer patients with isolated distal DVT,” he said in a press briefing.
The results provide support for 12 months of edoxaban in patients with active cancer and isolated distal DVD, he said in an email.
However, “considering the risk of bleeding associated with anticoagulation therapy, physicians should make the decision of anticoagulation strategies for these patients based on risk-benefit balance of anticoagulation therapy in individual patients,” he stressed.
The take-home message for clinicians is that, “if you find minor DVT in cancer patients, please be careful, because their thrombotic risk was not low” in this trial, Dr. Yamashita said.
The study was conducted in Japan, so whether or not the results are generalizable to other populations is not clear. “Subgroup analysis based on body weight did not show any signal of different effect,” he noted, which suggests that the main results could be applied to other populations, including the U.S. population. However, “generalizability of the current results should be carried out carefully.”
Caution needed when translating findings into clinical practice
The assigned discussant, Teresa Lopez-Fernandez, MD, from La Paz University Hospital, Madrid, who was co-chairperson of 2022 ESC guidelines on cardio-oncology, noted that the optimal anticoagulation therapy strategy is unclear in patients with cancer and isolated distal DVT.
“2022 ESC guidelines on cardio-oncology and [European Society for Medical Oncology] guidelines from this year,” she said, “are both in agreement that we need to prolong anticoagulation [therapy to prevent venous thromboembolism (VTE)] when active cancer exists, and particularly in patients with metastatic cancer. The problem is that none of this text refers specifically to distal DVT.”
The ONCO-DVT trial sheds light on this, but there are a few points to consider when interpreting the findings.
Major bleeding was slightly increased in the 12-month vs 3-month edoxaban groups, although this was not statistically significant, she noted. Moreover, 75% of the patients were treated with low-dose edoxaban, mainly due to their low weight. Also, bleeding risk probably differs in different cancer types.
“These are important things that we need to keep in mind when we try to transfer this data to [inform] our clinical practice,” Dr. Lopez-Fernandez said.
She drew attention to a recent study based on RIETE registry data that suggests that “isolated distal DVT is a big problem for patients with cancer in comparison with noncancer patients, where it seems it’s a low-risk problem.”
The main takeaways from ONCO-DVT, Dr. Lopez-Fernandez said, are that it confirms that cancer-associated isolated distal DVT is a marker of poor prognosis, and it supports the need for extended anticoagulation in patients with active, ongoing cancer and isolated distal DVT.
However, “we need to be cautious to try to really understand what the bleeding risks of these patients are,” she said, “particularly because it is not always easy to transfer the results from an Asian population to other populations.”
There is also a need for further studies with other doses, with other novel oral anticoagulants, and in patients at high risk for bleeding, in clinical practice.
Dr. Yamashita said that the study suggests that there is a potential benefit of prolonged duration of anticoagulant therapy for some patients with isolated distal DVT, but not all patients should receive this dosing strategy, because some patients may be at high risk for bleeding or VTE recurrence. A subanalysis of data from ONCO-DVT study should shed further light on this.
“We need to individualize our risk stratification,” Dr. Lopez-Fernandez said, adding that notably, “a lot of patients in the 12-month group did not continue with the 12-month treatment,” which may have affected bleeding results. Dr. Yamashita agreed.
Study design and findings
From April 2019 to June 2022, the researchers enrolled and randomly assigned 604 patients with active cancer who had newly diagnosed isolated distal DVT, confirmed by ultrasonography, and were scheduled for DVT treatment with anticoagulation therapy, at 60 centers.
Active cancer was defined as a cancer diagnosis or cancer treatment (surgery, chemotherapy, radiotherapy, etc.) within 6 months of randomization, or current recurrence, local invasion, distant metastases, or hematopoietic malignancy without complete remission.
The most common reasons for ultrasonography were elevated D-dimer levels (62%) and suspected DVT because of symptoms (20%).
The patients had a mean age of 70.8 years and 28% were men. The most common cancer sites were ovaries (14%), uterus (13%), lung (11%), colon (9%), and pancreas (8%), followed by stomach, blood, and breast (each 5%).
The patients were randomly assigned 1:1 to receive 12 months or 3 months of oral edoxaban at a dose of 60 mg once daily or 30 mg once daily in patients with body weight of 60 kg or less, creatinine clearance of 30-50 mL/minute, or concomitant treatment with a potent P-glycoprotein inhibitor.
After excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group.
About 70% of patients had a body weight of 60 kg or less and about 22% had a creatinine clearance less than 50 mL/min. About three quarters received the lower dose of edoxaban.
In the 12-month edoxaban group, 223 patients completed the 1-year follow-up (66 patients had died and 7 were lost to follow-up). In the 3-month edoxaban group, 224 patients completed the 1-year follow-up (77 had died and 4 were lost to follow-up).
In the 12-month edoxaban group, 41% of the patients had discontinued treatment by 12 months. In the 3-month edoxaban group, 41% of patients had discontinued treatment by 3 months.
The primary endpoint – a symptomatic recurrent VTE event or VTE-related death – occurred in 3 of the 222 patients (1.2%) in the 12-month edoxaban group and in 22 of the 210 (8.5%) in the 3-month edoxaban group (odds ratio,0.13; 95% confidence interval, 0.03-0.44, P < .001). There were no VTE-related deaths.
The major secondary endpoint – major bleeding, according to International Society on Thrombosis and Hemostasis criteria – occurred in 28 of the 210 patients (10.2%) in the 12-month edoxaban group and in 22 of the 217 (7.6%) in the 3-month edoxaban group (OR, 1.34; 95% CI, 0.75-2.41, P = NS).
The researchers acknowledged that study limitations include an open-label design, a lower-than-expected primary endpoint rate, and less than high adherence to edoxaban, as well as the need for caution when generalizing the results to other populations.
The study was funded by Daiichi Sankyo. Dr. Yamashita disclosed receiving lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Lopez-Fernandez disclosed receiving speaker fees from Phillips, Janssen, Daiichi Sankyo, Myocardial Solutions, AstraZeneca, Pfizer, Beigene, and Bayer not related to this study.
A version of this article appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
Factor XI inhibitors: The promise of a truly safe anticoagulant?
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
The quest to find an anticoagulant that can prevent strokes, cardiovascular events, and venous thrombosis without significantly increasing risk of bleeding is something of a holy grail in cardiovascular medicine. Could the latest focus of interest in this field – the factor XI inhibitors – be the long–sought-after answer?
Topline results from the largest study so far of a factor XI inhibitor – released on Sep. 18 – are indeed very encouraging. The phase 2 AZALEA-TIMI 71 study was stopped early because of an “overwhelming” reduction in major and clinically relevant nonmajor bleeding shown with the factor XI inhibitor abelacimab (Anthos), compared with apixaban for patients with atrial fibrillation (AFib).
Very few other data from this study have yet been released. Full results are due to be presented at the scientific sessions of the American Heart Association in November. Researchers in the field are optimistic that this new class of drugs may allow millions more patients who are at risk of thrombotic events but are concerned about bleeding risk to be treated, with a consequent reduction in strokes and possibly cardiovascular events as well.
Why factor XI?
In natural physiology, there are two ongoing processes: hemostasis – a set of actions that cause bleeding to stop after an injury – and thrombosis – a pathologic clotting process in which thrombus is formed and causes a stroke, MI, or deep venous thrombosis (DVT).
In patients prone to pathologic clotting, such as those with AFib, the balance of these two processes has shifted toward thrombosis, so anticoagulants are used to reduce the thrombotic risks. For many years, the only available oral anticoagulant was warfarin, a vitamin K antagonist that was very effective at preventing strokes but that comes with a high risk for bleeding, including intracranial hemorrhage (ICH) and fatal bleeding.
The introduction of the direct-acting anticoagulants (DOACs) a few years ago was a step forward in that these drugs have been shown to be as effective as warfarin but are associated with a lower risk of bleeding, particularly of ICH and fatal bleeding. But they still cause bleeding, and concerns over that risk of bleeding prevent millions of patients from taking these drugs and receiving protection against stroke.
John Alexander, MD, professor of medicine at Duke University Medical Center, Durham, N.C., a researcher active in this area, notes that “while the DOACs cause less bleeding than warfarin, they still cause two or three times more bleeding than placebo, and there is a huge, unmet need for safer anticoagulants that don’t cause as much bleeding. We are hopeful that factor XI inhibitors might be those anticoagulants.”
The lead investigator the AZALEA study, Christian Ruff, MD, professor of medicine at Brigham and Women’s Hospital, Boston, explained why it is thought that factor XI inhibitors may be different.
“There’s a lot of different clotting factors, and most of them converge in a central pathway. The problem, therefore, with anticoagulants used to date that block one of these factors is that they prevent clotting but also cause bleeding.
“It has been discovered that factor XI has a really unique position in the cascade of how our body forms clots in that it seems to be important in clot formation, but it doesn’t seem to play a major role in our ability to heal and repair blood vessels.”
Another doctor involved in the field, Manesh Patel, MD, chief of cardiology at Duke University Medical Center, added, “We think that factor XI inhibitors may prevent the pathologic formation of thrombosis while allowing formation of thrombus for natural hemostasis to prevent bleeding. That is why they are so promising.”
This correlates with epidemiologic data suggesting that patients with a genetic factor XI deficiency have low rates of stroke and MI but don’t appear to bleed spontaneously, Dr. Patel notes.
Candidates in development
The pharmaceutical industry is on the case with several factor XI inhibitors now in clinical development. At present, three main candidates lead the field. These are abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and two small molecules, milvexian (BMS/Janssen) and asundexian (Bayer), which are both given orally.
Phase 3 trials of these three factor XI inhibitors have recently started for a variety of thrombotic indications, including the prevention of stroke in patients with AFib, prevention of recurrent stroke in patients with ischemic stroke, and prevention of future cardiovascular events in patients with acute coronary syndrome (ACS).
Dr. Alexander, who has been involved in clinical trials of both milvexian and asundexian, commented: “We have pretty good data from a number of phase 2 trials now that these factor XI inhibitors at the doses used in these studies cause a lot less bleeding than therapeutic doses of DOACs and low-molecular-weight heparins.”
He pointed out that, in addition to the AZALEA trial with abelacimab, the phase 2 PACIFIC program of studies has shown less bleeding with asundexian than with apixaban in patients with AFib and a similar amount of bleeding as placebo in ACS/stroke patients on top of antiplatelet therapy. Milvexian has also shown similar results in the AXIOMATIC program of studies.
Dr. Ruff noted that the biggest need for new anticoagulants in general is in the AFib population. “Atrial fibrillation is one of the most common medical conditions in the world. Approximately one in every three people will develop AFib in their lifetime, and it is associated with more than a fivefold increased risk of stroke. But up to half of patients with AFib currently do not take anticoagulants because of concerns about bleeding risks, so these patients are being left unprotected from stroke risk.”
Dr. Ruff pointed out that the AZALEA study was the largest and longest study of a factor XI inhibitor to date; 1,287 patients were followed for a median of 2 years.
“This was the first trial of long-term administration of factor XI inhibitor against a full-dose DOAC, and it was stopped because of an overwhelming reduction in a major bleeding with abelacimab, compared with rivaroxaban,” he noted. “That is very encouraging. It looks like our quest to develop a safe anticoagulant with much lower rates of bleeding, compared with standard of care, seems to have been borne out. I think the field is very excited that we may finally have something that protects patients from thrombosis whilst being much safer than current agents.”
While all this sounds very promising, for these drugs to be successful, in addition to reducing bleeding risk, they will also have to be effective at preventing strokes and other thrombotic events.
“While we are pretty sure that factor XI inhibitors will cause less bleeding than current anticoagulants, what is unknown still is how effective they will be at preventing pathologic blood clots,” Dr. Alexander points out.
“We have some data from studies of these drugs in DVT prophylaxis after orthopedic surgery which suggest that they are effective in preventing blood clots in that scenario. But we don’t know yet about whether they can prevent pathologic blood clots that occur in AFib patients or in poststroke or post-ACS patients. Phase 3 studies are now underway with these three leading drug candidates which will answer some of these questions.”
Dr. Patel agrees that the efficacy data in the phase 3 trials will be key to the success of these drugs. “That is a very important part of the puzzle that is still missing,” he says.
Dr. Ruff notes that the AZALEA study will provide some data on efficacy. “But we already know that in the orthopedic surgery trials there was a 70%-80% reduction in VTE with abelacimab (at the 150-mg dose going forward) vs. prophylactic doses of low-molecular-weight heparin. And we know from the DOACs that the doses preventing clots on the venous side also translated into preventing strokes on the [AFib] side. So that is very encouraging,” Dr. Ruff adds.
Potential indications
The three leading factor XI inhibitors have slightly different phase 3 development programs.
Dr. Ruff notes that not every agent is being investigated in phase 3 trials for all the potential indications, but all three are going for the AFib indication. “This is by far the biggest population, the biggest market, and the biggest clinical need for these agents,” he says.
While the milvexian and asundexian trials are using an active comparator – pitting the factor XI inhibitors against apixaban in AFib patients – the Anthos LILAC trial is taking a slightly different approach and is comparing abelacimab with placebo in patients with AFib who are not currently taking an anticoagulant because of concerns about bleeding risk.
Janssen/BMS is conducting two other phase 3 trials of milvexian in their LIBREXIA phase 3 program. Those trials involve poststroke patients and ACS patients. Bayer is also involved in a poststroke trial of asundexian as part of its OCEANIC phase 3 program.
Dr. Ruff points out that anticoagulants currently do not have a large role in the poststroke or post-ACS population. “But the hope is that, if factor XI inhibitors are so safe, then there will be more enthusiasm about using an anticoagulant on top of antiplatelet therapy, which is the cornerstone of therapy in atherosclerotic cardiovascular disease.”
In addition to its phase 3 LILAC study in patients with AFib, Anthos is conducting two major phase 3 trials with abelacimab for the treatment of cancer-associated venous thromboembolism.
Dr. Ruff notes that the indication of postsurgery or general prevention of VTE is not being pursued at present.
“The orthopedic surgery studies were done mainly for dose finding and proof of principle reasons,” he explains. “In orthopedic surgery the window for anticoagulation is quite short – a few weeks or months. And for the prevention of recurrent VTE in general in the community, those people are at a relatively low risk of bleeding, so there may not be much advantage of the factor XI inhibitors, whereas AFib patients and those with stroke or ACS are usually older and have a much higher bleeding risk. I think this is where the advantages of an anticoagulant with a lower bleeding risk are most needed.”
Dr. Alexander points out that to date anticoagulants have shown more efficacy in venous clotting, which appears to be more dependent on coagulation factors and less dependent on platelets. “Atrial fibrillation is a mix between venous and arterial clotting, but it has more similarities to venous, so I think AFib is a place where new anticoagulants such as the factor XI inhibitors are more likely to have success,” he suggests.
“So far, anticoagulants have had a less clear long-term role in the poststroke and post-ACS populations, so these indications may be a more difficult goal,” he added.
The phase 3 studies are just starting and will take a few years before results are known.
Differences between the agents
The three factor XI inhibitors also have some differences. Dr. Ruff points out that most important will be the safety and efficacy of the drugs in phase 3 trials.
“Early data suggest that the various agents being developed may not have equal inhibition of factor XI. The monoclonal antibody abelacimab may produce a higher degree of inhibition than the small molecules. But we don’t know if that matters or not – whether we need to achieve a certain threshold to prevent stroke. The efficacy and safety data from the phase 3 trials are what will primarily guide use.”
There are also differences in formulations and dosage. Abelacimab is administered by subcutaneous injection once a month and has a long duration of activity, whereas the small molecules are taken orally and their duration of action is much shorter.
Dr. Ruff notes: “If these drugs cause bleeding, having a long-acting drug like abelacimab could be a disadvantage because we wouldn’t be able to stop it. But if they are very safe with regard to bleeding, then having the drug hang around for a long time is not necessarily a disadvantage, and it may improve compliance. These older patients often miss doses, and with a shorter-acting drug, that will mean they will be unprotected from stroke risk for a period of time, so there is a trade-off here.”
Dr. Ruff says that the AZALEA phase 2 study will provide some data on patients being managed around procedures. “The hope is that these drugs are so safe that they will not have to be stopped for procedures. And then the compliance issue of a once-a-month dosing would be an advantage.”
Dr. Patel says he believes there is a place for different formations. “Some patients may prefer a once-monthly injection; others will prefer a daily tablet. It may come down to patient preference, but a lot will depend on the study results with the different agents,” he commented.
What effect could these drugs have?
If these drugs do show efficacy in these phase 3 trials, what difference will they make to clinical practice? The potential appears to be very large.
“If these drugs are as effective at preventing strokes as DOACs, they will be a huge breakthrough, and there is good reason to think they would replace the DOACs,” Dr. Alexander says. “It would be a really big deal to have an anticoagulant that causes almost no bleeding and could prevent clots as well as the DOACs. This would enable a lot more patients to receive protection against stroke.”
Dr. Alexander believes the surgery studies are hopeful. “They show that the factor XI inhibitors are doing something to prevent blood clots. The big question is whether they are as effective as what we already have for the prevention of stroke and if not, what is the trade-off with bleeding?”
He points out that, even if the factor XI inhibitors are not as effective as DOACs but are found to be much safer, they might still have a potential clinical role, especially for those patients who currently do not take an anticoagulant because of concerns regarding bleeding.
But Dr. Patel points out that there is always the issue of costs with new drugs. “New drugs are always expensive. The DOACS are just about to become generic, and there will inevitably be concerns about access to an expensive new therapy.”
Dr. Alexander adds: “Yes, costs could be an issue, but a safer drug will definitely help to get more patients treated and in preventing more strokes, which would be a great thing.”
Dr. Patel has received grants from and acts as an adviser to Bayer (asundexian) and Janssen (milvexian). Dr. Alexander receives research funding from Bayer. Dr. Ruff receives research funding from Anthos for abelacimab trials, is on an AFib executive committee for BMS/Janssen, and has been on an advisory board for Bayer.
A version of this article first appeared on Medscape.com.
Nationwide hematologists shortage: What’s being done?
Over decades, the shrinking pool of CHs – who are compensated far less than hematologist-oncologists – has put patients at risk without access to adequate and timely care. To alleviate this crisis, individual doctors and national organizations are taking action and making more resources available to CHs and their patients.
`Vicious cycle’
The root cause of the CH shortage can be traced to a dramatic reduction in the number of physicians trained in this field, as Leonard Valentino, MD, President of the National Bleeding Disorders Foundation in New York, explained in an interview.
“There is a vicious cycle where there’s not enough classical hematologists to be program directors, and therefore trainees are often steered to fellowships in oncology,” said Dr. Valentino.
According to data published in JAMA, in 1995 there were 74 classical hematology programs in the United States; by 2018, there were only 2, During this same time period, the number of combined hematology/oncology training programs (HOPs) nearly doubled, from 75 to 146. However, it is estimated that less than 5% of graduates of adult HOPs pursued a career in classical hematology, as reported in Blood Advances. This low percentage can be attributed, at least in part, to the emphasis that most HOPs place on oncology.
Dr. Valentino noted that financial pressures are also diverting medical students from becoming CHs, adding that a hematologist-oncologist can make three times the annual salary of a CH.
Furthermore, when CHs treat bleeding and clotting disorders, they often need to meet with a patient for a 60- to 90-minute initial consultation, then they go on to provide a lifetime of labor-intensive care.
“This work is neither verticalized [that is, supported by radiologists, surgeons, and a cadre of nurses], nor is it billable per hour on a scale comparable to what oncologists can charge,” Dr. Valentino explained.
The survey published in Blood Advances illustrates the consequences of such a disparity in income potential: 34% of hematology/oncology fellows surveyed were likely to enter solid tumor oncology, while 20% and 4.6% would proceed to malignant hematology and CH, respectively.
Toll on patients
Primary care doctors treat some common blood disorders, but they almost always refer more difficult or complicated cases to a shrinking population of CHs.
“For many Americans, it is getting more difficult to find providers who subspecialize in hemostasis and thrombosis disorders. Patients can expect prolonged waiting times to get evaluated after a referral” said Mukul Singal, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
Dr. Singal said the shortage is so acute that “at many institutions, malignant hematologists or oncologists are having to staff in-patient hematology consult services and see outpatient classical hematology patients. General hematologist/oncologists or medical oncologists are often not as comfortable or experienced with dealing with some of the complex CH conditions.”
A working care model, without enough doctors
In 1975, responding to patient advocacy groups, the federal government began funding hemophilia treatment centers (HTCs). Such centers offer a comprehensive care model that gives patients access to practitioners and administrative staff with the expertise to help them stay as healthy as possible. According to the Centers for Disease Control and Prevention, people with hemophilia who used an HTC were 40% less likely to die of a hemophilia-related complication and 40% less likely to be hospitalized for bleeding complications, compared to those who did not receive such specialized care.
“HTCs are effective at keeping patients out of the hospital and engaged in their lives. Between 80% and 95% of hemophilia patients get their care from an HTC and more patients want more services from them,” said Joe Pugliese, president of the Hemophilia Alliance in Lansdale, Pa.
Expanding care to meet patient demand is challenged by the restrictions on doctors’ salaries. All 140 U.S.-based HTCs share a $4.9 million federal grant but, by law, they can’t pay any provider more than $211,000 a year. “These restrictions push many people to industry, leaving too few doctors to meet patient demand,” Mr. Pugliese explained.
The fact that most HTCs are located in or near major cities also presents patients with the challenge of commuting, sometimes across state lines, to see a specialist. However, an uptick in telemedicine has provided one bright spot for many patients, allowing care to be brought to them.
The Hemophilia Alliance is also working on a multifaceted approach to change the rules, so that CHs are offered better compensation. “We have lobbyists in Washington, as well as an advocacy committee and a payer committee working to better support the HTC model,” Mr. Pugliese said.
Beyond the paycheck: Supporting CHs and patients
As market and regulatory restrictions make it difficult to boost the pay of CHs, doctors and nonprofit organizations are collaborating to support young CHs and bring more into the field. The American Society of Hematology has started and fully funded the Hematology Focused Fellowship Training Program (HFFTP). This program pairs comprehensive classical hematology training with education in transfusion medicine, sickle cell disease, hemostasis/thrombosis, systems-based hematology, health equity research, and global health. According to the program’s website, HFFTP’s goal is to add 50 new academic hematologists nationwide by 2030, in an effort to “improve the lives of patients with blood and bone marrow disorders.”
Additionally, classic hematologists are aiming to attract younger physicians and trainees to their field by introducing them to the various rewarding aspects of dealing with patients with inherited, chronic blood diseases. Programs like the Partners Physicians Academy (PPA), a 5-day training course that is specifically designed to encourage and retain young hematology students as classical hematologists, are essential to this effort.
“Along with preparing physicians to work in an HTC, programs like the Hematology Focused Fellowship Training Program and the Partners Physicians Academy are so important because they might convince young doctors to stick with non–oncology-based hematology careers, through the right mix of knowing about exciting research like gene therapy, financial and mentorship support, and a desire to meet unmet medical need,” explained Dr. Valentino.
The next PPA is taking place Sept. 18-22 in Indianapolis.
Dr. Singal, Dr. Valentino, and Mr. Pugliese had no financial disclosures to report.
Over decades, the shrinking pool of CHs – who are compensated far less than hematologist-oncologists – has put patients at risk without access to adequate and timely care. To alleviate this crisis, individual doctors and national organizations are taking action and making more resources available to CHs and their patients.
`Vicious cycle’
The root cause of the CH shortage can be traced to a dramatic reduction in the number of physicians trained in this field, as Leonard Valentino, MD, President of the National Bleeding Disorders Foundation in New York, explained in an interview.
“There is a vicious cycle where there’s not enough classical hematologists to be program directors, and therefore trainees are often steered to fellowships in oncology,” said Dr. Valentino.
According to data published in JAMA, in 1995 there were 74 classical hematology programs in the United States; by 2018, there were only 2, During this same time period, the number of combined hematology/oncology training programs (HOPs) nearly doubled, from 75 to 146. However, it is estimated that less than 5% of graduates of adult HOPs pursued a career in classical hematology, as reported in Blood Advances. This low percentage can be attributed, at least in part, to the emphasis that most HOPs place on oncology.
Dr. Valentino noted that financial pressures are also diverting medical students from becoming CHs, adding that a hematologist-oncologist can make three times the annual salary of a CH.
Furthermore, when CHs treat bleeding and clotting disorders, they often need to meet with a patient for a 60- to 90-minute initial consultation, then they go on to provide a lifetime of labor-intensive care.
“This work is neither verticalized [that is, supported by radiologists, surgeons, and a cadre of nurses], nor is it billable per hour on a scale comparable to what oncologists can charge,” Dr. Valentino explained.
The survey published in Blood Advances illustrates the consequences of such a disparity in income potential: 34% of hematology/oncology fellows surveyed were likely to enter solid tumor oncology, while 20% and 4.6% would proceed to malignant hematology and CH, respectively.
Toll on patients
Primary care doctors treat some common blood disorders, but they almost always refer more difficult or complicated cases to a shrinking population of CHs.
“For many Americans, it is getting more difficult to find providers who subspecialize in hemostasis and thrombosis disorders. Patients can expect prolonged waiting times to get evaluated after a referral” said Mukul Singal, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
Dr. Singal said the shortage is so acute that “at many institutions, malignant hematologists or oncologists are having to staff in-patient hematology consult services and see outpatient classical hematology patients. General hematologist/oncologists or medical oncologists are often not as comfortable or experienced with dealing with some of the complex CH conditions.”
A working care model, without enough doctors
In 1975, responding to patient advocacy groups, the federal government began funding hemophilia treatment centers (HTCs). Such centers offer a comprehensive care model that gives patients access to practitioners and administrative staff with the expertise to help them stay as healthy as possible. According to the Centers for Disease Control and Prevention, people with hemophilia who used an HTC were 40% less likely to die of a hemophilia-related complication and 40% less likely to be hospitalized for bleeding complications, compared to those who did not receive such specialized care.
“HTCs are effective at keeping patients out of the hospital and engaged in their lives. Between 80% and 95% of hemophilia patients get their care from an HTC and more patients want more services from them,” said Joe Pugliese, president of the Hemophilia Alliance in Lansdale, Pa.
Expanding care to meet patient demand is challenged by the restrictions on doctors’ salaries. All 140 U.S.-based HTCs share a $4.9 million federal grant but, by law, they can’t pay any provider more than $211,000 a year. “These restrictions push many people to industry, leaving too few doctors to meet patient demand,” Mr. Pugliese explained.
The fact that most HTCs are located in or near major cities also presents patients with the challenge of commuting, sometimes across state lines, to see a specialist. However, an uptick in telemedicine has provided one bright spot for many patients, allowing care to be brought to them.
The Hemophilia Alliance is also working on a multifaceted approach to change the rules, so that CHs are offered better compensation. “We have lobbyists in Washington, as well as an advocacy committee and a payer committee working to better support the HTC model,” Mr. Pugliese said.
Beyond the paycheck: Supporting CHs and patients
As market and regulatory restrictions make it difficult to boost the pay of CHs, doctors and nonprofit organizations are collaborating to support young CHs and bring more into the field. The American Society of Hematology has started and fully funded the Hematology Focused Fellowship Training Program (HFFTP). This program pairs comprehensive classical hematology training with education in transfusion medicine, sickle cell disease, hemostasis/thrombosis, systems-based hematology, health equity research, and global health. According to the program’s website, HFFTP’s goal is to add 50 new academic hematologists nationwide by 2030, in an effort to “improve the lives of patients with blood and bone marrow disorders.”
Additionally, classic hematologists are aiming to attract younger physicians and trainees to their field by introducing them to the various rewarding aspects of dealing with patients with inherited, chronic blood diseases. Programs like the Partners Physicians Academy (PPA), a 5-day training course that is specifically designed to encourage and retain young hematology students as classical hematologists, are essential to this effort.
“Along with preparing physicians to work in an HTC, programs like the Hematology Focused Fellowship Training Program and the Partners Physicians Academy are so important because they might convince young doctors to stick with non–oncology-based hematology careers, through the right mix of knowing about exciting research like gene therapy, financial and mentorship support, and a desire to meet unmet medical need,” explained Dr. Valentino.
The next PPA is taking place Sept. 18-22 in Indianapolis.
Dr. Singal, Dr. Valentino, and Mr. Pugliese had no financial disclosures to report.
Over decades, the shrinking pool of CHs – who are compensated far less than hematologist-oncologists – has put patients at risk without access to adequate and timely care. To alleviate this crisis, individual doctors and national organizations are taking action and making more resources available to CHs and their patients.
`Vicious cycle’
The root cause of the CH shortage can be traced to a dramatic reduction in the number of physicians trained in this field, as Leonard Valentino, MD, President of the National Bleeding Disorders Foundation in New York, explained in an interview.
“There is a vicious cycle where there’s not enough classical hematologists to be program directors, and therefore trainees are often steered to fellowships in oncology,” said Dr. Valentino.
According to data published in JAMA, in 1995 there were 74 classical hematology programs in the United States; by 2018, there were only 2, During this same time period, the number of combined hematology/oncology training programs (HOPs) nearly doubled, from 75 to 146. However, it is estimated that less than 5% of graduates of adult HOPs pursued a career in classical hematology, as reported in Blood Advances. This low percentage can be attributed, at least in part, to the emphasis that most HOPs place on oncology.
Dr. Valentino noted that financial pressures are also diverting medical students from becoming CHs, adding that a hematologist-oncologist can make three times the annual salary of a CH.
Furthermore, when CHs treat bleeding and clotting disorders, they often need to meet with a patient for a 60- to 90-minute initial consultation, then they go on to provide a lifetime of labor-intensive care.
“This work is neither verticalized [that is, supported by radiologists, surgeons, and a cadre of nurses], nor is it billable per hour on a scale comparable to what oncologists can charge,” Dr. Valentino explained.
The survey published in Blood Advances illustrates the consequences of such a disparity in income potential: 34% of hematology/oncology fellows surveyed were likely to enter solid tumor oncology, while 20% and 4.6% would proceed to malignant hematology and CH, respectively.
Toll on patients
Primary care doctors treat some common blood disorders, but they almost always refer more difficult or complicated cases to a shrinking population of CHs.
“For many Americans, it is getting more difficult to find providers who subspecialize in hemostasis and thrombosis disorders. Patients can expect prolonged waiting times to get evaluated after a referral” said Mukul Singal, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
Dr. Singal said the shortage is so acute that “at many institutions, malignant hematologists or oncologists are having to staff in-patient hematology consult services and see outpatient classical hematology patients. General hematologist/oncologists or medical oncologists are often not as comfortable or experienced with dealing with some of the complex CH conditions.”
A working care model, without enough doctors
In 1975, responding to patient advocacy groups, the federal government began funding hemophilia treatment centers (HTCs). Such centers offer a comprehensive care model that gives patients access to practitioners and administrative staff with the expertise to help them stay as healthy as possible. According to the Centers for Disease Control and Prevention, people with hemophilia who used an HTC were 40% less likely to die of a hemophilia-related complication and 40% less likely to be hospitalized for bleeding complications, compared to those who did not receive such specialized care.
“HTCs are effective at keeping patients out of the hospital and engaged in their lives. Between 80% and 95% of hemophilia patients get their care from an HTC and more patients want more services from them,” said Joe Pugliese, president of the Hemophilia Alliance in Lansdale, Pa.
Expanding care to meet patient demand is challenged by the restrictions on doctors’ salaries. All 140 U.S.-based HTCs share a $4.9 million federal grant but, by law, they can’t pay any provider more than $211,000 a year. “These restrictions push many people to industry, leaving too few doctors to meet patient demand,” Mr. Pugliese explained.
The fact that most HTCs are located in or near major cities also presents patients with the challenge of commuting, sometimes across state lines, to see a specialist. However, an uptick in telemedicine has provided one bright spot for many patients, allowing care to be brought to them.
The Hemophilia Alliance is also working on a multifaceted approach to change the rules, so that CHs are offered better compensation. “We have lobbyists in Washington, as well as an advocacy committee and a payer committee working to better support the HTC model,” Mr. Pugliese said.
Beyond the paycheck: Supporting CHs and patients
As market and regulatory restrictions make it difficult to boost the pay of CHs, doctors and nonprofit organizations are collaborating to support young CHs and bring more into the field. The American Society of Hematology has started and fully funded the Hematology Focused Fellowship Training Program (HFFTP). This program pairs comprehensive classical hematology training with education in transfusion medicine, sickle cell disease, hemostasis/thrombosis, systems-based hematology, health equity research, and global health. According to the program’s website, HFFTP’s goal is to add 50 new academic hematologists nationwide by 2030, in an effort to “improve the lives of patients with blood and bone marrow disorders.”
Additionally, classic hematologists are aiming to attract younger physicians and trainees to their field by introducing them to the various rewarding aspects of dealing with patients with inherited, chronic blood diseases. Programs like the Partners Physicians Academy (PPA), a 5-day training course that is specifically designed to encourage and retain young hematology students as classical hematologists, are essential to this effort.
“Along with preparing physicians to work in an HTC, programs like the Hematology Focused Fellowship Training Program and the Partners Physicians Academy are so important because they might convince young doctors to stick with non–oncology-based hematology careers, through the right mix of knowing about exciting research like gene therapy, financial and mentorship support, and a desire to meet unmet medical need,” explained Dr. Valentino.
The next PPA is taking place Sept. 18-22 in Indianapolis.
Dr. Singal, Dr. Valentino, and Mr. Pugliese had no financial disclosures to report.
Steady VKA therapy beats switch to NOAC in frail AFib patients: FRAIL-AF
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
Using JAK inhibitors for myelofibrosis
“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”
Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.
Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.
A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.
JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”
He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”
Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 109/L.
“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”
One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.
Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.
Pacritinib is approved specifically for patients with platelet counts below 50 x 109/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.
“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.
Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.
There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.
Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.
“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.
No disclosure information was reported.
“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”
Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.
Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.
A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.
JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”
He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”
Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 109/L.
“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”
One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.
Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.
Pacritinib is approved specifically for patients with platelet counts below 50 x 109/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.
“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.
Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.
There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.
Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.
“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.
No disclosure information was reported.
“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”
Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.
Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.
A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.
JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”
He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”
Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 109/L.
“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”
One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.
Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.
Pacritinib is approved specifically for patients with platelet counts below 50 x 109/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.
“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.
Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.
There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.
Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.
“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.
No disclosure information was reported.
FROM SOHO 2023