Outcomes were mixed among ischemic stroke patients with large vessel occlusion who underwent thrombectomy by an interventional cardiologist as part of a multidisciplinary stroke team, in a single-center, prospective study from Poland.

Results from the 2-year experience show mechanical thrombectomy took longer when carried out by interventional cardiologists than by vascular surgeons and neuroradiologists (120 minutes vs. 105 minutes; P = .020).

The procedures were also less likely to achieve angiographic success, defined as a Thrombolysis in Cerebral Infarction (TICI) scale score of 2b or 3 (55.7% vs. 71.7%; P = .013), reported Krystian Wita, MD, PhD, Medical University of Silesia, Katowice, Poland, and colleagues.

The differences in duration and recanalization require further attention, they noted, and are related to a learning curve, more time dedicated to decision-making and, in some cases, needing a second opinion. Cardiologists performed 80 procedures compared with 116 for vascular surgeons and 52 for neuroradiologists, and treated twice as many patients with a previous stroke (13.9% vs. 6.5%).

Still, the interventional cardiologist- and noncardiologist-treated groups had similar functional independence at 3 months, defined by a modified Rankin Scale (mRS) score of 0 to 2 (44.4% vs. 54.8%; P = .275). Mortality was also similar at 3 months (31.3% vs. 28.0%; P = .595).

“This is the first analysis to prove the noninferiority of the cardiology services in the treatment of stroke with mechanical thrombectomy,” the authors reported in JACC: Cardiovascular Interventions.

But commenting for this news organization, J Mocco, MD, senior vice chair of neurosurgery and director of the Cerebrovascular Center at Mount Sinai Health System, New York, said this study isn’t designed as a noninferiority trial, is “grossly underpowered,” and the comparator cohort is not a gold standard comparator cohort.

“More importantly, they show that the cardiologists got significantly worse technical results and took longer, and we know that technical outcomes and the time to treatment are the two strongest predictors of outcome, which completely correlates with the fact that patients had 11% worse outcomes overall,” he said.

“It’s dumbfounding to me that this has been presented as evidence [that] an interventional cardiologist should be performing thrombectomy,” added Dr. Mocco, president-elect of the Society of NeuroInterventional Surgery.

Dr. Wita and coauthor Andrzej Kulach, MD, PhD, also with the Medical University of Silesia, told this news organization that timing is critical in mechanical thrombectomy (MT) and the sooner it’s performed, the better. But it cannot be performed by just any interventional cardiologist (IC).

“The IC must be trained in the procedure and cooperate with the neurologist to get good results,” they said. “We would like to stress that it is not a procedure for any cath lab and any cardiologist on duty. A network of cardiologists trained in MT must be organized and the stroke teams developed for the local unit to make the strategy reasonable and safe.”

The study was conducted from 2019 to 2020 and to participate, interventional cardiologists had to have performed a minimum of 700 angioplasties and 1,500 coronary angiographies and undergone complex training in thrombectomy, including 14-day training in a reference center and certified courses on a phantom and an animal model. They were also experienced in carotid angioplasty and participated as the second operators in neurointerventions.

“Considering the cardiologists are acting here in a multidisciplinary team led by neurologists, the findings are not surprising,” Dr. Wita and Dr. Kulach said. “What was surprising, is a certain level of skepticism among neurologists when cardiologists are to be involved in the procedure. We hope the quality of cardiology services will help to get over it.”

Major thrombectomy trials such as PRAGUE-16 have supported a role for interventional cardiologists to help meet demand for stroke thrombectomy. Dr. Wita and Dr. Kulach said there’s a lack of trained neuroradiologists and developed infrastructure for thrombectomy, whereas there’s a sufficient network of catheterization laboratories and trained cardiologists who could be involved.

The take-home message from the study, they said, is to “use the existing infrastructure to optimize the treatment of stroke. Building one from the very beginning is more time and resources-consuming.”

Dr. Mocco said a physician’s training is not a factor in the pathway to neurointerventional expertise, as long as they’re willing to put in the appropriate amount of specialization and training.

“There’s no way this represents a turf war or the neurology community somehow protecting its space, which is often used as a distraction, just like the idea that there’s not enough people,” he said. “It’s just not the case. Neurointervention is the most multispecialty space that I’m aware of.”

In the United States, at least, the problem isn’t a lack of resources or people to provide the service, but in getting patients to the correct hospitals, Dr. Mocco said. “We don’t have regionalized stroke care in the United States for the most part, so patients go to any hospital that says they provide stroke care rather than necessarily being triaged to capable centers that can provide the care.”

A 2021 Medicare analysis by Dr. Mocco and colleagues found that higher physician and hospital stroke thrombectomy volumes were associated with lower inpatient mortality and better outcomes.

Efforts are underway to regionalize care and delivery of patients in Los Angeles County and New York City, for example, where ambulances preferentially take patients with suspected large vessel occlusion to thrombectomy-capable stroke centers certified by independent organizations, Dr. Mocco said. In New York, “they’ve shown it has improved outcomes.”

Estêvão Carvalho de Campos Martins, MD, Hospital de Força Aérea do Galeão, Rio de Janeiro, and Fernando Luiz de Melo Bernardi, MD, Hospital Regional do Oeste, Chapecó, Brazil, noted in an accompanying editorial that the observational study is “hypothesis-generating only” and that the disconnect between technical and clinical outcomes is due to a type II error of low power.

They suggest that collaboration between specialties will be “essential for defining the optimal training program, so that ICs can reach solid procedural results.

“The accumulated experience with virtual simulation-based training for stroke could act as an educational accelerator but should be inserted in a prespecified program,” the editorialists said. “How to train and how to insert ICs into [an] MT interdisciplinary team is the current debate; meanwhile ICs are here, and many of them already contributing.”

Dr. Mocco is the principal investigator on research trials funded by Stryker Neurovascular, Microvention, and Penumbra; and is an investor in Cerebrotech, Imperative Care, Endostream, Viseon, BlinkTBI, Myra Medical, Serenity, Vastrax, NTI, RIST, Viz.ai , Synchron, Radical, and Truvic. He serves, or has recently served, as a consultant for: Cerebrotech, Viseon, Endostream, Vastrax, RIST, Synchron, Viz.ai , Perflow, and CVAid. Dr. Carvalho de Campos Martins and Dr. Luiz de Melo Bernardi have disclosed no relevant financial relationships.

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

Outcomes were mixed among ischemic stroke patients with large vessel occlusion who underwent thrombectomy by an interventional cardiologist as part of a multidisciplinary stroke team, in a single-center, prospective study from Poland.

Results from the 2-year experience show mechanical thrombectomy took longer when carried out by interventional cardiologists than by vascular surgeons and neuroradiologists (120 minutes vs. 105 minutes; P = .020).

The procedures were also less likely to achieve angiographic success, defined as a Thrombolysis in Cerebral Infarction (TICI) scale score of 2b or 3 (55.7% vs. 71.7%; P = .013), reported Krystian Wita, MD, PhD, Medical University of Silesia, Katowice, Poland, and colleagues.

The differences in duration and recanalization require further attention, they noted, and are related to a learning curve, more time dedicated to decision-making and, in some cases, needing a second opinion. Cardiologists performed 80 procedures compared with 116 for vascular surgeons and 52 for neuroradiologists, and treated twice as many patients with a previous stroke (13.9% vs. 6.5%).

Still, the interventional cardiologist- and noncardiologist-treated groups had similar functional independence at 3 months, defined by a modified Rankin Scale (mRS) score of 0 to 2 (44.4% vs. 54.8%; P = .275). Mortality was also similar at 3 months (31.3% vs. 28.0%; P = .595).

“This is the first analysis to prove the noninferiority of the cardiology services in the treatment of stroke with mechanical thrombectomy,” the authors reported in JACC: Cardiovascular Interventions.

But commenting for this news organization, J Mocco, MD, senior vice chair of neurosurgery and director of the Cerebrovascular Center at Mount Sinai Health System, New York, said this study isn’t designed as a noninferiority trial, is “grossly underpowered,” and the comparator cohort is not a gold standard comparator cohort.

“More importantly, they show that the cardiologists got significantly worse technical results and took longer, and we know that technical outcomes and the time to treatment are the two strongest predictors of outcome, which completely correlates with the fact that patients had 11% worse outcomes overall,” he said.

“It’s dumbfounding to me that this has been presented as evidence [that] an interventional cardiologist should be performing thrombectomy,” added Dr. Mocco, president-elect of the Society of NeuroInterventional Surgery.

Dr. Wita and coauthor Andrzej Kulach, MD, PhD, also with the Medical University of Silesia, told this news organization that timing is critical in mechanical thrombectomy (MT) and the sooner it’s performed, the better. But it cannot be performed by just any interventional cardiologist (IC).

“The IC must be trained in the procedure and cooperate with the neurologist to get good results,” they said. “We would like to stress that it is not a procedure for any cath lab and any cardiologist on duty. A network of cardiologists trained in MT must be organized and the stroke teams developed for the local unit to make the strategy reasonable and safe.”

The study was conducted from 2019 to 2020 and to participate, interventional cardiologists had to have performed a minimum of 700 angioplasties and 1,500 coronary angiographies and undergone complex training in thrombectomy, including 14-day training in a reference center and certified courses on a phantom and an animal model. They were also experienced in carotid angioplasty and participated as the second operators in neurointerventions.

“Considering the cardiologists are acting here in a multidisciplinary team led by neurologists, the findings are not surprising,” Dr. Wita and Dr. Kulach said. “What was surprising, is a certain level of skepticism among neurologists when cardiologists are to be involved in the procedure. We hope the quality of cardiology services will help to get over it.”

Major thrombectomy trials such as PRAGUE-16 have supported a role for interventional cardiologists to help meet demand for stroke thrombectomy. Dr. Wita and Dr. Kulach said there’s a lack of trained neuroradiologists and developed infrastructure for thrombectomy, whereas there’s a sufficient network of catheterization laboratories and trained cardiologists who could be involved.

The take-home message from the study, they said, is to “use the existing infrastructure to optimize the treatment of stroke. Building one from the very beginning is more time and resources-consuming.”

Dr. Mocco said a physician’s training is not a factor in the pathway to neurointerventional expertise, as long as they’re willing to put in the appropriate amount of specialization and training.

“There’s no way this represents a turf war or the neurology community somehow protecting its space, which is often used as a distraction, just like the idea that there’s not enough people,” he said. “It’s just not the case. Neurointervention is the most multispecialty space that I’m aware of.”

In the United States, at least, the problem isn’t a lack of resources or people to provide the service, but in getting patients to the correct hospitals, Dr. Mocco said. “We don’t have regionalized stroke care in the United States for the most part, so patients go to any hospital that says they provide stroke care rather than necessarily being triaged to capable centers that can provide the care.”

A 2021 Medicare analysis by Dr. Mocco and colleagues found that higher physician and hospital stroke thrombectomy volumes were associated with lower inpatient mortality and better outcomes.

Efforts are underway to regionalize care and delivery of patients in Los Angeles County and New York City, for example, where ambulances preferentially take patients with suspected large vessel occlusion to thrombectomy-capable stroke centers certified by independent organizations, Dr. Mocco said. In New York, “they’ve shown it has improved outcomes.”

Estêvão Carvalho de Campos Martins, MD, Hospital de Força Aérea do Galeão, Rio de Janeiro, and Fernando Luiz de Melo Bernardi, MD, Hospital Regional do Oeste, Chapecó, Brazil, noted in an accompanying editorial that the observational study is “hypothesis-generating only” and that the disconnect between technical and clinical outcomes is due to a type II error of low power.

They suggest that collaboration between specialties will be “essential for defining the optimal training program, so that ICs can reach solid procedural results.

“The accumulated experience with virtual simulation-based training for stroke could act as an educational accelerator but should be inserted in a prespecified program,” the editorialists said. “How to train and how to insert ICs into [an] MT interdisciplinary team is the current debate; meanwhile ICs are here, and many of them already contributing.”

Dr. Mocco is the principal investigator on research trials funded by Stryker Neurovascular, Microvention, and Penumbra; and is an investor in Cerebrotech, Imperative Care, Endostream, Viseon, BlinkTBI, Myra Medical, Serenity, Vastrax, NTI, RIST, Viz.ai , Synchron, Radical, and Truvic. He serves, or has recently served, as a consultant for: Cerebrotech, Viseon, Endostream, Vastrax, RIST, Synchron, Viz.ai , Perflow, and CVAid. Dr. Carvalho de Campos Martins and Dr. Luiz de Melo Bernardi have disclosed no relevant financial relationships.

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

Outcomes were mixed among ischemic stroke patients with large vessel occlusion who underwent thrombectomy by an interventional cardiologist as part of a multidisciplinary stroke team, in a single-center, prospective study from Poland.

Results from the 2-year experience show mechanical thrombectomy took longer when carried out by interventional cardiologists than by vascular surgeons and neuroradiologists (120 minutes vs. 105 minutes; P = .020).

The procedures were also less likely to achieve angiographic success, defined as a Thrombolysis in Cerebral Infarction (TICI) scale score of 2b or 3 (55.7% vs. 71.7%; P = .013), reported Krystian Wita, MD, PhD, Medical University of Silesia, Katowice, Poland, and colleagues.

The differences in duration and recanalization require further attention, they noted, and are related to a learning curve, more time dedicated to decision-making and, in some cases, needing a second opinion. Cardiologists performed 80 procedures compared with 116 for vascular surgeons and 52 for neuroradiologists, and treated twice as many patients with a previous stroke (13.9% vs. 6.5%).

Still, the interventional cardiologist- and noncardiologist-treated groups had similar functional independence at 3 months, defined by a modified Rankin Scale (mRS) score of 0 to 2 (44.4% vs. 54.8%; P = .275). Mortality was also similar at 3 months (31.3% vs. 28.0%; P = .595).

“This is the first analysis to prove the noninferiority of the cardiology services in the treatment of stroke with mechanical thrombectomy,” the authors reported in JACC: Cardiovascular Interventions.

But commenting for this news organization, J Mocco, MD, senior vice chair of neurosurgery and director of the Cerebrovascular Center at Mount Sinai Health System, New York, said this study isn’t designed as a noninferiority trial, is “grossly underpowered,” and the comparator cohort is not a gold standard comparator cohort.

“More importantly, they show that the cardiologists got significantly worse technical results and took longer, and we know that technical outcomes and the time to treatment are the two strongest predictors of outcome, which completely correlates with the fact that patients had 11% worse outcomes overall,” he said.

“It’s dumbfounding to me that this has been presented as evidence [that] an interventional cardiologist should be performing thrombectomy,” added Dr. Mocco, president-elect of the Society of NeuroInterventional Surgery.

Dr. Wita and coauthor Andrzej Kulach, MD, PhD, also with the Medical University of Silesia, told this news organization that timing is critical in mechanical thrombectomy (MT) and the sooner it’s performed, the better. But it cannot be performed by just any interventional cardiologist (IC).

“The IC must be trained in the procedure and cooperate with the neurologist to get good results,” they said. “We would like to stress that it is not a procedure for any cath lab and any cardiologist on duty. A network of cardiologists trained in MT must be organized and the stroke teams developed for the local unit to make the strategy reasonable and safe.”

The study was conducted from 2019 to 2020 and to participate, interventional cardiologists had to have performed a minimum of 700 angioplasties and 1,500 coronary angiographies and undergone complex training in thrombectomy, including 14-day training in a reference center and certified courses on a phantom and an animal model. They were also experienced in carotid angioplasty and participated as the second operators in neurointerventions.

“Considering the cardiologists are acting here in a multidisciplinary team led by neurologists, the findings are not surprising,” Dr. Wita and Dr. Kulach said. “What was surprising, is a certain level of skepticism among neurologists when cardiologists are to be involved in the procedure. We hope the quality of cardiology services will help to get over it.”

Major thrombectomy trials such as PRAGUE-16 have supported a role for interventional cardiologists to help meet demand for stroke thrombectomy. Dr. Wita and Dr. Kulach said there’s a lack of trained neuroradiologists and developed infrastructure for thrombectomy, whereas there’s a sufficient network of catheterization laboratories and trained cardiologists who could be involved.

The take-home message from the study, they said, is to “use the existing infrastructure to optimize the treatment of stroke. Building one from the very beginning is more time and resources-consuming.”

Dr. Mocco said a physician’s training is not a factor in the pathway to neurointerventional expertise, as long as they’re willing to put in the appropriate amount of specialization and training.

“There’s no way this represents a turf war or the neurology community somehow protecting its space, which is often used as a distraction, just like the idea that there’s not enough people,” he said. “It’s just not the case. Neurointervention is the most multispecialty space that I’m aware of.”

In the United States, at least, the problem isn’t a lack of resources or people to provide the service, but in getting patients to the correct hospitals, Dr. Mocco said. “We don’t have regionalized stroke care in the United States for the most part, so patients go to any hospital that says they provide stroke care rather than necessarily being triaged to capable centers that can provide the care.”

A 2021 Medicare analysis by Dr. Mocco and colleagues found that higher physician and hospital stroke thrombectomy volumes were associated with lower inpatient mortality and better outcomes.

Efforts are underway to regionalize care and delivery of patients in Los Angeles County and New York City, for example, where ambulances preferentially take patients with suspected large vessel occlusion to thrombectomy-capable stroke centers certified by independent organizations, Dr. Mocco said. In New York, “they’ve shown it has improved outcomes.”

Estêvão Carvalho de Campos Martins, MD, Hospital de Força Aérea do Galeão, Rio de Janeiro, and Fernando Luiz de Melo Bernardi, MD, Hospital Regional do Oeste, Chapecó, Brazil, noted in an accompanying editorial that the observational study is “hypothesis-generating only” and that the disconnect between technical and clinical outcomes is due to a type II error of low power.

They suggest that collaboration between specialties will be “essential for defining the optimal training program, so that ICs can reach solid procedural results.

“The accumulated experience with virtual simulation-based training for stroke could act as an educational accelerator but should be inserted in a prespecified program,” the editorialists said. “How to train and how to insert ICs into [an] MT interdisciplinary team is the current debate; meanwhile ICs are here, and many of them already contributing.”

Dr. Mocco is the principal investigator on research trials funded by Stryker Neurovascular, Microvention, and Penumbra; and is an investor in Cerebrotech, Imperative Care, Endostream, Viseon, BlinkTBI, Myra Medical, Serenity, Vastrax, NTI, RIST, Viz.ai , Synchron, Radical, and Truvic. He serves, or has recently served, as a consultant for: Cerebrotech, Viseon, Endostream, Vastrax, RIST, Synchron, Viz.ai , Perflow, and CVAid. Dr. Carvalho de Campos Martins and Dr. Luiz de Melo Bernardi have disclosed no relevant financial relationships.

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

Reports based on a press release in October 2021 suggested it, but now the full data tell the story: Early monitoring and treatment of anal high-grade squamous intraepithelial lesions (HSIL) cut risk for anal cancer by 57% in people living with HIV.

“We now show, for the first time, that treatment of anal HSIL is effective in reducing the incidence of anal cancer,” said Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the Anal Neoplasia Clinic at the University of California, San Francisco. “These data should be included in an overall assessment for inclusion of screening for and treating HSIL as standard of care in people living with HIV.”

Dr. Palefsky presented the full results in a special session at the Conference on Retroviruses and Opportunistic Infections, which drew excitement, gratitude, and relief from both researchers and clinicians, who flocked to the session.

But it’s not just people with HIV who will benefit from this research. Dr. Palefsky suggested that the findings should also be considered as guides for other people at high-risk for anal cancer, such as people who are immunocompromised for other reasons, including those with lupus, ulcerative colitis, Crohn’s disease, or cisgender women who have had vulvar or cervical cancer or precancer.

“If we can show efficacy in the most challenging group of all, which are people living with HIV, we think the results can be as good, if not even better, in the other groups at high risk of anal cancer,” Dr. Palefsky said.

But to serve anyone – whether living with HIV or not – infrastructure, algorithms, and workforce training are going be needed to meet the currently unserved people through use of high-resolution anoscopy (HRA) and other screening technology, he said.

Dr. Palefsy and colleagues screened 10,723 people living with HIV being served at 15 clinics nationwide. More than half, 52.2%, had anal HSIL – 53.3% of the cisgender men living with HIV in the trial, 45.8% of the cis women living with HIV, and a full 62.5% of transgender participants.

Those 4,446 participants were split evenly between the treatment arm and the control arm. Those in the treatment arm received treatment for HSIL on their first study visit via one of five options: hyfrecation, office-based electrocautery ablation, infrared coagulation, topical 5-fluorouracil cream, or topical imiquimod. Then, every 6 months after that, they came in for HRA, blood tests, anal Pap smears, and biopsies to check for any lingering or new HSIL. If clinicians found such cells, they received treatment again. If biopsies still showed HSIL and clinician and participant were worried about cancer, they could come in as frequently as every 3 months and receive treatment each time.

The active-monitoring control group still received an anal Pap smear, blood tests, biopsy, and HRA every 6 months – a level of care that is currently not mandated anywhere for people living with HIV, Dr. Palefsky said in an interview. They were also able to come in for more frequent monitoring (every 3 months) if clinicians were worried about cancer.

“Those in both arms would have been getting more attention than if they had not participated in the study,” he said.

In addition, during screening, researchers found that cancer was already present in 17 other people, who skipped the study to go right to treatment.

Participants reflected the demographics of the HIV epidemic in the United States. They were older (median age, 51 years), mostly gay (78%), and cisgender male (80%). Close to half, 42%, were Black, and 16% were Latinx. In addition, cisgender women made up 16% of the participants and transgender people, and nonbinary individuals accounted for more than 3% of the participants. In addition, one in three smoked.

The vast majority of participants had well-controlled HIV and healthy immune systems, though half in each arm had a history of AIDS, defined as lowest-ever CD4 immune cell counts below 200. Today, more than 80% of participants had undetectable viral loads, defined as a viral load less than 50 copies/mL, and another 7% had HIV viral loads below 200. In total, 9.3% in the treatment arm and 10.9% in the control arm had HIV viral loads higher than that. At time of enrollment, CD4 counts were above 600 in each group, indicating healthy immune systems.

Although all participants were there because they had anal HSIL, more than 1 in 10 – 13% – had abnormal cells so extensive that they covered more than half of the anal canal or the perianal region.

Once everyone was enrolled, researchers began monitoring and treatment, looking specifically for 31 cases of cancer – a number the team had determined that they’d need in order to draw any conclusions. Dr. Palefsky didn’t have to wait long. They were still trying to enroll the last 1,000 participants to have the power necessary to reach that number when the cancer diagnoses came in.

Dr. Palefsky told this news organization that the reason for that is unclear. It could be that some of those cases would have resolved on their own, and so the swiftness with which they reached the required number of cancer cases belies their seriousness. It could also be that the particular people who enrolled in this trial were engaging in behaviors that put them at even higher risk for anal cancer than the population of people living with HIV in the United States.

Or it could be that symptom-based screening is missing a lot of cancers that currently go untreated.

“So perhaps we will be seeing an increase in anal cancer reported in the future compared to the currently reported rates,” he said. “We don’t really know.”

Regardless of the reason for the speed to cases of cancer, the results were definitive: Nine participants were diagnosed with invasive anal cancer in the treatment arm, while 21 were diagnosed with invasive anal cancer in the control arm. That’s a 57% reduction in cancer occurrence between the arms. Or, to put it another way, the rate of anal cancer among people in the treatment arm was 173 per 100,000 people-years. In the active monitoring arm, it was 402 per 100,000 person-years. For context, the overall rate of anal cancer among people living with HIV is 50 per 100,000 person-years. The rate in the general U.S. population is 8 per 100,000 people-years.

The experimental treatment was such a definitive success that the investigators stopped the trial and shifted all participants in the control arm to treatment.
 

‘We have to build’

Before Dr. Palefsky was even done presenting the data, clinicians, people living with HIV, and experts at the session were already brainstorming as to how to get these results into practice.

“These data are what we have long needed to fuel some action on this important problem, including medical cost reimbursement through insurance and increasing the number of persons trained and capable in anal cancer screening,” John Brooks, MD, head of the epidemiology research team at the Centers for Disease Control and Prevention’s division of HIV/AIDS prevention, wrote in the virtual chat.

Jeff Taylor, a member of the ANCHOR advisory board and a person living with HIV who participated in one of the first azidothymidine trials in the late 1980s, responded quickly.

“What kind of advocacy from researchers, HIV clinicians and [people living with HIV] is needed to get this on treatment guidelines, HRA providers trained and certified, and payors to cover this so [people living with HIV] actually have access to lifesaving screening and [treatment]?” Mr. Taylor asked.

It’s a serious challenge. David Malebranche, MD, an Atlanta-based internal medicine physician who specializes in sexual health and HIV, commented in an interview. When he saw the initial press release last year on the ANCHOR findings, his first reaction was: “Thank god. We finally have some data to show what we’ve been trying to get people to do” all along.

But then he wondered, who is going to perform these tests? It’s a fair question. Currently, the wait for an HRA is 6-12 months in many parts of the country. And Dr. Malebranche can’t imagine this being added to his already full plate as a primary care provider.

“If you tell a primary care provider now that they have to do a rectal Pap smear, that’s going to be a problem while you’re also asking them to screen each patient for depression, anxiety, domestic abuse, intimate partner violence, all the healthcare maintenance and all the other screening tests – and then you deal with not only the urgent complaint but then all the complex medical issues on top of that – in a 15-minute or 10-minute visit,” he said.

Now that we have these data, he said, “we have to build.”

Dr. Palefsky agreed. Very few centers have enough people skilled at performing HRAs to meet the current demand, and it’s not realistic to expect clinicians to perform an HRA every 6 months like the study team did. There need to be algorithms put in place to help practitioners figure out who among their patients living with HIV could benefit from this increased screening, as well as biomarkers to identify HSIL progression and regression without the use of HRA, Dr. Palefsky told attendees. And more clinicians need to be recruited and trained to read HRAs, which can be difficult for the untrained eye to decipher.

Dr. Malebranche added another, more fundamental thing that needs to be built. Dr. Malebranche has worked in HIV clinics where the majority of his patients qualify for insurance under the Ryan White Program and get their medications through the AIDS Drug Assistance Program. While Ryan White programs can provide critical wraparound care, Dr. Malebranche has had to refer out for something like an HRA or cancer treatment. But the people who only access care through such programs may not have coverage with the clinics that perform HRA or that treat cancer. And that’s if they can even find someone to see them.

“If I live in a state like Georgia, which doesn’t have Medicaid expansion and we have people who are uninsured, where do you send them?” Dr. Malebranche asked. “This isn’t theoretical. I ran into this problem when I was working at the AIDS Healthcare Foundation last year. ... This is a call for infrastructure.”

The study was funded by the National Cancer Institute. Dr. Brooks reported no relevant financial relationships. Dr. Palefsky has received consultant fees from Merck, Vir Biotechnology, Virion Therapeutics, and Antiva Bioscience, as well as speaker fees from Merck. Dr. Malebranche has received consulting and advising fees from ViiV Healthcare.

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

Reports based on a press release in October 2021 suggested it, but now the full data tell the story: Early monitoring and treatment of anal high-grade squamous intraepithelial lesions (HSIL) cut risk for anal cancer by 57% in people living with HIV.

“We now show, for the first time, that treatment of anal HSIL is effective in reducing the incidence of anal cancer,” said Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the Anal Neoplasia Clinic at the University of California, San Francisco. “These data should be included in an overall assessment for inclusion of screening for and treating HSIL as standard of care in people living with HIV.”

Dr. Palefsky presented the full results in a special session at the Conference on Retroviruses and Opportunistic Infections, which drew excitement, gratitude, and relief from both researchers and clinicians, who flocked to the session.

But it’s not just people with HIV who will benefit from this research. Dr. Palefsky suggested that the findings should also be considered as guides for other people at high-risk for anal cancer, such as people who are immunocompromised for other reasons, including those with lupus, ulcerative colitis, Crohn’s disease, or cisgender women who have had vulvar or cervical cancer or precancer.

“If we can show efficacy in the most challenging group of all, which are people living with HIV, we think the results can be as good, if not even better, in the other groups at high risk of anal cancer,” Dr. Palefsky said.

But to serve anyone – whether living with HIV or not – infrastructure, algorithms, and workforce training are going be needed to meet the currently unserved people through use of high-resolution anoscopy (HRA) and other screening technology, he said.

Dr. Palefsy and colleagues screened 10,723 people living with HIV being served at 15 clinics nationwide. More than half, 52.2%, had anal HSIL – 53.3% of the cisgender men living with HIV in the trial, 45.8% of the cis women living with HIV, and a full 62.5% of transgender participants.

Those 4,446 participants were split evenly between the treatment arm and the control arm. Those in the treatment arm received treatment for HSIL on their first study visit via one of five options: hyfrecation, office-based electrocautery ablation, infrared coagulation, topical 5-fluorouracil cream, or topical imiquimod. Then, every 6 months after that, they came in for HRA, blood tests, anal Pap smears, and biopsies to check for any lingering or new HSIL. If clinicians found such cells, they received treatment again. If biopsies still showed HSIL and clinician and participant were worried about cancer, they could come in as frequently as every 3 months and receive treatment each time.

The active-monitoring control group still received an anal Pap smear, blood tests, biopsy, and HRA every 6 months – a level of care that is currently not mandated anywhere for people living with HIV, Dr. Palefsky said in an interview. They were also able to come in for more frequent monitoring (every 3 months) if clinicians were worried about cancer.

“Those in both arms would have been getting more attention than if they had not participated in the study,” he said.

In addition, during screening, researchers found that cancer was already present in 17 other people, who skipped the study to go right to treatment.

Participants reflected the demographics of the HIV epidemic in the United States. They were older (median age, 51 years), mostly gay (78%), and cisgender male (80%). Close to half, 42%, were Black, and 16% were Latinx. In addition, cisgender women made up 16% of the participants and transgender people, and nonbinary individuals accounted for more than 3% of the participants. In addition, one in three smoked.

The vast majority of participants had well-controlled HIV and healthy immune systems, though half in each arm had a history of AIDS, defined as lowest-ever CD4 immune cell counts below 200. Today, more than 80% of participants had undetectable viral loads, defined as a viral load less than 50 copies/mL, and another 7% had HIV viral loads below 200. In total, 9.3% in the treatment arm and 10.9% in the control arm had HIV viral loads higher than that. At time of enrollment, CD4 counts were above 600 in each group, indicating healthy immune systems.

Although all participants were there because they had anal HSIL, more than 1 in 10 – 13% – had abnormal cells so extensive that they covered more than half of the anal canal or the perianal region.

Once everyone was enrolled, researchers began monitoring and treatment, looking specifically for 31 cases of cancer – a number the team had determined that they’d need in order to draw any conclusions. Dr. Palefsky didn’t have to wait long. They were still trying to enroll the last 1,000 participants to have the power necessary to reach that number when the cancer diagnoses came in.

Dr. Palefsky told this news organization that the reason for that is unclear. It could be that some of those cases would have resolved on their own, and so the swiftness with which they reached the required number of cancer cases belies their seriousness. It could also be that the particular people who enrolled in this trial were engaging in behaviors that put them at even higher risk for anal cancer than the population of people living with HIV in the United States.

Or it could be that symptom-based screening is missing a lot of cancers that currently go untreated.

“So perhaps we will be seeing an increase in anal cancer reported in the future compared to the currently reported rates,” he said. “We don’t really know.”

Regardless of the reason for the speed to cases of cancer, the results were definitive: Nine participants were diagnosed with invasive anal cancer in the treatment arm, while 21 were diagnosed with invasive anal cancer in the control arm. That’s a 57% reduction in cancer occurrence between the arms. Or, to put it another way, the rate of anal cancer among people in the treatment arm was 173 per 100,000 people-years. In the active monitoring arm, it was 402 per 100,000 person-years. For context, the overall rate of anal cancer among people living with HIV is 50 per 100,000 person-years. The rate in the general U.S. population is 8 per 100,000 people-years.

The experimental treatment was such a definitive success that the investigators stopped the trial and shifted all participants in the control arm to treatment.
 

‘We have to build’

Before Dr. Palefsky was even done presenting the data, clinicians, people living with HIV, and experts at the session were already brainstorming as to how to get these results into practice.

“These data are what we have long needed to fuel some action on this important problem, including medical cost reimbursement through insurance and increasing the number of persons trained and capable in anal cancer screening,” John Brooks, MD, head of the epidemiology research team at the Centers for Disease Control and Prevention’s division of HIV/AIDS prevention, wrote in the virtual chat.

Jeff Taylor, a member of the ANCHOR advisory board and a person living with HIV who participated in one of the first azidothymidine trials in the late 1980s, responded quickly.

“What kind of advocacy from researchers, HIV clinicians and [people living with HIV] is needed to get this on treatment guidelines, HRA providers trained and certified, and payors to cover this so [people living with HIV] actually have access to lifesaving screening and [treatment]?” Mr. Taylor asked.

It’s a serious challenge. David Malebranche, MD, an Atlanta-based internal medicine physician who specializes in sexual health and HIV, commented in an interview. When he saw the initial press release last year on the ANCHOR findings, his first reaction was: “Thank god. We finally have some data to show what we’ve been trying to get people to do” all along.

But then he wondered, who is going to perform these tests? It’s a fair question. Currently, the wait for an HRA is 6-12 months in many parts of the country. And Dr. Malebranche can’t imagine this being added to his already full plate as a primary care provider.

“If you tell a primary care provider now that they have to do a rectal Pap smear, that’s going to be a problem while you’re also asking them to screen each patient for depression, anxiety, domestic abuse, intimate partner violence, all the healthcare maintenance and all the other screening tests – and then you deal with not only the urgent complaint but then all the complex medical issues on top of that – in a 15-minute or 10-minute visit,” he said.

Now that we have these data, he said, “we have to build.”

Dr. Palefsky agreed. Very few centers have enough people skilled at performing HRAs to meet the current demand, and it’s not realistic to expect clinicians to perform an HRA every 6 months like the study team did. There need to be algorithms put in place to help practitioners figure out who among their patients living with HIV could benefit from this increased screening, as well as biomarkers to identify HSIL progression and regression without the use of HRA, Dr. Palefsky told attendees. And more clinicians need to be recruited and trained to read HRAs, which can be difficult for the untrained eye to decipher.

Dr. Malebranche added another, more fundamental thing that needs to be built. Dr. Malebranche has worked in HIV clinics where the majority of his patients qualify for insurance under the Ryan White Program and get their medications through the AIDS Drug Assistance Program. While Ryan White programs can provide critical wraparound care, Dr. Malebranche has had to refer out for something like an HRA or cancer treatment. But the people who only access care through such programs may not have coverage with the clinics that perform HRA or that treat cancer. And that’s if they can even find someone to see them.

“If I live in a state like Georgia, which doesn’t have Medicaid expansion and we have people who are uninsured, where do you send them?” Dr. Malebranche asked. “This isn’t theoretical. I ran into this problem when I was working at the AIDS Healthcare Foundation last year. ... This is a call for infrastructure.”

The study was funded by the National Cancer Institute. Dr. Brooks reported no relevant financial relationships. Dr. Palefsky has received consultant fees from Merck, Vir Biotechnology, Virion Therapeutics, and Antiva Bioscience, as well as speaker fees from Merck. Dr. Malebranche has received consulting and advising fees from ViiV Healthcare.

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

Reports based on a press release in October 2021 suggested it, but now the full data tell the story: Early monitoring and treatment of anal high-grade squamous intraepithelial lesions (HSIL) cut risk for anal cancer by 57% in people living with HIV.

“We now show, for the first time, that treatment of anal HSIL is effective in reducing the incidence of anal cancer,” said Joel Palefsky, MD, lead investigator of the Anal Cancer/HSIL Outcomes Research (ANCHOR) study and founder/director of the Anal Neoplasia Clinic at the University of California, San Francisco. “These data should be included in an overall assessment for inclusion of screening for and treating HSIL as standard of care in people living with HIV.”

Dr. Palefsky presented the full results in a special session at the Conference on Retroviruses and Opportunistic Infections, which drew excitement, gratitude, and relief from both researchers and clinicians, who flocked to the session.

But it’s not just people with HIV who will benefit from this research. Dr. Palefsky suggested that the findings should also be considered as guides for other people at high-risk for anal cancer, such as people who are immunocompromised for other reasons, including those with lupus, ulcerative colitis, Crohn’s disease, or cisgender women who have had vulvar or cervical cancer or precancer.

“If we can show efficacy in the most challenging group of all, which are people living with HIV, we think the results can be as good, if not even better, in the other groups at high risk of anal cancer,” Dr. Palefsky said.

But to serve anyone – whether living with HIV or not – infrastructure, algorithms, and workforce training are going be needed to meet the currently unserved people through use of high-resolution anoscopy (HRA) and other screening technology, he said.

Dr. Palefsy and colleagues screened 10,723 people living with HIV being served at 15 clinics nationwide. More than half, 52.2%, had anal HSIL – 53.3% of the cisgender men living with HIV in the trial, 45.8% of the cis women living with HIV, and a full 62.5% of transgender participants.

Those 4,446 participants were split evenly between the treatment arm and the control arm. Those in the treatment arm received treatment for HSIL on their first study visit via one of five options: hyfrecation, office-based electrocautery ablation, infrared coagulation, topical 5-fluorouracil cream, or topical imiquimod. Then, every 6 months after that, they came in for HRA, blood tests, anal Pap smears, and biopsies to check for any lingering or new HSIL. If clinicians found such cells, they received treatment again. If biopsies still showed HSIL and clinician and participant were worried about cancer, they could come in as frequently as every 3 months and receive treatment each time.

The active-monitoring control group still received an anal Pap smear, blood tests, biopsy, and HRA every 6 months – a level of care that is currently not mandated anywhere for people living with HIV, Dr. Palefsky said in an interview. They were also able to come in for more frequent monitoring (every 3 months) if clinicians were worried about cancer.

“Those in both arms would have been getting more attention than if they had not participated in the study,” he said.

In addition, during screening, researchers found that cancer was already present in 17 other people, who skipped the study to go right to treatment.

Participants reflected the demographics of the HIV epidemic in the United States. They were older (median age, 51 years), mostly gay (78%), and cisgender male (80%). Close to half, 42%, were Black, and 16% were Latinx. In addition, cisgender women made up 16% of the participants and transgender people, and nonbinary individuals accounted for more than 3% of the participants. In addition, one in three smoked.

The vast majority of participants had well-controlled HIV and healthy immune systems, though half in each arm had a history of AIDS, defined as lowest-ever CD4 immune cell counts below 200. Today, more than 80% of participants had undetectable viral loads, defined as a viral load less than 50 copies/mL, and another 7% had HIV viral loads below 200. In total, 9.3% in the treatment arm and 10.9% in the control arm had HIV viral loads higher than that. At time of enrollment, CD4 counts were above 600 in each group, indicating healthy immune systems.

Although all participants were there because they had anal HSIL, more than 1 in 10 – 13% – had abnormal cells so extensive that they covered more than half of the anal canal or the perianal region.

Once everyone was enrolled, researchers began monitoring and treatment, looking specifically for 31 cases of cancer – a number the team had determined that they’d need in order to draw any conclusions. Dr. Palefsky didn’t have to wait long. They were still trying to enroll the last 1,000 participants to have the power necessary to reach that number when the cancer diagnoses came in.

Dr. Palefsky told this news organization that the reason for that is unclear. It could be that some of those cases would have resolved on their own, and so the swiftness with which they reached the required number of cancer cases belies their seriousness. It could also be that the particular people who enrolled in this trial were engaging in behaviors that put them at even higher risk for anal cancer than the population of people living with HIV in the United States.

Or it could be that symptom-based screening is missing a lot of cancers that currently go untreated.

“So perhaps we will be seeing an increase in anal cancer reported in the future compared to the currently reported rates,” he said. “We don’t really know.”

Regardless of the reason for the speed to cases of cancer, the results were definitive: Nine participants were diagnosed with invasive anal cancer in the treatment arm, while 21 were diagnosed with invasive anal cancer in the control arm. That’s a 57% reduction in cancer occurrence between the arms. Or, to put it another way, the rate of anal cancer among people in the treatment arm was 173 per 100,000 people-years. In the active monitoring arm, it was 402 per 100,000 person-years. For context, the overall rate of anal cancer among people living with HIV is 50 per 100,000 person-years. The rate in the general U.S. population is 8 per 100,000 people-years.

The experimental treatment was such a definitive success that the investigators stopped the trial and shifted all participants in the control arm to treatment.
 

‘We have to build’

Before Dr. Palefsky was even done presenting the data, clinicians, people living with HIV, and experts at the session were already brainstorming as to how to get these results into practice.

“These data are what we have long needed to fuel some action on this important problem, including medical cost reimbursement through insurance and increasing the number of persons trained and capable in anal cancer screening,” John Brooks, MD, head of the epidemiology research team at the Centers for Disease Control and Prevention’s division of HIV/AIDS prevention, wrote in the virtual chat.

Jeff Taylor, a member of the ANCHOR advisory board and a person living with HIV who participated in one of the first azidothymidine trials in the late 1980s, responded quickly.

“What kind of advocacy from researchers, HIV clinicians and [people living with HIV] is needed to get this on treatment guidelines, HRA providers trained and certified, and payors to cover this so [people living with HIV] actually have access to lifesaving screening and [treatment]?” Mr. Taylor asked.

It’s a serious challenge. David Malebranche, MD, an Atlanta-based internal medicine physician who specializes in sexual health and HIV, commented in an interview. When he saw the initial press release last year on the ANCHOR findings, his first reaction was: “Thank god. We finally have some data to show what we’ve been trying to get people to do” all along.

But then he wondered, who is going to perform these tests? It’s a fair question. Currently, the wait for an HRA is 6-12 months in many parts of the country. And Dr. Malebranche can’t imagine this being added to his already full plate as a primary care provider.

“If you tell a primary care provider now that they have to do a rectal Pap smear, that’s going to be a problem while you’re also asking them to screen each patient for depression, anxiety, domestic abuse, intimate partner violence, all the healthcare maintenance and all the other screening tests – and then you deal with not only the urgent complaint but then all the complex medical issues on top of that – in a 15-minute or 10-minute visit,” he said.

Now that we have these data, he said, “we have to build.”

Dr. Palefsky agreed. Very few centers have enough people skilled at performing HRAs to meet the current demand, and it’s not realistic to expect clinicians to perform an HRA every 6 months like the study team did. There need to be algorithms put in place to help practitioners figure out who among their patients living with HIV could benefit from this increased screening, as well as biomarkers to identify HSIL progression and regression without the use of HRA, Dr. Palefsky told attendees. And more clinicians need to be recruited and trained to read HRAs, which can be difficult for the untrained eye to decipher.

Dr. Malebranche added another, more fundamental thing that needs to be built. Dr. Malebranche has worked in HIV clinics where the majority of his patients qualify for insurance under the Ryan White Program and get their medications through the AIDS Drug Assistance Program. While Ryan White programs can provide critical wraparound care, Dr. Malebranche has had to refer out for something like an HRA or cancer treatment. But the people who only access care through such programs may not have coverage with the clinics that perform HRA or that treat cancer. And that’s if they can even find someone to see them.

“If I live in a state like Georgia, which doesn’t have Medicaid expansion and we have people who are uninsured, where do you send them?” Dr. Malebranche asked. “This isn’t theoretical. I ran into this problem when I was working at the AIDS Healthcare Foundation last year. ... This is a call for infrastructure.”

The study was funded by the National Cancer Institute. Dr. Brooks reported no relevant financial relationships. Dr. Palefsky has received consultant fees from Merck, Vir Biotechnology, Virion Therapeutics, and Antiva Bioscience, as well as speaker fees from Merck. Dr. Malebranche has received consulting and advising fees from ViiV Healthcare.

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

A new drug that is both the first in its class and the first disease-modifying agent for hemolytic anemia in adults with pyruvate kinase (PK) deficiency has been approved by the Food and Drug Administration.

The new drug, mitapivat (Pyrukynd, Agios), was approved on the basis of clinical trials that showed that it significantly improved hemolysis and anemia in patients with PK deficiency.

Clinical data

Clinical data that formed the basis of the approval came from two trials, one of which was a randomized, placebo-controlled trial, and the other a single-arm study, the FDA noted. In these studies, patients received up to 50 mg of mitapivat orally twice daily after an initial dose titration period

The randomized trial involved 80 adults with PK deficiency who were not having regular blood transfusions. They were allocated to receive either mitapivat or placebo and were followed for an average of 24 weeks. The primary endpoint was the number of patients who achieved a hemoglobin response (defined as a 1.5 g/dL or greater increase in hemoglobin concentration that was sustained at two or more scheduled assessments). At the end of the study, 40% of participants who received mitapivat had a hemoglobin response, compared with no participants who received placebo.

The single-arm study involved 27 adults with PK deficiency who were receiving regular blood transfusions. They took mitapivat for an average of 40 weeks. In this study, the primary endpoint was the reduction in transfusion burden, defined as at least a 33% reduction in the number of red blood cell units transfused during the last 24 weeks of treatment, compared with the historical transfusion burden on the individual participant (standardized to 24 weeks). The results show that 33% of participants who received mitapivat met this reduction in transfusion burden; 22% of participants did not require any transfusions over the last 24 weeks of treatment.

The most common side effects reported were decreases in estrone and estradiol in men, increased urate level, back pain, and joint stiffness. The effects of estrone and estradiol could not be reliably assessed in women because of normal changes in these hormone levels during the menstrual cycle and use of hormonal contraception.

The FDA warns of drug interactions that could necessitate dose adjustments, and also that abruptly stopping mitapivat could worsen premature red blood cell destruction.

The agency noted that this application received orphan drug designation, fast track designation, and priority review.

Agios is offering access programs aimed at reducing or eliminating patient out-of-pocket costs. Further details are on the myAgios patient support services program.

The company also noted that mitapivat is awaiting approval in the European Union. A decision is expected before the end of 2022.

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

A new drug that is both the first in its class and the first disease-modifying agent for hemolytic anemia in adults with pyruvate kinase (PK) deficiency has been approved by the Food and Drug Administration.

The new drug, mitapivat (Pyrukynd, Agios), was approved on the basis of clinical trials that showed that it significantly improved hemolysis and anemia in patients with PK deficiency.

Clinical data

Clinical data that formed the basis of the approval came from two trials, one of which was a randomized, placebo-controlled trial, and the other a single-arm study, the FDA noted. In these studies, patients received up to 50 mg of mitapivat orally twice daily after an initial dose titration period

The randomized trial involved 80 adults with PK deficiency who were not having regular blood transfusions. They were allocated to receive either mitapivat or placebo and were followed for an average of 24 weeks. The primary endpoint was the number of patients who achieved a hemoglobin response (defined as a 1.5 g/dL or greater increase in hemoglobin concentration that was sustained at two or more scheduled assessments). At the end of the study, 40% of participants who received mitapivat had a hemoglobin response, compared with no participants who received placebo.

The single-arm study involved 27 adults with PK deficiency who were receiving regular blood transfusions. They took mitapivat for an average of 40 weeks. In this study, the primary endpoint was the reduction in transfusion burden, defined as at least a 33% reduction in the number of red blood cell units transfused during the last 24 weeks of treatment, compared with the historical transfusion burden on the individual participant (standardized to 24 weeks). The results show that 33% of participants who received mitapivat met this reduction in transfusion burden; 22% of participants did not require any transfusions over the last 24 weeks of treatment.

The most common side effects reported were decreases in estrone and estradiol in men, increased urate level, back pain, and joint stiffness. The effects of estrone and estradiol could not be reliably assessed in women because of normal changes in these hormone levels during the menstrual cycle and use of hormonal contraception.

The FDA warns of drug interactions that could necessitate dose adjustments, and also that abruptly stopping mitapivat could worsen premature red blood cell destruction.

The agency noted that this application received orphan drug designation, fast track designation, and priority review.

Agios is offering access programs aimed at reducing or eliminating patient out-of-pocket costs. Further details are on the myAgios patient support services program.

The company also noted that mitapivat is awaiting approval in the European Union. A decision is expected before the end of 2022.

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

A new drug that is both the first in its class and the first disease-modifying agent for hemolytic anemia in adults with pyruvate kinase (PK) deficiency has been approved by the Food and Drug Administration.

The new drug, mitapivat (Pyrukynd, Agios), was approved on the basis of clinical trials that showed that it significantly improved hemolysis and anemia in patients with PK deficiency.

Clinical data

Clinical data that formed the basis of the approval came from two trials, one of which was a randomized, placebo-controlled trial, and the other a single-arm study, the FDA noted. In these studies, patients received up to 50 mg of mitapivat orally twice daily after an initial dose titration period

The randomized trial involved 80 adults with PK deficiency who were not having regular blood transfusions. They were allocated to receive either mitapivat or placebo and were followed for an average of 24 weeks. The primary endpoint was the number of patients who achieved a hemoglobin response (defined as a 1.5 g/dL or greater increase in hemoglobin concentration that was sustained at two or more scheduled assessments). At the end of the study, 40% of participants who received mitapivat had a hemoglobin response, compared with no participants who received placebo.

The single-arm study involved 27 adults with PK deficiency who were receiving regular blood transfusions. They took mitapivat for an average of 40 weeks. In this study, the primary endpoint was the reduction in transfusion burden, defined as at least a 33% reduction in the number of red blood cell units transfused during the last 24 weeks of treatment, compared with the historical transfusion burden on the individual participant (standardized to 24 weeks). The results show that 33% of participants who received mitapivat met this reduction in transfusion burden; 22% of participants did not require any transfusions over the last 24 weeks of treatment.

The most common side effects reported were decreases in estrone and estradiol in men, increased urate level, back pain, and joint stiffness. The effects of estrone and estradiol could not be reliably assessed in women because of normal changes in these hormone levels during the menstrual cycle and use of hormonal contraception.

The FDA warns of drug interactions that could necessitate dose adjustments, and also that abruptly stopping mitapivat could worsen premature red blood cell destruction.

The agency noted that this application received orphan drug designation, fast track designation, and priority review.

Agios is offering access programs aimed at reducing or eliminating patient out-of-pocket costs. Further details are on the myAgios patient support services program.

The company also noted that mitapivat is awaiting approval in the European Union. A decision is expected before the end of 2022.

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

The recent news that a third person has been “cured” of HIV through a unique transplant of stem cells has given hope for a larger-scale way to beat back the HIV epidemic that has plagued the world for decades.

But while this case is certainly cause for celebration, experts involved in the effort say we are still a long way from a universal cure.

Researcher Yvonne Bryson, MD, chief of pediatric infectious diseases at the University of California, Los Angeles, told those attending the Conference on Retroviruses and Opportunistic Infections that this case is special. The patient was a woman living with HIV who is multiracial. The previous two patients were men: one white, one Latinx.

The woman in this case was given transplants of stem cells and umbilical cord blood to treat leukemia. The treatment not only sent her cancer into remission, but her HIV as well.

The success of this case suggests that cord stem cell transplants should be considered to produce remission and cure for those with HIV who also have cancers and other diseases, the researchers said.

While the news was met with excitement in the scientific community, the approach will not be available universally, since the transplants were all done to treat cancers in the three HIV-infected patients. Overall, Dr. Bryson estimates that about 50 people per year may benefit from this procedure. 

Even so, other experts say the approach could provide insight into other ways to find cures. And Dr. Bryson says it opens up options for more diverse populations.

“A bone marrow transplant is not a viable large-scale strategy for curing HIV, but it does present a proof of concept that HIV can be cured,” said Sharon Lewin, MD, president-elect of the International AIDS Society. “It also further strengthens using gene therapy as a viable strategy for an HIV cure.”

The woman needed a stem cell transplant after being diagnosed with leukemia. The stem cell transplant technique used was also novel, Dr. Bryson said. The medical team used a combination of adult stem cells from a relative’s blood and umbilical cord blood from a cord-blood bank that had a rare mutation that makes the immune system resistant to HIV.

In the previous two cases of HIV cures after transplants, both patients were treated with stem cell transplants, with the same mutation, but from bone marrow transplants, a more difficult procedure. And no cord blood was used for those.

The combination of adult cells and cord-blood cells proved to be the ticket to success. Using the adult cells provides a kind of bridge that helps until the cord blood takes over, the researchers said. By day 100 after the transplant, Dr. Bryson said, the woman basically had a new immune system.

HIV remained undetectable in T cells and in bone marrow. And 37 months after the transplant, the woman stopped taking the antiretroviral treatment commonly given to treat HIV infection.

‘’She is currently clinically well,” Dr. Bryson said. Her cancer is in remission.
 

Case histories: Three patients

The woman, who is middle-aged, has requested privacy, asking that neither her age nor other details be released. But the researchers did provide some background on her medical history and her route back to health. She was diagnosed with HIV in 2013 and began treatment with antiretroviral therapy (ART). Four years after her HIV diagnosis, she developed high-risk acute myelogenous leukemia. The transplant was done to treat that.

Her recovery was much less bumpy than that of the previous two patients, the researchers said. She left the hospital 17 days after the transplant. She didn’t have serious complications like the first two, who developed a condition that occurs when donor bone marrow or stem cells attack the recipient.

“This case also suggests that it’s the transplant of HIV-resistant cells that was key to achieving a cure here,” said Dr. Lewin. The first patient who had HIV remission after a stem cell transplant, a White man, stayed in remission for 12 years and was termed cured. But he died of leukemia in September 2020. The other, a Latinx man, has been in remission for more than 30 months.
 

HIV statistics, ethnic/racial burdens

In the United States, about 1.2 million people have HIV, according to HIV.gov. Thirteen percent of those who have it do not know they have it. In 2019, 34,800 new infections were diagnosed.

Certain ethnic and racial groups are more affected by HIV than others, given their proportions in the U.S. population, federal statistics suggest. In 2019, for instance, African Americans were 13% of the U.S. population but 40% of those with HIV. Hispanics/Latinx represented 18.5% of the total population but 25% of those diagnosed with HIV.

Disparities also affect women unequally, with Black women disproportionately affected, compared to women of other ethnic and racial groups. Annual HIV infections remained stable overall among Black women from 2015 to 2019, but the rate of new HIV infections among Black women is 11 times that of White women and 4 times that of Latinx, according to federal statistics.
 

Expert perspective, reactions

Vincent Marconi, MD, professor of infectious diseases at Emory University, Atlanta, whose research focuses on disparities in HIV treatment responses, called the news “an exciting development for the cure agenda. This is the first woman to have been cured for at least 14 months, and they used cord blood, which could allow for potentially less toxic regimens and fewer adverse effects.”

Although the approach, meant to be used to treat the cancers, will not be widely available, he said that ‘’it does provide insight into somewhat related alternative models of cure involving gene therapy.”

Meanwhile, Dr. Marconi and other researchers are focusing on the concept of long-term HIV remission if a cure is not possible. Among the strategies under study are gene editing and immune-based treatments. HIV remission is generally defined as having an HIV viral load that is not detectable after stopping treatment.

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

The recent news that a third person has been “cured” of HIV through a unique transplant of stem cells has given hope for a larger-scale way to beat back the HIV epidemic that has plagued the world for decades.

But while this case is certainly cause for celebration, experts involved in the effort say we are still a long way from a universal cure.

Researcher Yvonne Bryson, MD, chief of pediatric infectious diseases at the University of California, Los Angeles, told those attending the Conference on Retroviruses and Opportunistic Infections that this case is special. The patient was a woman living with HIV who is multiracial. The previous two patients were men: one white, one Latinx.

The woman in this case was given transplants of stem cells and umbilical cord blood to treat leukemia. The treatment not only sent her cancer into remission, but her HIV as well.

The success of this case suggests that cord stem cell transplants should be considered to produce remission and cure for those with HIV who also have cancers and other diseases, the researchers said.

While the news was met with excitement in the scientific community, the approach will not be available universally, since the transplants were all done to treat cancers in the three HIV-infected patients. Overall, Dr. Bryson estimates that about 50 people per year may benefit from this procedure. 

Even so, other experts say the approach could provide insight into other ways to find cures. And Dr. Bryson says it opens up options for more diverse populations.

“A bone marrow transplant is not a viable large-scale strategy for curing HIV, but it does present a proof of concept that HIV can be cured,” said Sharon Lewin, MD, president-elect of the International AIDS Society. “It also further strengthens using gene therapy as a viable strategy for an HIV cure.”

The woman needed a stem cell transplant after being diagnosed with leukemia. The stem cell transplant technique used was also novel, Dr. Bryson said. The medical team used a combination of adult stem cells from a relative’s blood and umbilical cord blood from a cord-blood bank that had a rare mutation that makes the immune system resistant to HIV.

In the previous two cases of HIV cures after transplants, both patients were treated with stem cell transplants, with the same mutation, but from bone marrow transplants, a more difficult procedure. And no cord blood was used for those.

The combination of adult cells and cord-blood cells proved to be the ticket to success. Using the adult cells provides a kind of bridge that helps until the cord blood takes over, the researchers said. By day 100 after the transplant, Dr. Bryson said, the woman basically had a new immune system.

HIV remained undetectable in T cells and in bone marrow. And 37 months after the transplant, the woman stopped taking the antiretroviral treatment commonly given to treat HIV infection.

‘’She is currently clinically well,” Dr. Bryson said. Her cancer is in remission.
 

Case histories: Three patients

The woman, who is middle-aged, has requested privacy, asking that neither her age nor other details be released. But the researchers did provide some background on her medical history and her route back to health. She was diagnosed with HIV in 2013 and began treatment with antiretroviral therapy (ART). Four years after her HIV diagnosis, she developed high-risk acute myelogenous leukemia. The transplant was done to treat that.

Her recovery was much less bumpy than that of the previous two patients, the researchers said. She left the hospital 17 days after the transplant. She didn’t have serious complications like the first two, who developed a condition that occurs when donor bone marrow or stem cells attack the recipient.

“This case also suggests that it’s the transplant of HIV-resistant cells that was key to achieving a cure here,” said Dr. Lewin. The first patient who had HIV remission after a stem cell transplant, a White man, stayed in remission for 12 years and was termed cured. But he died of leukemia in September 2020. The other, a Latinx man, has been in remission for more than 30 months.
 

HIV statistics, ethnic/racial burdens

In the United States, about 1.2 million people have HIV, according to HIV.gov. Thirteen percent of those who have it do not know they have it. In 2019, 34,800 new infections were diagnosed.

Certain ethnic and racial groups are more affected by HIV than others, given their proportions in the U.S. population, federal statistics suggest. In 2019, for instance, African Americans were 13% of the U.S. population but 40% of those with HIV. Hispanics/Latinx represented 18.5% of the total population but 25% of those diagnosed with HIV.

Disparities also affect women unequally, with Black women disproportionately affected, compared to women of other ethnic and racial groups. Annual HIV infections remained stable overall among Black women from 2015 to 2019, but the rate of new HIV infections among Black women is 11 times that of White women and 4 times that of Latinx, according to federal statistics.
 

Expert perspective, reactions

Vincent Marconi, MD, professor of infectious diseases at Emory University, Atlanta, whose research focuses on disparities in HIV treatment responses, called the news “an exciting development for the cure agenda. This is the first woman to have been cured for at least 14 months, and they used cord blood, which could allow for potentially less toxic regimens and fewer adverse effects.”

Although the approach, meant to be used to treat the cancers, will not be widely available, he said that ‘’it does provide insight into somewhat related alternative models of cure involving gene therapy.”

Meanwhile, Dr. Marconi and other researchers are focusing on the concept of long-term HIV remission if a cure is not possible. Among the strategies under study are gene editing and immune-based treatments. HIV remission is generally defined as having an HIV viral load that is not detectable after stopping treatment.

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

The recent news that a third person has been “cured” of HIV through a unique transplant of stem cells has given hope for a larger-scale way to beat back the HIV epidemic that has plagued the world for decades.

But while this case is certainly cause for celebration, experts involved in the effort say we are still a long way from a universal cure.

Researcher Yvonne Bryson, MD, chief of pediatric infectious diseases at the University of California, Los Angeles, told those attending the Conference on Retroviruses and Opportunistic Infections that this case is special. The patient was a woman living with HIV who is multiracial. The previous two patients were men: one white, one Latinx.

The woman in this case was given transplants of stem cells and umbilical cord blood to treat leukemia. The treatment not only sent her cancer into remission, but her HIV as well.

The success of this case suggests that cord stem cell transplants should be considered to produce remission and cure for those with HIV who also have cancers and other diseases, the researchers said.

While the news was met with excitement in the scientific community, the approach will not be available universally, since the transplants were all done to treat cancers in the three HIV-infected patients. Overall, Dr. Bryson estimates that about 50 people per year may benefit from this procedure. 

Even so, other experts say the approach could provide insight into other ways to find cures. And Dr. Bryson says it opens up options for more diverse populations.

“A bone marrow transplant is not a viable large-scale strategy for curing HIV, but it does present a proof of concept that HIV can be cured,” said Sharon Lewin, MD, president-elect of the International AIDS Society. “It also further strengthens using gene therapy as a viable strategy for an HIV cure.”

The woman needed a stem cell transplant after being diagnosed with leukemia. The stem cell transplant technique used was also novel, Dr. Bryson said. The medical team used a combination of adult stem cells from a relative’s blood and umbilical cord blood from a cord-blood bank that had a rare mutation that makes the immune system resistant to HIV.

In the previous two cases of HIV cures after transplants, both patients were treated with stem cell transplants, with the same mutation, but from bone marrow transplants, a more difficult procedure. And no cord blood was used for those.

The combination of adult cells and cord-blood cells proved to be the ticket to success. Using the adult cells provides a kind of bridge that helps until the cord blood takes over, the researchers said. By day 100 after the transplant, Dr. Bryson said, the woman basically had a new immune system.

HIV remained undetectable in T cells and in bone marrow. And 37 months after the transplant, the woman stopped taking the antiretroviral treatment commonly given to treat HIV infection.

‘’She is currently clinically well,” Dr. Bryson said. Her cancer is in remission.
 

Case histories: Three patients

The woman, who is middle-aged, has requested privacy, asking that neither her age nor other details be released. But the researchers did provide some background on her medical history and her route back to health. She was diagnosed with HIV in 2013 and began treatment with antiretroviral therapy (ART). Four years after her HIV diagnosis, she developed high-risk acute myelogenous leukemia. The transplant was done to treat that.

Her recovery was much less bumpy than that of the previous two patients, the researchers said. She left the hospital 17 days after the transplant. She didn’t have serious complications like the first two, who developed a condition that occurs when donor bone marrow or stem cells attack the recipient.

“This case also suggests that it’s the transplant of HIV-resistant cells that was key to achieving a cure here,” said Dr. Lewin. The first patient who had HIV remission after a stem cell transplant, a White man, stayed in remission for 12 years and was termed cured. But he died of leukemia in September 2020. The other, a Latinx man, has been in remission for more than 30 months.
 

HIV statistics, ethnic/racial burdens

In the United States, about 1.2 million people have HIV, according to HIV.gov. Thirteen percent of those who have it do not know they have it. In 2019, 34,800 new infections were diagnosed.

Certain ethnic and racial groups are more affected by HIV than others, given their proportions in the U.S. population, federal statistics suggest. In 2019, for instance, African Americans were 13% of the U.S. population but 40% of those with HIV. Hispanics/Latinx represented 18.5% of the total population but 25% of those diagnosed with HIV.

Disparities also affect women unequally, with Black women disproportionately affected, compared to women of other ethnic and racial groups. Annual HIV infections remained stable overall among Black women from 2015 to 2019, but the rate of new HIV infections among Black women is 11 times that of White women and 4 times that of Latinx, according to federal statistics.
 

Expert perspective, reactions

Vincent Marconi, MD, professor of infectious diseases at Emory University, Atlanta, whose research focuses on disparities in HIV treatment responses, called the news “an exciting development for the cure agenda. This is the first woman to have been cured for at least 14 months, and they used cord blood, which could allow for potentially less toxic regimens and fewer adverse effects.”

Although the approach, meant to be used to treat the cancers, will not be widely available, he said that ‘’it does provide insight into somewhat related alternative models of cure involving gene therapy.”

Meanwhile, Dr. Marconi and other researchers are focusing on the concept of long-term HIV remission if a cure is not possible. Among the strategies under study are gene editing and immune-based treatments. HIV remission is generally defined as having an HIV viral load that is not detectable after stopping treatment.

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

What is the most appropriate treatment for a pregnant woman who is moderately to severely ill with COVID-19 infection?

Continue to the answer...

Moderately to severely ill pregnant women with COVID-19 infection should be hospitalized and treated with supplementary oxygen, remdesivir, and dexamethasone. Other possible therapies include inhaled nitric oxide, baricitinib (a Janus kinase inhibitor), and tocilizumab (an anti-interleukin 6 receptor antibody). (RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384:693-704. Kalil AC, Patterson TF, Mehta AK, et al; ACTT-2 Study Group. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021;384:795-807. Berlin DA, Gulick RM, Martinez FJ, et al. Severe COVID-19. N Engl J Med. 2020;383;2451-2460.)

What is the most appropriate treatment for a pregnant woman who is moderately to severely ill with COVID-19 infection?

Continue to the answer...

Moderately to severely ill pregnant women with COVID-19 infection should be hospitalized and treated with supplementary oxygen, remdesivir, and dexamethasone. Other possible therapies include inhaled nitric oxide, baricitinib (a Janus kinase inhibitor), and tocilizumab (an anti-interleukin 6 receptor antibody). (RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384:693-704. Kalil AC, Patterson TF, Mehta AK, et al; ACTT-2 Study Group. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021;384:795-807. Berlin DA, Gulick RM, Martinez FJ, et al. Severe COVID-19. N Engl J Med. 2020;383;2451-2460.)

What is the most appropriate treatment for a pregnant woman who is moderately to severely ill with COVID-19 infection?

Continue to the answer...

Moderately to severely ill pregnant women with COVID-19 infection should be hospitalized and treated with supplementary oxygen, remdesivir, and dexamethasone. Other possible therapies include inhaled nitric oxide, baricitinib (a Janus kinase inhibitor), and tocilizumab (an anti-interleukin 6 receptor antibody). (RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384:693-704. Kalil AC, Patterson TF, Mehta AK, et al; ACTT-2 Study Group. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N Engl J Med. 2021;384:795-807. Berlin DA, Gulick RM, Martinez FJ, et al. Severe COVID-19. N Engl J Med. 2020;383;2451-2460.)

Use of direct oral anticoagulant drugs (DOACs) appears to be just as effective as warfarin in preventing future thrombotic events in patients with cerebral venous thrombosis (CVT) stroke and are less likely to result in major bleeding, a retrospective study suggests.

The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.

It was also simultaneously published online in Stroke.

“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.

But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.

Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.

Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.

She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.

A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.

A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.

As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.

The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.

The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.

The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.

The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.

The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.

Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.

Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.

When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).

But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).

When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
 

Similar efficacy, better safety

Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”

Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”

“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”

In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”

They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”

They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”

The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.

The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.

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

Use of direct oral anticoagulant drugs (DOACs) appears to be just as effective as warfarin in preventing future thrombotic events in patients with cerebral venous thrombosis (CVT) stroke and are less likely to result in major bleeding, a retrospective study suggests.

The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.

It was also simultaneously published online in Stroke.

“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.

But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.

Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.

Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.

She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.

A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.

A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.

As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.

The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.

The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.

The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.

The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.

The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.

Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.

Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.

When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).

But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).

When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
 

Similar efficacy, better safety

Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”

Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”

“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”

In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”

They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”

They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”

The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.

The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.

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

Use of direct oral anticoagulant drugs (DOACs) appears to be just as effective as warfarin in preventing future thrombotic events in patients with cerebral venous thrombosis (CVT) stroke and are less likely to result in major bleeding, a retrospective study suggests.

The ACTION CVT study was presented at the International Stroke Conference (ISC) 2022 by Ekaterina Bakradze, MD, assistant professor of neurology at the University of Alabama at Birmingham.

It was also simultaneously published online in Stroke.

“This real-world data supports use of direct oral anticoagulant drugs as a reasonable alternative to warfarin in patients with cerebral venous thrombosis,” Dr. Bakradze concluded.

But she added that because this study was based on retrospective observational data, the findings should be interpreted with caution and require confirmation by larger prospective studies.

Two such studies are now underway: the Direct Oral Anticoagulants in the Treatment of Cerebral Venous Thrombosis (DOAC-CVT) study and the randomized Study of Rivaroxaban for Cerebral Venous Thrombosis (SECRET) trial.

Dr. Bakradze explained that cerebral venous thrombosis is a less common cause of stroke and occurs more often in women and younger patients, with a median age of 37 years. Current recommended treatment consists of heparin followed by oral anticoagulation.

She noted that although randomized trials and current guidelines indicate that DOACs are a preferred alternative to warfarin for the treatment of patients with venous thromboembolism, there are limited data on their use in patients with CVT.

A small, randomized trial (RESPECT-CVT) showed no significant difference in efficacy and safety outcomes between dabigatran and warfarin in patients with cerebral venous thrombosis, but with only 120 patients, this trial was too small for definite answers to this question.

A better understanding of this issue is important, because the mechanisms underlying cerebral venous thrombosis and other thromboembolism and their subsequent risks may differ, Dr. Bakradze said.

As randomized trials in patients with cerebral venous thrombosis are difficult to perform because the condition has a low incidence and low event rates, the researchers decided to look at this question with a large retrospective multicenter study.

The ACTION-CVT study involved 845 consecutive patients with cerebral venous thrombosis over 6 years (from January 2015 and December 2020) from 27 centers in Italy, New Zealand, Switzerland, and the United States. Patients were identified from medical records with diagnostic codes and confirmed with imaging.

The primary predictor in the study was oral anticoagulant type (DOAC vs. warfarin). Study outcomes were abstracted by individual sites through review of all available medical records.

The primary outcome was recurrent venous thrombosis (venous thromboembolism or cerebral venous thrombosis) during follow-up. Imaging outcomes based on recanalization status on last venous imaging study abstracted from radiology reports were also reported.

The safety outcome was major hemorrhage, defined as new or worsening intracranial hemorrhage (ICH), or major extracranial hemorrhage. Results were adjusted for age, sex, and relevant medical conditions.

The mean age of the patients included was 44.8 years, 64.7% were women, 33% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times.

Results showed that during a median follow-up of 345 days, there were 5.68 recurrent venous thrombosis events, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years.

Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization.

When compared with warfarin, DOAC treatment was associated with similar risk for recurrent venous thrombosis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73; P = .84), death (aHR, 0.71, 95% CI, 0.24-2.08; P = .53), and rate of partial/complete recanalization (aHR, 0.92, 95% CI, 0.48-1.73; P = .79).

But patients who received a DOAC had a significantly lower rate of major hemorrhage (aHR, 0.35; 95% CI, 0.15-0.81; P = .02).

When examined separately, the occurrence of ICH per 100 patient-years was much lower among the patients prescribed DOACs than those who were prescribed warfarin (1.52 vs. 3.51), whereas the occurrence of major bleeding outside the brain was similar (0.91 vs. 1.15).
 

Similar efficacy, better safety

Commenting on the study at an ISC press conference, Mitchell Elkind, MD, immediate past president of the American Heart Association/American Stroke Association and professor of neurology at Columbia University, New York, said: “The community has been concerned about extending the use of these new direct-acting oral anticoagulant drugs to cerebral venous thrombosis, but this study suggests that these patients may benefit from these new agents too.”

Tudor Jovin, MD, chair of neurology at Cooper University Hospital, Cherry Hill, New Jersey, also commented: “This study confirms what we already know from other indications about these DOAC drugs: that they have similar efficacy to warfarin but a better safety profile. These results are really spot on with that. These drugs are also much easier and more convenient to use than warfarin.”

“This is a great step forward,” he added. “Only 30% of patients in this study received DOACs, reflecting the fact that clinicians may be a little reluctant to use them in this condition. But this study now has the potential to change practice.”

In an editorial accompanying the publication in Stroke, Johnathon Gorman, MD, and Thalia Field, MD, from the Vancouver Stroke Program at the University of British Columbia, say that despite its methodological limitations, the ACTION-CVT study “provides added value to the current state of knowledge by virtue of its size and ‘real world’ setting that is reflective of how DOACs are being used to manage CVT in current clinical practice.”

They point out that although baseline characteristics between the DOAC and warfarin groups were similar, the possibility of confounding cannot be excluded, and “other characteristics not easily captured in a retrospective study may sway anticoagulation strategy.”

They acknowledge, however, that an additional propensity score analysis “provides reassurance that the groups are reasonably balanced, adjusting for variables associated with recurrent cerebral venous thrombosis, recanalization, and hemorrhage.”

The editorialists conclude that ACTION-CVT gives additional reassurance for DOACs as an alternative approach to warfarin as a treatment for cerebral venous thrombosis and for the shifts in clinical practice that are already occurring at many centers.

The study was partially supported by the Italian Ministry of Health Ricerca Corrente–IRCCS MultiMedica. Dr. Bakradze reports no disclosures. Dr. Field is the principal investigator of the SECRET trial, which received in-kind study medication from Bayer Canada. She reports honoraria from HLS Therapeutics outside the submitted work and is on the board of Destine Health. The other editorialist reports no conflicts.

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

A high percentage of people with type 2 diabetes also have atherosclerotic cardiovascular disease (ASCVD), but fewer than 1 in 20 get the triumvirate of evidence-based medications – drugs to lower cholesterol, blood pressure, and glucose levels – that can mitigate the dominant health risks they face, a large multicenter cohort study reported.

The cohort consisted of 324,706 patients with diabetes and ASCVD in the National Patient-Centered Clinical Research Network in 2018.

Senior study author Christopher B. Granger, MD, said in an interview that the findings represent “a shocking underuse of treatments proven to improve outcomes in this high-risk population.” For example, he noted that high-intensity statins are “inexpensive, well tolerated, and highly effective, but the fact that they’re only used in 26.8% of this population is really an indictment and embarrassment for our health-care system.”

The study analyzed prescriptions of high-intensity statins to lower cholesterol, ACE inhibitors or angiotensin-receptor blockers (ARBs) for blood pressure, and SGLT2 inhibitors or GLP-1 receptor agonists for hyperglycemia in a population with both diabetes and ASCVD.

This study amplifies the perceived treatment gap in cardiovascular risk reduction in persons with diabetes,” Paul S. Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “The unfortunate treatment deficiency documented among 325,000 patients in 12 health systems is carefully quantitated and the message is loud, clear, and simple: There is gross underutilization of agents – ACE inhibitors and ARBs, SGLT-2 inhibitors, GLP-1 receptor agonists, and high-intensity statins – with definitively proven ASCVD benefit.”

Overcoming barriers to prescriptions

The study noted that more work needs to be done to overcome the barriers to more widespread use of these therapies in patients with both diabetes and ASCVD.

Specifically with SGLT2 inhibitors and GLP-1 receptor agonists, cost was more likely to be a barrier than with the other drug groups, but that didn’t explain the low levels of high-intensity statin prescriptions, said Dr. Granger of Duke University, Durham, N.C.

The first barrier he mentioned is what he called “clinical inertia.” He said: “I’m a cardiologist who cares for these patients in my clinic each week, and there are so many different things that we need to be trying to achieve with the brief time we have with each patient in our clinic setting that people tend to miss the opportunity.”

The cost barrier, especially with the glucose-lowering therapies, can be overcome with clinic and health care system programs that aid patients in getting discounted drugs, he noted.

Other barriers Dr. Granger pointed out are lack of education – “So many people think that people with previous muscle aches can’t take a high-intensity statin, and we know that’s not true” – and misinformation, which he called “the more nefarious issue.”

He said, “Part of the problem is that misinformation travels much faster than accurate information. There’s so much out there about statins being toxic, which is just not true.”

Fragmentation of the U.S. health care system and the lack of feedback on quality measures, and physicians deferring decisions on glucose-lowering therapy to endocrinologists also pose barriers to more widespread use of evidence-based therapies in patients with diabetes and ASCVD, Dr. Granger said.

“This is a call to action,” Dr. Granger said. “By clearly describing these gaps, we hope that people will see this as an important opportunity to improve care not only at the level of individual providers, but even more importantly at the level of health systems.”

Dr. Jellinger said the “dismal results” of the study serve as a “wake-up call,” adding that “my own perception among my colleagues, along with the data referred to in this article, point to definitely higher usage among commercially insured patients. However, even in more enriched populations the message is not having its full impact. We have remarkable agents for our patients with diabetes that can make a real impact in diabetes-related morbidity and mortality. Our twofold goal should be to aggressively educate a broad slate of health care professionals and, of course, make patient access easy and affordable without ‘prior authorization.’ ”

The study noted the need to bring the prescribing patterns for patients with both diabetes and ASCVD more in line with evidence-based guidelines. To that end, said Dr. Granger, the researchers are moving ahead on a randomized study of a quality improvement project involving about 45 U.S. cardiology clinics using a feedback loop to apply more consistent prescribing patterns for the three therapy groups. “Hopefully a year from now we’ll have a lot more information about this problem,” Dr. Granger added.

Boehringer Ingelheim and Lilly funded the study. Dr. Granger reported financial relationships with Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, Medtronic, Akros Pharma, Apple, AstraZeneca, Daichi-Sankyo, Novartis, AbbVie, Bayer, Boston Scientific, CeleCor, Correvio, Espero, Merck, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Jellinger is on speaker’s bureaus for Esperion and Amgen.
 

A high percentage of people with type 2 diabetes also have atherosclerotic cardiovascular disease (ASCVD), but fewer than 1 in 20 get the triumvirate of evidence-based medications – drugs to lower cholesterol, blood pressure, and glucose levels – that can mitigate the dominant health risks they face, a large multicenter cohort study reported.

The cohort consisted of 324,706 patients with diabetes and ASCVD in the National Patient-Centered Clinical Research Network in 2018.

Senior study author Christopher B. Granger, MD, said in an interview that the findings represent “a shocking underuse of treatments proven to improve outcomes in this high-risk population.” For example, he noted that high-intensity statins are “inexpensive, well tolerated, and highly effective, but the fact that they’re only used in 26.8% of this population is really an indictment and embarrassment for our health-care system.”

The study analyzed prescriptions of high-intensity statins to lower cholesterol, ACE inhibitors or angiotensin-receptor blockers (ARBs) for blood pressure, and SGLT2 inhibitors or GLP-1 receptor agonists for hyperglycemia in a population with both diabetes and ASCVD.

This study amplifies the perceived treatment gap in cardiovascular risk reduction in persons with diabetes,” Paul S. Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “The unfortunate treatment deficiency documented among 325,000 patients in 12 health systems is carefully quantitated and the message is loud, clear, and simple: There is gross underutilization of agents – ACE inhibitors and ARBs, SGLT-2 inhibitors, GLP-1 receptor agonists, and high-intensity statins – with definitively proven ASCVD benefit.”

Overcoming barriers to prescriptions

The study noted that more work needs to be done to overcome the barriers to more widespread use of these therapies in patients with both diabetes and ASCVD.

Specifically with SGLT2 inhibitors and GLP-1 receptor agonists, cost was more likely to be a barrier than with the other drug groups, but that didn’t explain the low levels of high-intensity statin prescriptions, said Dr. Granger of Duke University, Durham, N.C.

The first barrier he mentioned is what he called “clinical inertia.” He said: “I’m a cardiologist who cares for these patients in my clinic each week, and there are so many different things that we need to be trying to achieve with the brief time we have with each patient in our clinic setting that people tend to miss the opportunity.”

The cost barrier, especially with the glucose-lowering therapies, can be overcome with clinic and health care system programs that aid patients in getting discounted drugs, he noted.

Other barriers Dr. Granger pointed out are lack of education – “So many people think that people with previous muscle aches can’t take a high-intensity statin, and we know that’s not true” – and misinformation, which he called “the more nefarious issue.”

He said, “Part of the problem is that misinformation travels much faster than accurate information. There’s so much out there about statins being toxic, which is just not true.”

Fragmentation of the U.S. health care system and the lack of feedback on quality measures, and physicians deferring decisions on glucose-lowering therapy to endocrinologists also pose barriers to more widespread use of evidence-based therapies in patients with diabetes and ASCVD, Dr. Granger said.

“This is a call to action,” Dr. Granger said. “By clearly describing these gaps, we hope that people will see this as an important opportunity to improve care not only at the level of individual providers, but even more importantly at the level of health systems.”

Dr. Jellinger said the “dismal results” of the study serve as a “wake-up call,” adding that “my own perception among my colleagues, along with the data referred to in this article, point to definitely higher usage among commercially insured patients. However, even in more enriched populations the message is not having its full impact. We have remarkable agents for our patients with diabetes that can make a real impact in diabetes-related morbidity and mortality. Our twofold goal should be to aggressively educate a broad slate of health care professionals and, of course, make patient access easy and affordable without ‘prior authorization.’ ”

The study noted the need to bring the prescribing patterns for patients with both diabetes and ASCVD more in line with evidence-based guidelines. To that end, said Dr. Granger, the researchers are moving ahead on a randomized study of a quality improvement project involving about 45 U.S. cardiology clinics using a feedback loop to apply more consistent prescribing patterns for the three therapy groups. “Hopefully a year from now we’ll have a lot more information about this problem,” Dr. Granger added.

Boehringer Ingelheim and Lilly funded the study. Dr. Granger reported financial relationships with Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, Medtronic, Akros Pharma, Apple, AstraZeneca, Daichi-Sankyo, Novartis, AbbVie, Bayer, Boston Scientific, CeleCor, Correvio, Espero, Merck, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Jellinger is on speaker’s bureaus for Esperion and Amgen.
 

A high percentage of people with type 2 diabetes also have atherosclerotic cardiovascular disease (ASCVD), but fewer than 1 in 20 get the triumvirate of evidence-based medications – drugs to lower cholesterol, blood pressure, and glucose levels – that can mitigate the dominant health risks they face, a large multicenter cohort study reported.

The cohort consisted of 324,706 patients with diabetes and ASCVD in the National Patient-Centered Clinical Research Network in 2018.

Senior study author Christopher B. Granger, MD, said in an interview that the findings represent “a shocking underuse of treatments proven to improve outcomes in this high-risk population.” For example, he noted that high-intensity statins are “inexpensive, well tolerated, and highly effective, but the fact that they’re only used in 26.8% of this population is really an indictment and embarrassment for our health-care system.”

The study analyzed prescriptions of high-intensity statins to lower cholesterol, ACE inhibitors or angiotensin-receptor blockers (ARBs) for blood pressure, and SGLT2 inhibitors or GLP-1 receptor agonists for hyperglycemia in a population with both diabetes and ASCVD.

This study amplifies the perceived treatment gap in cardiovascular risk reduction in persons with diabetes,” Paul S. Jellinger, MD, of the Center for Diabetes and Endocrine Care in Hollywood, Fla., said in an interview. “The unfortunate treatment deficiency documented among 325,000 patients in 12 health systems is carefully quantitated and the message is loud, clear, and simple: There is gross underutilization of agents – ACE inhibitors and ARBs, SGLT-2 inhibitors, GLP-1 receptor agonists, and high-intensity statins – with definitively proven ASCVD benefit.”

Overcoming barriers to prescriptions

The study noted that more work needs to be done to overcome the barriers to more widespread use of these therapies in patients with both diabetes and ASCVD.

Specifically with SGLT2 inhibitors and GLP-1 receptor agonists, cost was more likely to be a barrier than with the other drug groups, but that didn’t explain the low levels of high-intensity statin prescriptions, said Dr. Granger of Duke University, Durham, N.C.

The first barrier he mentioned is what he called “clinical inertia.” He said: “I’m a cardiologist who cares for these patients in my clinic each week, and there are so many different things that we need to be trying to achieve with the brief time we have with each patient in our clinic setting that people tend to miss the opportunity.”

The cost barrier, especially with the glucose-lowering therapies, can be overcome with clinic and health care system programs that aid patients in getting discounted drugs, he noted.

Other barriers Dr. Granger pointed out are lack of education – “So many people think that people with previous muscle aches can’t take a high-intensity statin, and we know that’s not true” – and misinformation, which he called “the more nefarious issue.”

He said, “Part of the problem is that misinformation travels much faster than accurate information. There’s so much out there about statins being toxic, which is just not true.”

Fragmentation of the U.S. health care system and the lack of feedback on quality measures, and physicians deferring decisions on glucose-lowering therapy to endocrinologists also pose barriers to more widespread use of evidence-based therapies in patients with diabetes and ASCVD, Dr. Granger said.

“This is a call to action,” Dr. Granger said. “By clearly describing these gaps, we hope that people will see this as an important opportunity to improve care not only at the level of individual providers, but even more importantly at the level of health systems.”

Dr. Jellinger said the “dismal results” of the study serve as a “wake-up call,” adding that “my own perception among my colleagues, along with the data referred to in this article, point to definitely higher usage among commercially insured patients. However, even in more enriched populations the message is not having its full impact. We have remarkable agents for our patients with diabetes that can make a real impact in diabetes-related morbidity and mortality. Our twofold goal should be to aggressively educate a broad slate of health care professionals and, of course, make patient access easy and affordable without ‘prior authorization.’ ”

The study noted the need to bring the prescribing patterns for patients with both diabetes and ASCVD more in line with evidence-based guidelines. To that end, said Dr. Granger, the researchers are moving ahead on a randomized study of a quality improvement project involving about 45 U.S. cardiology clinics using a feedback loop to apply more consistent prescribing patterns for the three therapy groups. “Hopefully a year from now we’ll have a lot more information about this problem,” Dr. Granger added.

Boehringer Ingelheim and Lilly funded the study. Dr. Granger reported financial relationships with Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, Medtronic, Akros Pharma, Apple, AstraZeneca, Daichi-Sankyo, Novartis, AbbVie, Bayer, Boston Scientific, CeleCor, Correvio, Espero, Merck, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics. Dr. Jellinger is on speaker’s bureaus for Esperion and Amgen.
 

Loss of smell. Fatigue. Mental health challenges. Difficulty breathing and other lower respiratory diseases. Fluid and electrolyte disorders. Cardiac dysrhythmia and other nonspecific chest pains. Trouble with urination. Diabetes?

Statistically, these are the conditions that defined post-acute SARS-CoV-2 (PASC) infection, or long COVID, for 28,118 people who tested positive for SARS-CoV-2 by PCR before the Omicron wave. The data, presented at the Conference on Retroviruses and Opportunistic Infections, can be used to guide diagnoses of long COVID, and may be the guide soon at Kaiser Permanente offices, Michael Horberg, MD, executive director of research, community benefit, and Medicaid strategy at the Mid-Atlantic Permanente Research Institute, said in an interview.

Medscape Illustration/Dreamstime/Getty Images

More than 1 in 10

About one in four people who’d had COVID reported symptoms they thought might be long COVID, but through the analysis, they found that only 13% actually developed new conditions that could be categorized as long COVID.

“When you start controlling for all those chronic conditions, a lot of symptoms fall out,” Dr. Horberg told this news organization. “Plus, when you start comparing to the COVID-negative population, especially in the first 30 days of your positive diagnosis, actually, the COVID-negative patients have essentially almost the same amount, sometimes more.”

For instance, in the first month after diagnosis, though people with COVID reported anxiety symptoms after their diagnoses, people who’d never had COVID were coming in even more often with that symptom. And although gastrointestinal disorders were common in people who’d had COVID, they were just as likely in people who had not. Nausea and vomiting were actually 19% more common in people without COVID than in those with it. And people without COVID were nearly twice as likely to develop nutritional and endocrine disorders.

In the longer run, people who’d had COVID were 25% more likely to develop dysrhythmias, 20% more likely to develop diabetes, 60% more likely to develop fatigue, 21% more likely to develop genitourinary conditions, 39% more likely to develop chest pains, and a full 3.88 times more likely to develop trouble with olfaction.

And although people who’d had COVID were numerically 5% more likely to develop both abdominal pain and vertigo, 4% more likely to develop nervous system disorders, and 1% more likely to develop anxiety disorders longer term, none of those reached statistical significance.

The only diagnosis that doesn’t make sense to Dr. Horberg is diabetes.

“At this point I don’t think it’s been fully explained,” Dr. Horberg said. “I don’t think COVID is affecting the pancreas. But I do think that these are people who probably sought medical care, who hadn’t been seeking medical care and that the findings of diabetes were incidental diagnoses.”

Still, Dr. Horberg isn’t saying never on that. “As they say, more research is needed,” he added.
 

Ready to define long COVID?

As an intensive care unit physician and pulmonologist, Michael Risbano, MD, assistant professor of medicine at the University of Pittsburgh, has seen a lot of COVID. As the co-manager of the medical system’s post-COVID clinic, he’s also seen a lot of people coming in for help with what could be long COVID. When he saw the data from Dr. Horberg’s presentation, at first it seemed to confirm what he’d already known. But then he looked further.

“Well, this is actually making sense,” Dr. Risbano thought. At his clinic, it’s been an ongoing challenge to tease out what symptoms existed before COVID. Unlike Kaiser, the University of Pittsburgh Medical Center is not a closed system.

“We know some people who tend to get sick [with COVID] have some underlying medical issues already,” Dr. Risbano said in an interview. “But we don’t always have a good baseline as to what they were like beforehand, so we don’t always know what’s changed.”

He said the study design here, though retrospective and based on chart review rather than prospective observation, starts to put symptoms into the larger context of a patient’s life. And the diabetes association really stood out to him. He recalled one patient who, when she was admitted to the ICU, had a hemoglobin A1c that was totally normal. But when that patient returned a few months later, her blood sugar had skyrocketed.

“It was sky-high, like 13, and she was in diabetic ketoacidosis,” he said. “I know that’s an N of 1, but my wife is a dietitian and a case manager, and she’s having a lot of people coming in with a new diagnosis of diabetes.”

Still, he said he’s not sure that the conditions the study identified should be the basis for a definition of long COVID.

“I don’t know if you can come up with a definition out of this,” he said. “But I think this is at least helpful in telling us what disease states are different pre- and post-COVID, and what sorts of diagnoses clinicians should look for when a patient comes in after having a COVID diagnosis.”

Dr. Horberg and Dr. Risbano have disclosed no relevant financial relationships. The study was funded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

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

Loss of smell. Fatigue. Mental health challenges. Difficulty breathing and other lower respiratory diseases. Fluid and electrolyte disorders. Cardiac dysrhythmia and other nonspecific chest pains. Trouble with urination. Diabetes?

Statistically, these are the conditions that defined post-acute SARS-CoV-2 (PASC) infection, or long COVID, for 28,118 people who tested positive for SARS-CoV-2 by PCR before the Omicron wave. The data, presented at the Conference on Retroviruses and Opportunistic Infections, can be used to guide diagnoses of long COVID, and may be the guide soon at Kaiser Permanente offices, Michael Horberg, MD, executive director of research, community benefit, and Medicaid strategy at the Mid-Atlantic Permanente Research Institute, said in an interview.

Medscape Illustration/Dreamstime/Getty Images

More than 1 in 10

About one in four people who’d had COVID reported symptoms they thought might be long COVID, but through the analysis, they found that only 13% actually developed new conditions that could be categorized as long COVID.

“When you start controlling for all those chronic conditions, a lot of symptoms fall out,” Dr. Horberg told this news organization. “Plus, when you start comparing to the COVID-negative population, especially in the first 30 days of your positive diagnosis, actually, the COVID-negative patients have essentially almost the same amount, sometimes more.”

For instance, in the first month after diagnosis, though people with COVID reported anxiety symptoms after their diagnoses, people who’d never had COVID were coming in even more often with that symptom. And although gastrointestinal disorders were common in people who’d had COVID, they were just as likely in people who had not. Nausea and vomiting were actually 19% more common in people without COVID than in those with it. And people without COVID were nearly twice as likely to develop nutritional and endocrine disorders.

In the longer run, people who’d had COVID were 25% more likely to develop dysrhythmias, 20% more likely to develop diabetes, 60% more likely to develop fatigue, 21% more likely to develop genitourinary conditions, 39% more likely to develop chest pains, and a full 3.88 times more likely to develop trouble with olfaction.

And although people who’d had COVID were numerically 5% more likely to develop both abdominal pain and vertigo, 4% more likely to develop nervous system disorders, and 1% more likely to develop anxiety disorders longer term, none of those reached statistical significance.

The only diagnosis that doesn’t make sense to Dr. Horberg is diabetes.

“At this point I don’t think it’s been fully explained,” Dr. Horberg said. “I don’t think COVID is affecting the pancreas. But I do think that these are people who probably sought medical care, who hadn’t been seeking medical care and that the findings of diabetes were incidental diagnoses.”

Still, Dr. Horberg isn’t saying never on that. “As they say, more research is needed,” he added.
 

Ready to define long COVID?

As an intensive care unit physician and pulmonologist, Michael Risbano, MD, assistant professor of medicine at the University of Pittsburgh, has seen a lot of COVID. As the co-manager of the medical system’s post-COVID clinic, he’s also seen a lot of people coming in for help with what could be long COVID. When he saw the data from Dr. Horberg’s presentation, at first it seemed to confirm what he’d already known. But then he looked further.

“Well, this is actually making sense,” Dr. Risbano thought. At his clinic, it’s been an ongoing challenge to tease out what symptoms existed before COVID. Unlike Kaiser, the University of Pittsburgh Medical Center is not a closed system.

“We know some people who tend to get sick [with COVID] have some underlying medical issues already,” Dr. Risbano said in an interview. “But we don’t always have a good baseline as to what they were like beforehand, so we don’t always know what’s changed.”

He said the study design here, though retrospective and based on chart review rather than prospective observation, starts to put symptoms into the larger context of a patient’s life. And the diabetes association really stood out to him. He recalled one patient who, when she was admitted to the ICU, had a hemoglobin A1c that was totally normal. But when that patient returned a few months later, her blood sugar had skyrocketed.

“It was sky-high, like 13, and she was in diabetic ketoacidosis,” he said. “I know that’s an N of 1, but my wife is a dietitian and a case manager, and she’s having a lot of people coming in with a new diagnosis of diabetes.”

Still, he said he’s not sure that the conditions the study identified should be the basis for a definition of long COVID.

“I don’t know if you can come up with a definition out of this,” he said. “But I think this is at least helpful in telling us what disease states are different pre- and post-COVID, and what sorts of diagnoses clinicians should look for when a patient comes in after having a COVID diagnosis.”

Dr. Horberg and Dr. Risbano have disclosed no relevant financial relationships. The study was funded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

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

Loss of smell. Fatigue. Mental health challenges. Difficulty breathing and other lower respiratory diseases. Fluid and electrolyte disorders. Cardiac dysrhythmia and other nonspecific chest pains. Trouble with urination. Diabetes?

Statistically, these are the conditions that defined post-acute SARS-CoV-2 (PASC) infection, or long COVID, for 28,118 people who tested positive for SARS-CoV-2 by PCR before the Omicron wave. The data, presented at the Conference on Retroviruses and Opportunistic Infections, can be used to guide diagnoses of long COVID, and may be the guide soon at Kaiser Permanente offices, Michael Horberg, MD, executive director of research, community benefit, and Medicaid strategy at the Mid-Atlantic Permanente Research Institute, said in an interview.

Medscape Illustration/Dreamstime/Getty Images

More than 1 in 10

About one in four people who’d had COVID reported symptoms they thought might be long COVID, but through the analysis, they found that only 13% actually developed new conditions that could be categorized as long COVID.

“When you start controlling for all those chronic conditions, a lot of symptoms fall out,” Dr. Horberg told this news organization. “Plus, when you start comparing to the COVID-negative population, especially in the first 30 days of your positive diagnosis, actually, the COVID-negative patients have essentially almost the same amount, sometimes more.”

For instance, in the first month after diagnosis, though people with COVID reported anxiety symptoms after their diagnoses, people who’d never had COVID were coming in even more often with that symptom. And although gastrointestinal disorders were common in people who’d had COVID, they were just as likely in people who had not. Nausea and vomiting were actually 19% more common in people without COVID than in those with it. And people without COVID were nearly twice as likely to develop nutritional and endocrine disorders.

In the longer run, people who’d had COVID were 25% more likely to develop dysrhythmias, 20% more likely to develop diabetes, 60% more likely to develop fatigue, 21% more likely to develop genitourinary conditions, 39% more likely to develop chest pains, and a full 3.88 times more likely to develop trouble with olfaction.

And although people who’d had COVID were numerically 5% more likely to develop both abdominal pain and vertigo, 4% more likely to develop nervous system disorders, and 1% more likely to develop anxiety disorders longer term, none of those reached statistical significance.

The only diagnosis that doesn’t make sense to Dr. Horberg is diabetes.

“At this point I don’t think it’s been fully explained,” Dr. Horberg said. “I don’t think COVID is affecting the pancreas. But I do think that these are people who probably sought medical care, who hadn’t been seeking medical care and that the findings of diabetes were incidental diagnoses.”

Still, Dr. Horberg isn’t saying never on that. “As they say, more research is needed,” he added.
 

Ready to define long COVID?

As an intensive care unit physician and pulmonologist, Michael Risbano, MD, assistant professor of medicine at the University of Pittsburgh, has seen a lot of COVID. As the co-manager of the medical system’s post-COVID clinic, he’s also seen a lot of people coming in for help with what could be long COVID. When he saw the data from Dr. Horberg’s presentation, at first it seemed to confirm what he’d already known. But then he looked further.

“Well, this is actually making sense,” Dr. Risbano thought. At his clinic, it’s been an ongoing challenge to tease out what symptoms existed before COVID. Unlike Kaiser, the University of Pittsburgh Medical Center is not a closed system.

“We know some people who tend to get sick [with COVID] have some underlying medical issues already,” Dr. Risbano said in an interview. “But we don’t always have a good baseline as to what they were like beforehand, so we don’t always know what’s changed.”

He said the study design here, though retrospective and based on chart review rather than prospective observation, starts to put symptoms into the larger context of a patient’s life. And the diabetes association really stood out to him. He recalled one patient who, when she was admitted to the ICU, had a hemoglobin A1c that was totally normal. But when that patient returned a few months later, her blood sugar had skyrocketed.

“It was sky-high, like 13, and she was in diabetic ketoacidosis,” he said. “I know that’s an N of 1, but my wife is a dietitian and a case manager, and she’s having a lot of people coming in with a new diagnosis of diabetes.”

Still, he said he’s not sure that the conditions the study identified should be the basis for a definition of long COVID.

“I don’t know if you can come up with a definition out of this,” he said. “But I think this is at least helpful in telling us what disease states are different pre- and post-COVID, and what sorts of diagnoses clinicians should look for when a patient comes in after having a COVID diagnosis.”

Dr. Horberg and Dr. Risbano have disclosed no relevant financial relationships. The study was funded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

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

The purpose of this commentary is to provide a brief summary of discussions centering around reproductive health experiences and obstetrical care for gender-diverse patients from the recent Society of Maternal & Fetal Medicine meeting. Two presentations featured patient perspectives combined with physician lectures to provide a comprehensive outlook on unique reproductive care needs for this growing population.

One of the speakers, Trystan Reese, is a transgender activist, educator, and transgender male who chose to carry his own pregnancy and subsequently delivered his son in 2017. During the summit, he described many barriers that he faced during his pregnancy and offered providers suggestions on how to improve the care for members of the gender-diverse community seeking to start a family.

We often think of conception and pregnancy as experiences unique to one gender. This is simply not the case. In discussing preconceptual care and pregnancy, it is paramount for providers to make the distinction between gender identity and natal sex. Gender identity is an internal sense of self in relation to natal sex. Depending on this intrinsic feeling, people may identify as cisgender, transgender, or as a gender outside of the standard binary. Natal sex describes biologic characteristics such as chromosomal makeup, reproductive anatomy, and secondary sexual changes. In keeping these distinctions in mind, pregnancy is therefore exclusive to a person’s natal sex, not gender identity. One of the biggest challenges in caring for transgender patients who desire pregnancy, is the psychological distress related to the gendered notions surrounding this experience.¹

There are many ways in which patients encounter unintentional marginalization within the medical system. For example, many electronic medical record systems don’t allow for pronouns or give error messages if the patient’s gender identity is different from their sex assigned at birth. Patients who attend prenatal appointments or birth classes are given documents that center around cisgender women and heterosexual relationships. The labor and delivery wards themselves typically include language such as “maternity,” and birth certificates have distinct “mother” and “father” denotations.¹ Insurance coverage for prenatal care and delivery can be problematic if a patient who is assigned female at birth has changed their gender marker to “male” on their insurance card.

Many of these roadblocks can be ameliorated by utilizing more inclusive terminology. Terms such as “maternal” can be replaced with “pregnant patients, parent, or patients giving birth.” Names of maternity wards can be altered to perinatal units, which is more inclusive and more descriptive of the wide variety of patients that may experience childbirth and parenthood.¹ Introducing “you-centered” language can also be helpful. Instead of saying “women may find ...” providers can try saying “patients may find ...” or “individuals may find.”¹

Most of the medical and obstetrical care of gender-diverse patients is routine. Prenatal labs, aneuploidy screening, ultrasounds, and fetal surveillance do not differ between transgender and cisgender patients. However, the experience of pregnancy itself can significantly heighten feelings of dysphoria as it inherently leads to patients confronting aspects of their biological sex.² Because of the teratogenic nature of testosterone, patients are required to stop taking testosterone prior to conception and for the duration of pregnancy. This can also heighten dysphoria and lead to increased rates of anxiety and depression.³

Many transgender patients can safely achieve a normal vaginal birth.⁴ A small survey of 41 people demonstrated that more transgender men who had taken testosterone were delivered by cesarean section (36% vs. 19%).³ Staff training is an important aspect of caring for a transgender patient in labor to ensure that all members of the labor unit are cognizant of appropriate name and pronoun usage. Another interesting, although unsurprising, fact is that many transgender gestational parents chose a community-based (out-of-hospital) birth according to a 2014 study.¹ This is predominantly because of the discrimination patients face when delivering within a hospital setting.

Postpartum depression screening should be conducted prior to patients leaving the hospital and individualized during postpartum appointments. Reinitiation of testosterone can occur 4-6 weeks after delivery.¹

While pregnancy can pose some unique challenges to gender-diverse individuals, these intricacies are not insurmountable. The result of pregnancy, regardless of one’s gender identity, is the same – parenthood. One patient’s description of his experience was particularly poignant: “Pregnancy and childbirth were very male experiences for me. When I birthed my children, I was born into fatherhood.”¹ It is up to all providers to modify clinical settings, as well as our patient interactions and use of language, if we are to provide inclusion in obstetrics.^1,5

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Brandt JS et al. “Understanding intersections: Care for transgender and gender diverse patient populations.” SMFM 2022 annual meeting. 2022 Feb 2.

2. Hoffkling A et al. BMC Pregnancy Childbirth. 2017 Nov 8;17(Suppl 2):332.

3. Light AD et al. Obstet Gynecol. 2014;124:1120-7.

4. Moseson H et al. Int J Transgend Health. 2021 Nov 17;22(1-2):30-41.

5. Brandt JS et al. Obstetrical care for trans*person, in “Trans*gynecology: Managing transgender patients in obstetrics and gynecology practice.” (Cambridge, England: Cambridge University Press, 2022).

The purpose of this commentary is to provide a brief summary of discussions centering around reproductive health experiences and obstetrical care for gender-diverse patients from the recent Society of Maternal & Fetal Medicine meeting. Two presentations featured patient perspectives combined with physician lectures to provide a comprehensive outlook on unique reproductive care needs for this growing population.

One of the speakers, Trystan Reese, is a transgender activist, educator, and transgender male who chose to carry his own pregnancy and subsequently delivered his son in 2017. During the summit, he described many barriers that he faced during his pregnancy and offered providers suggestions on how to improve the care for members of the gender-diverse community seeking to start a family.

We often think of conception and pregnancy as experiences unique to one gender. This is simply not the case. In discussing preconceptual care and pregnancy, it is paramount for providers to make the distinction between gender identity and natal sex. Gender identity is an internal sense of self in relation to natal sex. Depending on this intrinsic feeling, people may identify as cisgender, transgender, or as a gender outside of the standard binary. Natal sex describes biologic characteristics such as chromosomal makeup, reproductive anatomy, and secondary sexual changes. In keeping these distinctions in mind, pregnancy is therefore exclusive to a person’s natal sex, not gender identity. One of the biggest challenges in caring for transgender patients who desire pregnancy, is the psychological distress related to the gendered notions surrounding this experience.¹

There are many ways in which patients encounter unintentional marginalization within the medical system. For example, many electronic medical record systems don’t allow for pronouns or give error messages if the patient’s gender identity is different from their sex assigned at birth. Patients who attend prenatal appointments or birth classes are given documents that center around cisgender women and heterosexual relationships. The labor and delivery wards themselves typically include language such as “maternity,” and birth certificates have distinct “mother” and “father” denotations.¹ Insurance coverage for prenatal care and delivery can be problematic if a patient who is assigned female at birth has changed their gender marker to “male” on their insurance card.

Many of these roadblocks can be ameliorated by utilizing more inclusive terminology. Terms such as “maternal” can be replaced with “pregnant patients, parent, or patients giving birth.” Names of maternity wards can be altered to perinatal units, which is more inclusive and more descriptive of the wide variety of patients that may experience childbirth and parenthood.¹ Introducing “you-centered” language can also be helpful. Instead of saying “women may find ...” providers can try saying “patients may find ...” or “individuals may find.”¹

Most of the medical and obstetrical care of gender-diverse patients is routine. Prenatal labs, aneuploidy screening, ultrasounds, and fetal surveillance do not differ between transgender and cisgender patients. However, the experience of pregnancy itself can significantly heighten feelings of dysphoria as it inherently leads to patients confronting aspects of their biological sex.² Because of the teratogenic nature of testosterone, patients are required to stop taking testosterone prior to conception and for the duration of pregnancy. This can also heighten dysphoria and lead to increased rates of anxiety and depression.³

Many transgender patients can safely achieve a normal vaginal birth.⁴ A small survey of 41 people demonstrated that more transgender men who had taken testosterone were delivered by cesarean section (36% vs. 19%).³ Staff training is an important aspect of caring for a transgender patient in labor to ensure that all members of the labor unit are cognizant of appropriate name and pronoun usage. Another interesting, although unsurprising, fact is that many transgender gestational parents chose a community-based (out-of-hospital) birth according to a 2014 study.¹ This is predominantly because of the discrimination patients face when delivering within a hospital setting.

Postpartum depression screening should be conducted prior to patients leaving the hospital and individualized during postpartum appointments. Reinitiation of testosterone can occur 4-6 weeks after delivery.¹

While pregnancy can pose some unique challenges to gender-diverse individuals, these intricacies are not insurmountable. The result of pregnancy, regardless of one’s gender identity, is the same – parenthood. One patient’s description of his experience was particularly poignant: “Pregnancy and childbirth were very male experiences for me. When I birthed my children, I was born into fatherhood.”¹ It is up to all providers to modify clinical settings, as well as our patient interactions and use of language, if we are to provide inclusion in obstetrics.^1,5

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Brandt JS et al. “Understanding intersections: Care for transgender and gender diverse patient populations.” SMFM 2022 annual meeting. 2022 Feb 2.

2. Hoffkling A et al. BMC Pregnancy Childbirth. 2017 Nov 8;17(Suppl 2):332.

3. Light AD et al. Obstet Gynecol. 2014;124:1120-7.

4. Moseson H et al. Int J Transgend Health. 2021 Nov 17;22(1-2):30-41.

5. Brandt JS et al. Obstetrical care for trans*person, in “Trans*gynecology: Managing transgender patients in obstetrics and gynecology practice.” (Cambridge, England: Cambridge University Press, 2022).

The purpose of this commentary is to provide a brief summary of discussions centering around reproductive health experiences and obstetrical care for gender-diverse patients from the recent Society of Maternal & Fetal Medicine meeting. Two presentations featured patient perspectives combined with physician lectures to provide a comprehensive outlook on unique reproductive care needs for this growing population.

One of the speakers, Trystan Reese, is a transgender activist, educator, and transgender male who chose to carry his own pregnancy and subsequently delivered his son in 2017. During the summit, he described many barriers that he faced during his pregnancy and offered providers suggestions on how to improve the care for members of the gender-diverse community seeking to start a family.

We often think of conception and pregnancy as experiences unique to one gender. This is simply not the case. In discussing preconceptual care and pregnancy, it is paramount for providers to make the distinction between gender identity and natal sex. Gender identity is an internal sense of self in relation to natal sex. Depending on this intrinsic feeling, people may identify as cisgender, transgender, or as a gender outside of the standard binary. Natal sex describes biologic characteristics such as chromosomal makeup, reproductive anatomy, and secondary sexual changes. In keeping these distinctions in mind, pregnancy is therefore exclusive to a person’s natal sex, not gender identity. One of the biggest challenges in caring for transgender patients who desire pregnancy, is the psychological distress related to the gendered notions surrounding this experience.¹

There are many ways in which patients encounter unintentional marginalization within the medical system. For example, many electronic medical record systems don’t allow for pronouns or give error messages if the patient’s gender identity is different from their sex assigned at birth. Patients who attend prenatal appointments or birth classes are given documents that center around cisgender women and heterosexual relationships. The labor and delivery wards themselves typically include language such as “maternity,” and birth certificates have distinct “mother” and “father” denotations.¹ Insurance coverage for prenatal care and delivery can be problematic if a patient who is assigned female at birth has changed their gender marker to “male” on their insurance card.

Many of these roadblocks can be ameliorated by utilizing more inclusive terminology. Terms such as “maternal” can be replaced with “pregnant patients, parent, or patients giving birth.” Names of maternity wards can be altered to perinatal units, which is more inclusive and more descriptive of the wide variety of patients that may experience childbirth and parenthood.¹ Introducing “you-centered” language can also be helpful. Instead of saying “women may find ...” providers can try saying “patients may find ...” or “individuals may find.”¹

Most of the medical and obstetrical care of gender-diverse patients is routine. Prenatal labs, aneuploidy screening, ultrasounds, and fetal surveillance do not differ between transgender and cisgender patients. However, the experience of pregnancy itself can significantly heighten feelings of dysphoria as it inherently leads to patients confronting aspects of their biological sex.² Because of the teratogenic nature of testosterone, patients are required to stop taking testosterone prior to conception and for the duration of pregnancy. This can also heighten dysphoria and lead to increased rates of anxiety and depression.³

Many transgender patients can safely achieve a normal vaginal birth.⁴ A small survey of 41 people demonstrated that more transgender men who had taken testosterone were delivered by cesarean section (36% vs. 19%).³ Staff training is an important aspect of caring for a transgender patient in labor to ensure that all members of the labor unit are cognizant of appropriate name and pronoun usage. Another interesting, although unsurprising, fact is that many transgender gestational parents chose a community-based (out-of-hospital) birth according to a 2014 study.¹ This is predominantly because of the discrimination patients face when delivering within a hospital setting.

Postpartum depression screening should be conducted prior to patients leaving the hospital and individualized during postpartum appointments. Reinitiation of testosterone can occur 4-6 weeks after delivery.¹

While pregnancy can pose some unique challenges to gender-diverse individuals, these intricacies are not insurmountable. The result of pregnancy, regardless of one’s gender identity, is the same – parenthood. One patient’s description of his experience was particularly poignant: “Pregnancy and childbirth were very male experiences for me. When I birthed my children, I was born into fatherhood.”¹ It is up to all providers to modify clinical settings, as well as our patient interactions and use of language, if we are to provide inclusion in obstetrics.^1,5

Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.

References

1. Brandt JS et al. “Understanding intersections: Care for transgender and gender diverse patient populations.” SMFM 2022 annual meeting. 2022 Feb 2.

2. Hoffkling A et al. BMC Pregnancy Childbirth. 2017 Nov 8;17(Suppl 2):332.

3. Light AD et al. Obstet Gynecol. 2014;124:1120-7.

4. Moseson H et al. Int J Transgend Health. 2021 Nov 17;22(1-2):30-41.

5. Brandt JS et al. Obstetrical care for trans*person, in “Trans*gynecology: Managing transgender patients in obstetrics and gynecology practice.” (Cambridge, England: Cambridge University Press, 2022).

Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.

“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.

bowdenimages/iStock/Getty Images

“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.

IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.

However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.

They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
 

Monogenic disorders that mimic IBD

To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.

Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.

Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.

While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
 

Celiac disease

Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.

The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.

In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”

Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
 

Other considerations besides IBD

Additional non-IBD phenotype disorders mimicking IBD to consider include the following:

Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.

Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.

“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”

Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.

Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.

Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.

Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.

“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.

Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.

Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
 

Key indicators that it’s not IBD

Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.

“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”

Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.

“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.

In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”

Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.

Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.

Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.

“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.” 

The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.

Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.

“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.

bowdenimages/iStock/Getty Images

“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.

IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.

However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.

They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
 

Monogenic disorders that mimic IBD

To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.

Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.

Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.

While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
 

Celiac disease

Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.

The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.

In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”

Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
 

Other considerations besides IBD

Additional non-IBD phenotype disorders mimicking IBD to consider include the following:

Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.

Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.

“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”

Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.

Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.

Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.

Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.

“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.

Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.

Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
 

Key indicators that it’s not IBD

Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.

“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”

Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.

“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.

In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”

Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.

Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.

Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.

“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.” 

The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.

Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.

“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.

bowdenimages/iStock/Getty Images

“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.

IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.

However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.

They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
 

Monogenic disorders that mimic IBD

To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.

Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.

Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.

While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
 

Celiac disease

Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.

The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.

In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”

Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
 

Other considerations besides IBD

Additional non-IBD phenotype disorders mimicking IBD to consider include the following:

Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.

Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.

“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”

Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.

Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.

Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.

Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.

“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.

Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.

Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
 

Key indicators that it’s not IBD

Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.

“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”

Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.

“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.

In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”

Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.

Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.

Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.

“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.” 

The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.