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Psilocybin matches SSRI for moderate to severe depression in phase 2 study
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
PTSD linked to ischemic heart disease
A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).
The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.
“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”
The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”
The article was published online in JAMA Cardiology on March 17.
Increasing number of VHA users
“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.
The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.
IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.
For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.
Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.
Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.
IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.
The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.
Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).
In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)
The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).
Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.
The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.
In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.
A call to action
In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.
As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).
These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”
The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”
Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”
Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.
“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.
She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.
This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
A version of this article first appeared on Medscape.com.
A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).
The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.
“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”
The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”
The article was published online in JAMA Cardiology on March 17.
Increasing number of VHA users
“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.
The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.
IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.
For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.
Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.
Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.
IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.
The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.
Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).
In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)
The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).
Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.
The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.
In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.
A call to action
In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.
As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).
These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”
The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”
Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”
Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.
“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.
She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.
This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
A version of this article first appeared on Medscape.com.
A study using data from Veterans Health Administration (VHA) electronic medical records shows a significant association between posttraumatic stress disorder (PTSD) among female veterans and an increased risk for incident ischemic heart disease (IHD).
The increased risk for IHD was highest among women younger than 40 with PTSD, and among racial and ethnic minorities.
“These women have been emerging as important targets for cardiovascular prevention, and our study suggests that PTSD may be an important psychosocial risk factor for IHD in these individuals,” wrote the researchers, led by Ramin Ebrahimi, MD, department of medicine, cardiology section, Veterans Affairs Greater Los Angeles Health Care System. “With the number of women veterans growing, it is critical to appreciate the health care needs of this relatively young and diverse patient population.”
The study results also have “important implications for earlier and more aggressive IHD risk assessment, monitoring and management in vulnerable women veterans,” they added. “Indeed, our findings support recent calls for cardiovascular risk screening in younger individuals and for the need to harness a broad range of clinicians who routinely treat younger women to maximize prevention efforts.”
The article was published online in JAMA Cardiology on March 17.
Increasing number of VHA users
“As an interventional cardiologist and the director of the cardiac catheterization laboratory, I noticed a significant number of the patients referred to the cath lab carried a diagnosis of posttraumatic stress disorder,” Dr. Ebrahimi said in an interview. “This intrigued me and started my journey into trying to understand how psychiatric disorders in general, and PTSD, may impact/interact with cardiovascular disorders,” he added.
The number of female veterans in the military has been increasing, and they now make up about 10% of the 20 million American veterans; that number is projected to exceed 2.2 million in the next 20 years, the authors wrote. Female veterans are also the fastest growing group of users of the VHA, they added.
IHD is the leading cause of death in women in the United States, despite the advancements in prevention and treatment. Although women are twice as likely to develop PTSD as are men, and it is even more likely in female veterans, much of the research has predominately been on male veterans, the authors wrote.
For this retrospective study, which used data from the VHA Corporate Data Warehouse, the authors examined a cohort of female veterans who were 18 years or older who had used the VHA health care system between Jan. 1, 2000, and Dec. 31, 2017.
Of the 828,997 female veterans, 151,030 had PTSD. Women excluded from the study were those who did not have any clinical encounters after their index visit, participants who had a diagnosis of IHD at or before the index visit, and those with incident IHD within 90 days of the index visit, allowing time between a PTSD diagnosis and IHD.
Propensity score matching on age at index visit, the number of previous visits, and the presence of traditional and female-specific cardiovascular risk factors, as well as mental and physical health conditions, was conducted to identify female veterans ever diagnosed with PTSD, who were matched in a 1:2 ratio to those never diagnosed with PTSD. In all, 132,923 women with PTSD and 265,846 women without PTSD were included, and data were analyzed for the period of Oct. 1, 2018, to Oct. 30, 2020.
IHD was defined as new-onset coronary artery disease, angina, or myocardial infarction–based ICD-9 and ICD-10 diagnostic codes. Age, race, and ethnicity were self-reported.
The analytic sample consisted of relatively young female veterans (mean [SD] age at baseline, 40.1 [12.2] years) of various races (White, 57.6%; Black, 29.8%) and ethnicities, the authors reported.
Of the 9,940 women who experienced incident IHD during follow-up, 5,559 did not have PTSD (2.1% of the overall population examined) and 4,381 had PTSD (3.3%). PTSD was significantly associated with an increased risk for IHD. Over the median follow-up of 4.9 years, female veterans with PTSD had a 44% higher rate of developing incident IHD compared with the female veterans without PTSD (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.38-1.50).
In addition, those with PTSD who developed IHD were younger at diagnosis (mean [SD] age, 55.5 [9.7]) than were patients without PTSD (mean [SD] age, 57.8 [10.7]). Effect sizes were largest in the group younger than 40 years (HR, 1.72; 95% CI, 1.55-1.90) and decreased for older participants (HR for those ≥60 years, 1.24; 95% CI, 1.12-1.38)
The authors found a 49% to 66% increase in risk for IHD associated with PTSD in Black women (HR, 1.49; 95% CI, 1.38-1.62) and those identified as non-White and non-Black (HR, 1.66; 95%, 1.33-2.08).
Women of all ethnic groups with PTSD were at higher risk of developing IHD, but this was especially true for Hispanic/Latina women (HR, 1.50; 95% CI 1.22-1.84), they noted.
The authors reported some limitations to their findings. The analytic sample could result in a lower ascertainment of certain conditions, such as psychiatric disorders, they wrote. Substance disorders were low in this study, possibly because of the younger age of female veterans in the sample. Because this study used VHA electronic medical records data, medical care outside of the VHA that was not paid for by the VHA could not be considered.
In addition, although this study used a large sample of female veterans, the findings cannot be generalized to female veterans outside of the VHA system, nonveteran women, or men, the researchers wrote.
A call to action
In an accompanying comment, Beth E. Cohen, MD, of the University of California, San Francisco, and the San Francisco Veterans Affairs Health Care System, points out that the physical implications for psychosocial conditions, including depression and PTSD, have been recognized for quite some time. For example, results of the INTERHEART case-control study of 30,000 people showed stress, depression, and stressful life events accounted for one-third the population-attributable risk for myocardial infarction.
As was also noted by Dr. Ebrahimi and colleagues, much of the current research has been on male veterans, yet types of trauma differ among genders; women experience higher rates of military sexual trauma but lower rates of combat trauma, Dr. Cohen wrote. The PTSD symptoms, trajectory, and biological effects can differ for women and men, as can the pathogenesis, presentation, and outcomes of cardiovascular disease (CVD).
These findings, she said, “are an important extension of the prior literature and represent the largest study in female veterans to date. Although methods differ across studies, the magnitude of risk associated with PTSD was consistent with that found in prior studies of male veterans and nonveteran samples.”
The assessment of age-specific risk is also a strength of the study, “and has implications for clinical practice, because PTSD-associated risk was greatest in a younger group in whom CVD may be overlooked.”
Dr. Cohen addressed the limitations outlined by the authors, including ascertainment bias, severity of PTSD symptoms, and their chronicity, but added that “even in the context of these limitations, this study illustrates the importance of PTSD to the health of women veterans and the additional work needed to reduce their CVD risk.”
Clinical questions remain, she added. Screens for PTSD are widely used in the VHA, yet no studies have examined whether screening or early detection decrease CVD risk. In addition, no evidence suggests that screening for or treatment of PTSD improves cardiovascular outcomes.
“Given the challenges of answering these questions in observational studies, it will be important to incorporate measures of CVD risk and outcomes in trials of behavioral and medical therapies for patients with PTSD,” she wrote.
She added that collaborations among multidisciplinary patient care teams will be important. “The findings of this study represent a call to action for this important work to understand the cardiovascular effects of PTSD and improve the health and well-being of women veterans,” Dr. Cohen concluded.
This research was supported by Investigator-Initiated Research Award from the Department of Defense U.S. Army Medical Research and Material Command Congressionally Directed Medical Research Programs (Dr. Ebrahimi) and in part by grants from the VA Informatics and Computing Infrastructure and the Offices of Research and Development at the Northport, Durham, and Greater Los Angeles Veterans Affairs medical centers. Dr. Ebrahimi reported receiving grants from the Department of Defense during the conduct of the study. Disclosures for other authors are available in the paper. Dr. Cohen reports no disclosures.
A version of this article first appeared on Medscape.com.
Transgender hormone therapy linked to blood pressure changes
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Cell-free DNA improves response prediction in breast cancer
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
FROM AACR 2021
Considerations for the surgical management of diaphragmatic endometriosis
Severe obesity persists, takes high cardiovascular toll
In a U.K. cohort of more than 260,000 mostly middle-aged adults in primary care with overweight or obesity, body mass index remained relatively stable over a decade.
However, compared to overweight individuals, those with severe (class 3) obesity were more socioeconomically disadvantaged and had triple the risk for incident heart failure or all-cause or cardiovascular disease (CVD)–related mortality in a study published online April 15 in BMC Public Health.
“This is the first study to evaluate the long-term impact of overweight and obese individuals’ BMI trajectory on cardiovascular endpoints, heart failure, and mortality outcomes,” wrote Barbara Iyen, PhD, University of Nottingham, England, and colleagues.
The findings emphasize “the high cardiovascular toll exacted by continuing failure to tackle obesity, particularly among more socioeconomically deprived populations,” they warned.
“We have found that despite widespread efforts to prevent and manage obesity, the majority of adults who are overweight or obese in the general population continue to remain so in the long term,” Dr. Iyen said in a statement from her university.
“More effective policies and weight-management interventions are needed urgently to address this increasing burden and associated adverse health outcomes,” she stressed.
Invited to comment, Sadiya S. Khan, MD, Northwestern University, Chicago, said in an interview: “This research adds to the growing body of evidence [that] earlier and more intensive interventions for weight loss are necessary to promote cardiovascular health and reduce morbidity and mortality.
“Adjunctive pharmacotherapy and bariatric surgery are both options that should be considered in addition to intensive lifestyle interventions in overweight and obesity groups,” she added.
“I would always advocate for earlier prevention efforts focused on weight loss, because years lived with obesity are associated with future CVD, so every year counts,” Dr. Khan said.
Does BMI remain elevated, predict worse heart health?
Although obesity is a well-recognized risk factor for CVD, long-term changes in BMI and the impact of BMI on the risk for heart failure, CVD, and mortality have not been quantified among adults with overweight and obesity, Dr. Iyen and colleagues explained.
The researchers examined data from the UK Clinical Practice Research Datalink and secondary care and mortality records to determine BMI trajectories among adults with overweight or obesity and to quantify the risk for heart failure, CVD (defined as coronary heart disease, stroke, transient ischemic attack, or peripheral vascular disease, CVD-related mortality, and all-cause mortality.
They identified 264,230 adults with overweight or obesity who were seen in 790 primary care practices in the United Kingdom from 1999 to 2018 and who did not initially have heart failure or CVD and for whom baseline BMI measurements and at least one other BMI measurement 2, 5, 8, and 10 years later was available.
The researchers divided the cohort into four groups on the basis of initial BMI: overweight (36% of patients; mean BMI, 28.7 kg/m2); class 1 obesity (40%; mean BMI, 33.7 kg/m2); class 2 obesity (19%; mean BMI, 39.9 kg/m2), and class 3 obesity (5%; mean BMI, 49.1 kg/m2).
The mean age of the individuals was 50 years, and 64% were White. Race/ethnicity data were unavailable for 31%. Asian Indian, Asian, and Black patients comprised 5% of the cohort.
“Strong significant gradient in heart failure risk”
Compared to the overweight (reference) group, the severe-obesity group comprised a higher percentage of women (74% vs. 70%), and the prevalence of comorbidities and socioeconomic deprivation was higher.
BMI remained relatively stable in each BMI group. The mean BMI increase was 1.06 kg/m2 during a median follow-up of 10.9 years.
There were 30,400 incident cases of CVD, 7,662 incident cases of heart failure, and 24,022 deaths, of which 2,827 (11.8%) were from CVD.
The risk for heart failure and CVD-related or all-cause mortality increased with increasing obesity severity.
Compared with overweight individuals, those with class 3 obesity were at significantly increased risk for heart failure (hazard ratio [HR], 3.26), all-cause mortality (HR, 2.72), and CVD-related mortality (HR, 3.31) after adjustment for age, sex, and comorbidities (hypertension, type 2 diabetes, atrial fibrillation, and chronic kidney disease).
The risk for stroke/TIA or coronary heart disease was similar among those with severe obesity and the other individuals. The risk for PVD was significantly lower (HR, 0.73).
The reduced risk for PVD in the most severely obese group is similar to findings in the Framingham heart study, the authors noted, and may be due to underdiagnosis or differences in the underlying mechanism.
Compelling evidence of poor health outcomes associated with obesity
Study limitations include the fact that the findings may not be generalizable to other race/ethnicity groups, the lack of information on diet and exercise, and the fact that BMI was used as a surrogate of adiposity. As such, it does not account for an age-related decrease in heavier-than-fat muscle mass and differences between sexes and ethnic groups.
The finding of stable obesity over time accords with two smaller studies that included Canadian and American adults.
The current study did not uncover an obesity paradox, unlike some studies that included patients with preexisting CVD or a history of acute coronary events. Those studies reported better clinical outcomes among patients with overweight or obesity.
The current study included individuals who did not initially have CVD. Those with more severe obesity were younger than individuals with overweight at the time of the occurrence of incident CVD (age 64 vs. 66) and at the age of death (age 67 vs. age 75), which “provides compelling evidence of poor health outcomes associated with obesity,” the authors emphasized.
“Further research is ... needed to explore whether interventions to change BMI trajectories would have an impact on future CVD outcomes,” they concluded.
Dr. Iyen’s clinical academic lectureship is fully funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and are not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Dr. Khan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a U.K. cohort of more than 260,000 mostly middle-aged adults in primary care with overweight or obesity, body mass index remained relatively stable over a decade.
However, compared to overweight individuals, those with severe (class 3) obesity were more socioeconomically disadvantaged and had triple the risk for incident heart failure or all-cause or cardiovascular disease (CVD)–related mortality in a study published online April 15 in BMC Public Health.
“This is the first study to evaluate the long-term impact of overweight and obese individuals’ BMI trajectory on cardiovascular endpoints, heart failure, and mortality outcomes,” wrote Barbara Iyen, PhD, University of Nottingham, England, and colleagues.
The findings emphasize “the high cardiovascular toll exacted by continuing failure to tackle obesity, particularly among more socioeconomically deprived populations,” they warned.
“We have found that despite widespread efforts to prevent and manage obesity, the majority of adults who are overweight or obese in the general population continue to remain so in the long term,” Dr. Iyen said in a statement from her university.
“More effective policies and weight-management interventions are needed urgently to address this increasing burden and associated adverse health outcomes,” she stressed.
Invited to comment, Sadiya S. Khan, MD, Northwestern University, Chicago, said in an interview: “This research adds to the growing body of evidence [that] earlier and more intensive interventions for weight loss are necessary to promote cardiovascular health and reduce morbidity and mortality.
“Adjunctive pharmacotherapy and bariatric surgery are both options that should be considered in addition to intensive lifestyle interventions in overweight and obesity groups,” she added.
“I would always advocate for earlier prevention efforts focused on weight loss, because years lived with obesity are associated with future CVD, so every year counts,” Dr. Khan said.
Does BMI remain elevated, predict worse heart health?
Although obesity is a well-recognized risk factor for CVD, long-term changes in BMI and the impact of BMI on the risk for heart failure, CVD, and mortality have not been quantified among adults with overweight and obesity, Dr. Iyen and colleagues explained.
The researchers examined data from the UK Clinical Practice Research Datalink and secondary care and mortality records to determine BMI trajectories among adults with overweight or obesity and to quantify the risk for heart failure, CVD (defined as coronary heart disease, stroke, transient ischemic attack, or peripheral vascular disease, CVD-related mortality, and all-cause mortality.
They identified 264,230 adults with overweight or obesity who were seen in 790 primary care practices in the United Kingdom from 1999 to 2018 and who did not initially have heart failure or CVD and for whom baseline BMI measurements and at least one other BMI measurement 2, 5, 8, and 10 years later was available.
The researchers divided the cohort into four groups on the basis of initial BMI: overweight (36% of patients; mean BMI, 28.7 kg/m2); class 1 obesity (40%; mean BMI, 33.7 kg/m2); class 2 obesity (19%; mean BMI, 39.9 kg/m2), and class 3 obesity (5%; mean BMI, 49.1 kg/m2).
The mean age of the individuals was 50 years, and 64% were White. Race/ethnicity data were unavailable for 31%. Asian Indian, Asian, and Black patients comprised 5% of the cohort.
“Strong significant gradient in heart failure risk”
Compared to the overweight (reference) group, the severe-obesity group comprised a higher percentage of women (74% vs. 70%), and the prevalence of comorbidities and socioeconomic deprivation was higher.
BMI remained relatively stable in each BMI group. The mean BMI increase was 1.06 kg/m2 during a median follow-up of 10.9 years.
There were 30,400 incident cases of CVD, 7,662 incident cases of heart failure, and 24,022 deaths, of which 2,827 (11.8%) were from CVD.
The risk for heart failure and CVD-related or all-cause mortality increased with increasing obesity severity.
Compared with overweight individuals, those with class 3 obesity were at significantly increased risk for heart failure (hazard ratio [HR], 3.26), all-cause mortality (HR, 2.72), and CVD-related mortality (HR, 3.31) after adjustment for age, sex, and comorbidities (hypertension, type 2 diabetes, atrial fibrillation, and chronic kidney disease).
The risk for stroke/TIA or coronary heart disease was similar among those with severe obesity and the other individuals. The risk for PVD was significantly lower (HR, 0.73).
The reduced risk for PVD in the most severely obese group is similar to findings in the Framingham heart study, the authors noted, and may be due to underdiagnosis or differences in the underlying mechanism.
Compelling evidence of poor health outcomes associated with obesity
Study limitations include the fact that the findings may not be generalizable to other race/ethnicity groups, the lack of information on diet and exercise, and the fact that BMI was used as a surrogate of adiposity. As such, it does not account for an age-related decrease in heavier-than-fat muscle mass and differences between sexes and ethnic groups.
The finding of stable obesity over time accords with two smaller studies that included Canadian and American adults.
The current study did not uncover an obesity paradox, unlike some studies that included patients with preexisting CVD or a history of acute coronary events. Those studies reported better clinical outcomes among patients with overweight or obesity.
The current study included individuals who did not initially have CVD. Those with more severe obesity were younger than individuals with overweight at the time of the occurrence of incident CVD (age 64 vs. 66) and at the age of death (age 67 vs. age 75), which “provides compelling evidence of poor health outcomes associated with obesity,” the authors emphasized.
“Further research is ... needed to explore whether interventions to change BMI trajectories would have an impact on future CVD outcomes,” they concluded.
Dr. Iyen’s clinical academic lectureship is fully funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and are not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Dr. Khan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a U.K. cohort of more than 260,000 mostly middle-aged adults in primary care with overweight or obesity, body mass index remained relatively stable over a decade.
However, compared to overweight individuals, those with severe (class 3) obesity were more socioeconomically disadvantaged and had triple the risk for incident heart failure or all-cause or cardiovascular disease (CVD)–related mortality in a study published online April 15 in BMC Public Health.
“This is the first study to evaluate the long-term impact of overweight and obese individuals’ BMI trajectory on cardiovascular endpoints, heart failure, and mortality outcomes,” wrote Barbara Iyen, PhD, University of Nottingham, England, and colleagues.
The findings emphasize “the high cardiovascular toll exacted by continuing failure to tackle obesity, particularly among more socioeconomically deprived populations,” they warned.
“We have found that despite widespread efforts to prevent and manage obesity, the majority of adults who are overweight or obese in the general population continue to remain so in the long term,” Dr. Iyen said in a statement from her university.
“More effective policies and weight-management interventions are needed urgently to address this increasing burden and associated adverse health outcomes,” she stressed.
Invited to comment, Sadiya S. Khan, MD, Northwestern University, Chicago, said in an interview: “This research adds to the growing body of evidence [that] earlier and more intensive interventions for weight loss are necessary to promote cardiovascular health and reduce morbidity and mortality.
“Adjunctive pharmacotherapy and bariatric surgery are both options that should be considered in addition to intensive lifestyle interventions in overweight and obesity groups,” she added.
“I would always advocate for earlier prevention efforts focused on weight loss, because years lived with obesity are associated with future CVD, so every year counts,” Dr. Khan said.
Does BMI remain elevated, predict worse heart health?
Although obesity is a well-recognized risk factor for CVD, long-term changes in BMI and the impact of BMI on the risk for heart failure, CVD, and mortality have not been quantified among adults with overweight and obesity, Dr. Iyen and colleagues explained.
The researchers examined data from the UK Clinical Practice Research Datalink and secondary care and mortality records to determine BMI trajectories among adults with overweight or obesity and to quantify the risk for heart failure, CVD (defined as coronary heart disease, stroke, transient ischemic attack, or peripheral vascular disease, CVD-related mortality, and all-cause mortality.
They identified 264,230 adults with overweight or obesity who were seen in 790 primary care practices in the United Kingdom from 1999 to 2018 and who did not initially have heart failure or CVD and for whom baseline BMI measurements and at least one other BMI measurement 2, 5, 8, and 10 years later was available.
The researchers divided the cohort into four groups on the basis of initial BMI: overweight (36% of patients; mean BMI, 28.7 kg/m2); class 1 obesity (40%; mean BMI, 33.7 kg/m2); class 2 obesity (19%; mean BMI, 39.9 kg/m2), and class 3 obesity (5%; mean BMI, 49.1 kg/m2).
The mean age of the individuals was 50 years, and 64% were White. Race/ethnicity data were unavailable for 31%. Asian Indian, Asian, and Black patients comprised 5% of the cohort.
“Strong significant gradient in heart failure risk”
Compared to the overweight (reference) group, the severe-obesity group comprised a higher percentage of women (74% vs. 70%), and the prevalence of comorbidities and socioeconomic deprivation was higher.
BMI remained relatively stable in each BMI group. The mean BMI increase was 1.06 kg/m2 during a median follow-up of 10.9 years.
There were 30,400 incident cases of CVD, 7,662 incident cases of heart failure, and 24,022 deaths, of which 2,827 (11.8%) were from CVD.
The risk for heart failure and CVD-related or all-cause mortality increased with increasing obesity severity.
Compared with overweight individuals, those with class 3 obesity were at significantly increased risk for heart failure (hazard ratio [HR], 3.26), all-cause mortality (HR, 2.72), and CVD-related mortality (HR, 3.31) after adjustment for age, sex, and comorbidities (hypertension, type 2 diabetes, atrial fibrillation, and chronic kidney disease).
The risk for stroke/TIA or coronary heart disease was similar among those with severe obesity and the other individuals. The risk for PVD was significantly lower (HR, 0.73).
The reduced risk for PVD in the most severely obese group is similar to findings in the Framingham heart study, the authors noted, and may be due to underdiagnosis or differences in the underlying mechanism.
Compelling evidence of poor health outcomes associated with obesity
Study limitations include the fact that the findings may not be generalizable to other race/ethnicity groups, the lack of information on diet and exercise, and the fact that BMI was used as a surrogate of adiposity. As such, it does not account for an age-related decrease in heavier-than-fat muscle mass and differences between sexes and ethnic groups.
The finding of stable obesity over time accords with two smaller studies that included Canadian and American adults.
The current study did not uncover an obesity paradox, unlike some studies that included patients with preexisting CVD or a history of acute coronary events. Those studies reported better clinical outcomes among patients with overweight or obesity.
The current study included individuals who did not initially have CVD. Those with more severe obesity were younger than individuals with overweight at the time of the occurrence of incident CVD (age 64 vs. 66) and at the age of death (age 67 vs. age 75), which “provides compelling evidence of poor health outcomes associated with obesity,” the authors emphasized.
“Further research is ... needed to explore whether interventions to change BMI trajectories would have an impact on future CVD outcomes,” they concluded.
Dr. Iyen’s clinical academic lectureship is fully funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and are not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. Dr. Khan has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Early palliative care consultation in the medical ICU
Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.
Study design: Single-center cluster randomized crossover trial.
Setting: Two medical ICUs at Barnes Jewish Hospital, St. Louis.
Synopsis: 199 patients were enrolled using palliative care criteria to identify patients at high risk for morbidity and mortality. In the intervention arm patients received a palliative care consultation from an inter-professional team led by board-certified palliative care providers within 48 hours of ICU admission.
The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.
Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.
Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.
Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.
Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.
Study design: Single-center cluster randomized crossover trial.
Setting: Two medical ICUs at Barnes Jewish Hospital, St. Louis.
Synopsis: 199 patients were enrolled using palliative care criteria to identify patients at high risk for morbidity and mortality. In the intervention arm patients received a palliative care consultation from an inter-professional team led by board-certified palliative care providers within 48 hours of ICU admission.
The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.
Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.
Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.
Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.
Background: Mortality rates in critically ill patients remain in excess of 20% in many institutions. In the last 2 decades, palliative care has become a core component of ICU care. Current literature recommends a palliative care consult in the ICU setting; however, implementing this recommendation in a meaningful way has been challenging. The purpose of this study is to evaluate whether consulting palliative care in ICU earlier improves patient outcomes.
Study design: Single-center cluster randomized crossover trial.
Setting: Two medical ICUs at Barnes Jewish Hospital, St. Louis.
Synopsis: 199 patients were enrolled using palliative care criteria to identify patients at high risk for morbidity and mortality. In the intervention arm patients received a palliative care consultation from an inter-professional team led by board-certified palliative care providers within 48 hours of ICU admission.
The primary outcome of this study was a change in code status to Do Not Resuscitate/Do Not Intubate (DNR/DNI), which was significantly higher in the intervention group (50.5% vs. 23.4%; P less than .0001). The intervention group also had more hospice discharges, fewer ventilated days, a lower rate of tracheostomy, and fewer hospital readmissions. However, mortality and ICU/hospital length of stay were not significantly different between the two arms. Limitations of this study include using a single academic center and the fact that establishing a DNR/DNI may not measure quality of life or patient/family satisfaction. Further studies are needed to focus on clinical outcomes as well as patient and family satisfaction.
Bottom line: Early goal-directed palliative care consults with experienced clinicians board certified in palliative care influences goals of care, code status, and discharge plans for the critically ill and can improve medical resource utilization.
Citation: Ma J et al. Early palliative care consultation in the medical ICU: A cluster randomized crossover trial. Crit Care Med. 2019 Dec;47: 1707-15.
Dr. Ahmed is assistant professor in the division of hospital medicine, Loyola University Medical Center, Maywood, Ill.
Tislelizumab bests docetaxel in NSCLC
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
‘Very important trial’
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
FROM AACR 2021
Frontline brentuximab vedotin shows promise in high-risk pediatric Hodgkin lymphoma
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
GENUINE improvements: Ublituximab plus ibrutinib for CLL
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.