Conference Coverage

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

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

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

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

Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.

A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.

Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.

“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.

Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
 

Larger benefit for EF > 40% to < 60%

PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.

The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.

The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).

Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).

A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.

The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).

As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).

“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.

The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.

“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”

He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46). 

“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.
 

Data ‘far from conclusive’

In a comment, Sean Pinney, MD, chief of cardiology at Mount Sinai Morningside, New York, said that the study results “help expand the current evidence base supporting the use of an ARNI in patients” with an EF greater than 40% up to 60%, and “provide confidence that ARNIs help to lower natriuretic peptides.

“It comes as little surprise that not everyone was able to tolerate these medications due to intolerable side effects like dizziness or hypotension,” he said.

Nevertheless, he added, “hopefully, these trial data help strengthen clinicians’ resolve to prescribe sacubitril/valsartan to a growing population of vulnerable patients.”

In a related editorial, Hector O. Ventura, MD, of the Ochsner Clinical School–University of Queensland, New Orleans, and colleagues express several concerns about the study.

Although the trial achieved significance for the primary endpoint, the margin of benefit was less than expected and the magnitude of the NT-proBNP reduction may not have been enough to reach the threshold for clinical benefit, they wrote.

Diuretic dosing in the two groups was not reported, and between-group differences may have contributed to both the differential NT-proBNP reduction and the rates of hypotension.

Furthermore, the sacubitril-valsartan group had a higher proportion of missing NT-proBNP data, which may have biased the results.

“In aggregate,” they wrote, “while the study suggests some evidence of a beneficial trend of sacubitril-valsartan in HFpEF and a recent episode of worsening HF, the data are far from conclusive.”

“Clinicians who elect to use sacubitril-valsartan in this population should be mindful of the risk for hypotension and select patients carefully, while providing close ambulatory follow up to ensure stability and adherence,” they noted.

“This important trial provides some wins that support selective use of sacubitril-valsartan in HFpEF [as well as] observed losses, which too may help to define better implementation strategies in appropriately selected patients,” the editorialists concluded.

The study was funded by Novartis. Dr. Mentz and other coauthors have received fees from Novartis. Dr. Pinney, Dr. Ventura, and the other editorialists disclosed no relevant financial relationships.

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

BALTIMORE – The off-label prescribing of compounded, bioidentical hormone therapy – in pills, creams, or pellets – for symptoms of perimenopause or menopause can put physicians at legal risk because the products lack scientific backing, according to an expert at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists (ACOG).

Clinicians write an estimated 26 to 33 million prescriptions for compounded bioidentical hormone therapy (cBHT) every year, and almost 41% of menopausal women who need treatment try cBHT during their lives. But these drugs lack the approval for this indication from the Food and Drug Administration.

“There is a public perception that this is natural, safer, and anti-aging,” said Robert Kauffman, MD, a professor of obstetrics and gynecology and assistant dean for research at Texas Tech University Health Sciences Center in Amarillo.

Following the 2002 Women’s Health Initiative report showing a link between hormone therapy (HT) and an increase in the incidence of breast cancer, medical schools have slowed or paused instructing trainees on the traditional treatment, Dr. Kauffman said. The association was later determined to be spurious: HT is not associated with a risk for all-cause mortality or deaths from cardiovascular disease or cancer. However, HT still is largely ignored by younger physicians, Dr. Kauffman said, because of unsubstantiated “dangers” such as heart attack, stroke, and deep vein thrombosis.

The lack of education on HT for medical school students and residents has “opened the door to unsubstantiated marketing claims and practices” for cBHT, Dr. Kauffman said. “Hence, the use of compounded bioidentical hormone therapy has increased” as clinicians look for alternatives.

Groups including ACOG, the North American Menopause Society (NAMS), and the U.S. Preventive Services Task Force recommend against the use of Non–FDA-approved therapies such as cBHT, except for narrow indications. Dr. Kauffman said that drug manufacturers have not conducted randomized controlled trials or observational studies on cBHT in treating menopause.

He cited studies showing quality problems with the compounding process of these drugs, and wide variations in the amount of actual ingredients from product labels. One 2021 study published in Menopause comparing patients taking cBHT or FDA-approved HT found that side effects were significantly higher in the cBHT group (57.6% vs. 14.8%; P < .0001).

But manufacturers of cBHT claim that their products prevent cardiovascular disease and Alzheimer’s disease and decrease the risk for breast cancer and stroke – assertions that are at best unproven, according to Dr. Kauffman.

The National Academies of Sciences, Engineering, and Medicine in 2020 said that clinicians have a duty to inform patients of the insufficient evidence to support clinical use of cBHT and should prescribe the products only to patients with documented allergies to an active ingredient in an FDA-approved agent or who require an alternative dosage.

Patients may also have to pay much more out of pocket for cBHT products because they often are not covered by insurance. Generic HT products, meanwhile, are relatively inexpensive and typically are covered, he noted.

“We have to be careful to avoid financial harm to patients by prescribing things, which are much more expensive than those which are usually available,” Dr. Kauffman said.

Prescribing any non–FDA-approved product, especially when biosimilars are available, places physicians at legal risk, Dr. Kauffman said. Physicians who recommend cBHT should inform patients that the products are not FDA approved and carefully document this discussion in the patient’s electronic health record. State boards of medicine can sanction physicians for “coercion” for prescribing cBHT products without mentioning alternatives, he added.

JoAnn Pinkerton, MD, professor of obstetrics and gynecology at the University of Virginia, Charlottesville, and executive director emeritus of NAMS, who attended the session, praised Dr. Kauffman for providing a balanced and evidence-based overview of the subject.

University of Virginia Health System

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

BALTIMORE – The off-label prescribing of compounded, bioidentical hormone therapy – in pills, creams, or pellets – for symptoms of perimenopause or menopause can put physicians at legal risk because the products lack scientific backing, according to an expert at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists (ACOG).

Clinicians write an estimated 26 to 33 million prescriptions for compounded bioidentical hormone therapy (cBHT) every year, and almost 41% of menopausal women who need treatment try cBHT during their lives. But these drugs lack the approval for this indication from the Food and Drug Administration.

“There is a public perception that this is natural, safer, and anti-aging,” said Robert Kauffman, MD, a professor of obstetrics and gynecology and assistant dean for research at Texas Tech University Health Sciences Center in Amarillo.

Following the 2002 Women’s Health Initiative report showing a link between hormone therapy (HT) and an increase in the incidence of breast cancer, medical schools have slowed or paused instructing trainees on the traditional treatment, Dr. Kauffman said. The association was later determined to be spurious: HT is not associated with a risk for all-cause mortality or deaths from cardiovascular disease or cancer. However, HT still is largely ignored by younger physicians, Dr. Kauffman said, because of unsubstantiated “dangers” such as heart attack, stroke, and deep vein thrombosis.

The lack of education on HT for medical school students and residents has “opened the door to unsubstantiated marketing claims and practices” for cBHT, Dr. Kauffman said. “Hence, the use of compounded bioidentical hormone therapy has increased” as clinicians look for alternatives.

Groups including ACOG, the North American Menopause Society (NAMS), and the U.S. Preventive Services Task Force recommend against the use of Non–FDA-approved therapies such as cBHT, except for narrow indications. Dr. Kauffman said that drug manufacturers have not conducted randomized controlled trials or observational studies on cBHT in treating menopause.

He cited studies showing quality problems with the compounding process of these drugs, and wide variations in the amount of actual ingredients from product labels. One 2021 study published in Menopause comparing patients taking cBHT or FDA-approved HT found that side effects were significantly higher in the cBHT group (57.6% vs. 14.8%; P < .0001).

But manufacturers of cBHT claim that their products prevent cardiovascular disease and Alzheimer’s disease and decrease the risk for breast cancer and stroke – assertions that are at best unproven, according to Dr. Kauffman.

The National Academies of Sciences, Engineering, and Medicine in 2020 said that clinicians have a duty to inform patients of the insufficient evidence to support clinical use of cBHT and should prescribe the products only to patients with documented allergies to an active ingredient in an FDA-approved agent or who require an alternative dosage.

Patients may also have to pay much more out of pocket for cBHT products because they often are not covered by insurance. Generic HT products, meanwhile, are relatively inexpensive and typically are covered, he noted.

“We have to be careful to avoid financial harm to patients by prescribing things, which are much more expensive than those which are usually available,” Dr. Kauffman said.

Prescribing any non–FDA-approved product, especially when biosimilars are available, places physicians at legal risk, Dr. Kauffman said. Physicians who recommend cBHT should inform patients that the products are not FDA approved and carefully document this discussion in the patient’s electronic health record. State boards of medicine can sanction physicians for “coercion” for prescribing cBHT products without mentioning alternatives, he added.

JoAnn Pinkerton, MD, professor of obstetrics and gynecology at the University of Virginia, Charlottesville, and executive director emeritus of NAMS, who attended the session, praised Dr. Kauffman for providing a balanced and evidence-based overview of the subject.

University of Virginia Health System

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

BALTIMORE – The off-label prescribing of compounded, bioidentical hormone therapy – in pills, creams, or pellets – for symptoms of perimenopause or menopause can put physicians at legal risk because the products lack scientific backing, according to an expert at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists (ACOG).

Clinicians write an estimated 26 to 33 million prescriptions for compounded bioidentical hormone therapy (cBHT) every year, and almost 41% of menopausal women who need treatment try cBHT during their lives. But these drugs lack the approval for this indication from the Food and Drug Administration.

“There is a public perception that this is natural, safer, and anti-aging,” said Robert Kauffman, MD, a professor of obstetrics and gynecology and assistant dean for research at Texas Tech University Health Sciences Center in Amarillo.

Following the 2002 Women’s Health Initiative report showing a link between hormone therapy (HT) and an increase in the incidence of breast cancer, medical schools have slowed or paused instructing trainees on the traditional treatment, Dr. Kauffman said. The association was later determined to be spurious: HT is not associated with a risk for all-cause mortality or deaths from cardiovascular disease or cancer. However, HT still is largely ignored by younger physicians, Dr. Kauffman said, because of unsubstantiated “dangers” such as heart attack, stroke, and deep vein thrombosis.

The lack of education on HT for medical school students and residents has “opened the door to unsubstantiated marketing claims and practices” for cBHT, Dr. Kauffman said. “Hence, the use of compounded bioidentical hormone therapy has increased” as clinicians look for alternatives.

Groups including ACOG, the North American Menopause Society (NAMS), and the U.S. Preventive Services Task Force recommend against the use of Non–FDA-approved therapies such as cBHT, except for narrow indications. Dr. Kauffman said that drug manufacturers have not conducted randomized controlled trials or observational studies on cBHT in treating menopause.

He cited studies showing quality problems with the compounding process of these drugs, and wide variations in the amount of actual ingredients from product labels. One 2021 study published in Menopause comparing patients taking cBHT or FDA-approved HT found that side effects were significantly higher in the cBHT group (57.6% vs. 14.8%; P < .0001).

But manufacturers of cBHT claim that their products prevent cardiovascular disease and Alzheimer’s disease and decrease the risk for breast cancer and stroke – assertions that are at best unproven, according to Dr. Kauffman.

The National Academies of Sciences, Engineering, and Medicine in 2020 said that clinicians have a duty to inform patients of the insufficient evidence to support clinical use of cBHT and should prescribe the products only to patients with documented allergies to an active ingredient in an FDA-approved agent or who require an alternative dosage.

Patients may also have to pay much more out of pocket for cBHT products because they often are not covered by insurance. Generic HT products, meanwhile, are relatively inexpensive and typically are covered, he noted.

“We have to be careful to avoid financial harm to patients by prescribing things, which are much more expensive than those which are usually available,” Dr. Kauffman said.

Prescribing any non–FDA-approved product, especially when biosimilars are available, places physicians at legal risk, Dr. Kauffman said. Physicians who recommend cBHT should inform patients that the products are not FDA approved and carefully document this discussion in the patient’s electronic health record. State boards of medicine can sanction physicians for “coercion” for prescribing cBHT products without mentioning alternatives, he added.

JoAnn Pinkerton, MD, professor of obstetrics and gynecology at the University of Virginia, Charlottesville, and executive director emeritus of NAMS, who attended the session, praised Dr. Kauffman for providing a balanced and evidence-based overview of the subject.

University of Virginia Health System

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

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

A combination of simple interventions for acute patients with stroke attributable to intracerebral hemorrhage (ICH) has been shown to significantly improve the chances of survival without major disability.
 

The INTERACT3 study showed that timely administration of a care bundle that included early intensive lowering of systolic blood pressure, strict glucose control, treatment of fever, and rapid reversal of abnormal anticoagulation led to less disability, lower rates of death, and better overall quality of life.

“This is a groundbreaking result. It is the first-ever published trial in ICH patients to show a clear benefit on functional outcomes and on mortality,” lead investigator Craig Anderson, MD, director of global brain health at the George Institute for Global Health, Sydney, said in an interview.

“These results show that, if we can organize care and focus on optimal management of these four aspects of the health of the patient, they do better,” Dr. Anderson said.

‘Game changer’

“This is a game changer because now we have level A evidence showing something is definitely beneficial for these patients,” Dr. Anderson added. “That means hospitals have the imperative to organize their systems to do these things and maximize care. We have never had that before.”

Dr. Anderson noted that, while some previous studies have suggested benefit from various interventions, such as early lowering of blood pressure, the results have not been conclusive.

“This means the intervention has not always been implemented, leading to large variations in clinical practice. But now we have a package that is proven to work; this should become a guideline-recommended practice,” he commented.

The INTERACT-3 results were presented at the European Stroke Organisation conference in Munich. They were also simultaneously published online in The Lancet.

Dr. Anderson explained that, until now, there haven’t been any proven treatments for ICH. “There has been a lot of energy and research put into the field, but this has resulted in several interventions that are ‘probably useful’ or which have a level B recommendation,” he said. “No therapy has been shown to be beneficial in a totally conclusive way, so we are still not entirely sure exactly whether the treatments we use actually make a difference.”

The INTERACT3 researchers therefore decided to evaluate a care package consisting of a bundle of several treatments in the hope that they may have additive or synergistic effects.

The study involved 7,036 patients with imaging-confirmed spontaneous ICH who presented within 6 hours of symptom onset to one of 121 hospitals in 10 mainly low- and middle-income countries: Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, Vietnam, and Chile.

Using a cluster design, all hospitals started with usual care as a control and then at some point during the study started using the care bundle intervention.

The care-bundle protocol included the early intensive lowering of systolic blood pressure (target, < 140 mm Hg), strict glucose control (target, 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature, ≤ 37.5° C), and rapid reversal of warfarin-related anticoagulation (target international normalized ratio, 1.5) in patients for whom these variables were abnormal.

Overall, the modified intention-to-treat population included 3,221 patients who were assigned to the care-bundle group and 3,815 who were assigned to the usual-care group. Primary outcome data were available for 2,892 patients in the care-bundle group and 3,363 patients in the usual-care group.

The primary outcome was functional recovery, measured with the Modified Rankin Scale at 6 months. Results show that the likelihood of a poor functional outcome was lower in the care-bundle group (common odds ratio, 0.86; P = .015).

Patients who received the interventional care bundle also had a significantly lower rate of serious adverse events (16.0% vs. 20.1%) and mortality (14.1% vs. 17.0%).

NNT of 35 to save one life free of disability

“The number needed to treat (NNT) is just 35 to save a life free of disability,” Dr. Anderson commented. “That’s pretty good. We estimate that this care bundle would save tens of thousands of lives a year if universally adopted.”

The intervention group also spent less time in hospital and had improved health-related quality of life.

Dr. Anderson pointed out that the interventions included in the care bundle were all relatively easy to perform.

“They just require a bit more nursing time and the use of a few inexpensive medicines and maybe infusion pumps, but we’re not talking about the need for skilled surgery or a new therapy costing hundreds of thousands of dollars, so this care bundle should be very straightforward to implement. While we haven’t done a formal cost-effectiveness analysis, I would say it will definitely be good value for money.”

Dr. Anderson believes the rapid lowering of blood pressure is a very important part of the care bundle. He noted that target levels were achieved, on average, in 2.3 hours, compared with 4.0 hours in the control group. But he stressed that this was not just a trial of blood pressure reduction and that the whole package is important.

He gave a couple of possible reasons why this trial was successful whereas previous trials did not show a clear benefit of blood pressure lowering in ICH.

“Firstly, it was a very large trial with more than 7,000 patients – that is more than three times larger than any other trial in ICH. And secondly, the package of care means there are several different interventions that together show a real benefit,” he said. “It’s like the polypill, or a rehabilitation program – if you put several different things together, the whole package can show really positive results.”

Dr. Anderson also pointed out that the study included a wide spectrum of ICH patients, and the benefit of the care bundle was seen across all groups and all stroke severities.

“There were a lot of patients with a large ICH, and if anything, they showed an even larger benefit with the bundle of care,” he said.

The researchers note that the burden of ICH is greatest in low- and middle-income countries. In 2019, 30% of all stroke cases in these countries were ICH, almost double the proportion seen in high-income countries (16%). This is in part attributable to high rates of hypertension and limited resources for primary prevention, including identification and management of stroke risk factors by health care services.

‘Outstanding example’ of less therapeutic negativity

Lili Song, MD, PhD, joint lead author and head of the Stroke Program at the George Institute China, Beijing, said, “A lack of proven treatments for ICH has led to a pessimistic view that not much can be done for these patients.

“However, with INTERACT3, we demonstrate on a large scale how readily available treatments can be used to improve outcomes in resource-limited settings,” she said. “We hope this evidence will inform clinical practice guidelines across the globe and help save many lives.”

In a comment that accompanied the article, Wendy Ziai, MD, Matthew Bower, MD, and Daniel Hanley, MD, Johns Hopkins University, Baltimore, say the INTERACT3 study shows that “an intracerebral hemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimized sustained interventions.”

Pointing out that the care bundle has minimal risks of cost and coordination and a high public health effect, they conclude: “This effort is an outstanding example of why less therapeutic negativity, and more intervention might benefit survivors of intracerebral hemorrhage.”

The INTERACT3 study was funded by the Department of Health and Social Care, the Foreign, Commonwealth and Development Office, the Medical Research Council, and the Wellcome Trust (all in the United Kingdom), the West China Hospital Outstanding Discipline Development 1–3-5 Programme, the National Health and Medical Research Council of Australia, Sichuan Credit Pharmaceutical, and Takeda (China).

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

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

The first-in-class erythroid maturation agent luspatercept showed significant improvement over the erythropoiesis-stimulating agent epoetin alfa in reducing dependency on red blood cell transfusions among patients with lower-risk myelodysplastic syndromes (LR-MDS) who are ESA naive.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs in [transfusion-dependent] LR-MDS,” first author Guillermo Garcia-Manero, MD, chief of the MDS section, department of leukemia, at the University of Texas MD Anderson Cancer Center, Houston, said in a premeeting press briefing in advance of the annual meeting of the American Society of Clinical Oncology.

“It should be considered a paradigm shift in the treatment of LR-MDS–associated anemia,” Dr. Garcia-Manero said.

Commenting on the study, Andrew Artz, MD, a professor at the Hematologic Malignancies Research Institute, City of Hope National Medical Center, Duarte, Calif., agreed that the results could be practice changing.

“We biologically expected luspatercept to best ESA [in ring sideroblast transfusion–dependent MDS], based on luspatercept often rescuing ESA failures in this setting,” Dr. Artz said in an interview.

“The results have the potential to change initial therapy for patients with low-risk red blood cell transfusion-dependent MDS,” he said.

In LR-MDS, which encompasses a variety of bone marrow disorders, chronic anemia is very common, and patients, who are typically elderly, can become burdened by developing dependencies on RBC transfusions.

Transfusion dependency, in addition to creating a host of challenges, can increase the risk of death by as much as 50%, compared with patients who are not transfusion dependent, Dr. Garcia-Manero noted.

While ESAs such as epoetin alfa are the first-line treatment for LR-MDS, patients who are dependent on transfusions are less likely to respond to the agents, hence “there is an unmet need for effective and durable options other than ESAs for treating anemia in patients with LR-MDS,” Dr. Garcia-Manero said.

Luspatercept, a first-in-class monoclonal antibody, has a mechanism of action that is distinct from ESAs, modulating the transforming growth factor–beta pathway and increasing erythrocytosis.

In the previous phase 3 MEDALIST trial, the drug was shown to have efficacy over placebo in reducing the severity of anemia in LR-MDS. In 2020, in what was deemed the first advance in MDS treatment in more than a decade, those results led to approval by the Food and Drug Administration for patients with LR-MDS with ring sideroblasts who are transfusion dependent and are refractory, intolerant, or ineligible to receive ESAs.

To further investigate luspatercept’s efficacy in a head-to-head comparison with an ESA in LR-MDS patients who are ESA naive, Dr. Garcia-Manero and colleagues conducted the phase 3 COMMANDS trial.

For the global, open-label study, patients with LR-MDS who were dependent on RBC transfusions and had no prior use of ESAs were randomized 1:1 to treatment either with subcutaneous luspatercept (starting dose, 1.0 mg/kg with titration up to 1.75 mg/kg; n = 178) once every 3 weeks or subcutaneous epoetin alfa (starting dose, 450 IU/kg with titration up to 1,050 IU/kg; n = 176) once every week, for a minimum of 24 weeks.

Patients in each arm were also able to receive best supportive care, including blood transfusions. Their baseline characteristics were similar in each arm.

For the primary endpoint, patients receiving luspatercept in the intent-to-treat population were nearly twice as likely as those treated with epoetin alfa to become independent of RBC transfusions, with a concurrent mean hemoglobin increase of 1.5 g/dL or more, for at least 12 weeks in the first 24 weeks on study, at a rate of 58.5% with luspatercept versus 31.2% with epoetin alfa (P < .0001).

In addition, patients treated with luspatercept had a longer median duration of transfusion independence, at 126.6 weeks versus 77 weeks in the epoetin alfa group (hazard ratio, 0.456).

Importantly, the statistically significant improvement with luspatercept was consistent among patients with ring sideroblasts (HR, 0.626) as well as without them (HR, 0.492). Dr. Garcia-Manero noted that about 70% of patients in the study had ring sideroblasts, consistent with their common occurrence in LR-MDS.

Luspatercept was also superior in secondary endpoints, including in achieving hematologic improvement, with an erythroid response of at least 8 weeks, per International Working Group 2006 criteria, which was achieved by 74.1% with luspatercept versus 51.3% with epoetin alfa (P < .0001).

The greater improvement with luspatercept was also observed in other subgroups, including based on baseline serum erythropoietin or levels of transfusion dependence, as well as SF381 mutation status.

In terms of safety, treatment emergent adverse events (TEAEs) of any grade were reported among 92.1% of luspatercept and 85.2% of epoetin alfa patients. Longer-term posttreatment safety analyses showed no significant differences between the groups in terms of progression to high-risk MDS, in five (2.8%) with luspatercept and seven(4.0%) epoetin alfa, and progression to acute myeloid leukemia, occurring in four (2.2%) luspatercept and five (2.8%) epoetin alfa patients.

Overall rates of death between the groups were also similar during the treatment and posttreatment periods (32 [18.0%] luspatercept; 32 [18.2%] epoetin alfa patients).

“The toxicity profile was consistent with previous clinical experience,” Dr. Garcia-Manero said.

Dr. Garcia-Manero underscored that “the results of the COMMANDS trial are very important.”

“ESAs are really not optimal agents [for LR-MDS], and these results indicate that luspatercept almost doubles response rates in this patient population, therefore becoming potentially the standard of care for patients with transfusion-dependent LR-MDS who have not received prior ESA treatment,” he said.

Further commenting, Dr. Artz added that the effects in patient subgroups will be of great interest as further data on luspatercept emerges.

“Of highest interest will be the differential responses among patients with and without ring sideroblasts, as well as by SF3B1 mutational status,” he said. Furthermore, “patient-centric data emerge as even more relevant when considering the quantitatively higher rates of treatment-emergent adverse effects in the luspatercept arm.”

“We need to understand how to best sequence anemia therapies in low-risk MDS when we have two active agents, or even if [there is] a role for combined ESA/luspatercept therapy,” he noted.

“The results are exciting, but we need the final data including relevant subsets before declaring luspatercept the winner,” Dr. Artz concluded.

The study was sponsored by Celgene/Bristol-Myers Squibb. Dr. Garcia-Manero reported relationships with Abbvie, Acceleron Pharma, Aprea Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Genentech, Gilead Sciences, and Novartis. Dr. Artz disclosed previous consulting relationships with Abbvie and Magenta Therapeutics.

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

In patients with heart failure (HF) and reduced ejection fraction (HFrEF), the copper chelator trientine reduced NT-proBNP levels up to 8 weeks by restoring normal intracellular copper.

In models of HF, intracellular copper depletion is associated with myocardial hypertrophy and fibrosis, and thus an increased risk for cardiac remodeling, James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, told attendees at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions.

Although trientine has been used for over 40 years to treat Wilson disease – a rare inherited disease characterized by copper overload – “paradoxically, it acts as a copper chaperone and can restore intracellular copper concentrations at low doses,” Dr. Januzzi explained during his presentation of the TRACER-HF results.

Although the dose-ranging study found that at 300 mg twice daily trientine effectively reduced NT-proBNP levels at 4 and 8 weeks, by 12 weeks, the effect had disappeared.

Nevertheless, Dr. Januzzi told the meeting attendees that the same dose was “most consistently” associated with most favorable Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) changes, as well as improvements in left ventricular (LV) function and 6-minute walk distance.
 

‘Challenging is an understatement’

Asked why the improvement in NT-proBNP levels was no longer evident at week 12, Dr. Januzzi acknowledged, “We just don’t know.” However, the team speculates that the disrupted nature of the study might play a role.

The phase 2, placebo-controlled trial started recruiting at 27 sites in North America in 2019. When the pandemic hit in 2020, enrollment was suspended, then pivoted to China in 2021. A total of 190 participants were ultimately enrolled.

However, 91% of participants in China were finishing their follow-up in late 2022, when the country was hit by a COVID-19 surge, which might have affected the 12-week outcomes – though this is speculation for now.

Overall, participants had a mean age of 57 years; about 80% were men; 91% were Asian; the mean left ventricular ejection fraction (LVEF) was 30%; and most (77%) were New York Heart Association class II. All were stable on optimal drug therapy, including chronic loop diuretics.

All had elevated NT-proBNP: ≥ 400 pg/mL without atrial fibrillation or flutter, or ≥ 1200 pg/mL with atrial fibrillation or flutter.

Participants were randomized to placebo or twice-daily trientine doses of 50 mg, 150 mg, or 300 mg.

The primary endpoint was the proportional change in NT-proBNP from baseline to 12 weeks. Key secondary endpoints included the effect of trientine compared with placebo on mechanistic outcomes such as change in cardiac remodeling indices, 6-minute walk distance, and the KCCQ-OSS.

As noted, the greatest reduction in NT-proBNP at 4 and 8 weeks was in the 300-mg group, with a geometric mean ratio of 0.82 at week 4 vs. 1.03 for placebo; 0.92 for 50 mg; and 0.83 for 150 mg; and 0.79 at week 8 vs 1.02 for placebo; 0.85 for 50 mg; and 0.91 for 150 mg.

LV volumes improved at all doses, though by the most at 50 mg (–11.7 mL).

The change in 6-minute walk distance was greatest at the 300-mg dose at 42 meters.

The responder analysis showed that 300 mg was most consistently associated with most of the favorable KCCQ changes.

From a safety standpoint, trientine was well tolerated without any adverse outcomes. Notably, Dr. Januzzi told meeting attendees, blood pressure and heart rate were not affected by the addition of trientine to background medical care.

In addition, a post hoc interaction was identified between treatment response and a baseline LVEF ≤ 30%, data that, for now, are “compelling but hypothesis-generating,” he said. Data on secondary endpoints specifically for that group “are forthcoming.”
 

Looking ahead

Dr. Januzzi said in an interview that the team is now finalizing the main report “and will turn our attention to the interaction analyses suggesting exaggerated benefit in those with lower LVEF.

“We are examining all possible options for this novel therapy, which may include progressing to phase 3,” he said.

Challenges going forward include the need to understand which patients are most appropriate for the drug. “Given that it does not affect blood pressure or heart rate, it is an attractive consideration for any patient on guideline-directed medical therapy, but we need to have more clarity about the mechanism of benefit and understanding about the subgroup interactions that we have detected.

“Even in a well-managed population of patients with heart failure, there may still be room for therapies with benefit,” he concluded.

Danyaal Moin, MD, assistant professor of medicine at NYU Langone Health in New York and a specialist in advanced heart failure and transplantation, commented on these findings for this article.

“It is always exciting to consider new pathways to treat patients with systolic dysfunction, given the residual risk even for patients on contemporary quadruple therapy for HFrEF,” he said. “However, certain challenges with this phase 2 study will need to be addressed in an eventual phase 3 clinical trial.

“The study sample was predominately recruited in China and is not necessarily representative of a heart failure population in many clinical practices,” he said.

“It would be important that future studies with trientine-HCL assess endpoints such as heart failure hospitalizations and mortality that would help elucidate where this therapy would stand relative to current established heart failure therapies.”

Longer follow-up is needed and, he noted, “while it appears the investigators will ultimately favor the 300-mg dosage, it is interesting that left ventricular volume indices changed most favorably with the 50-mg dose of the therapy.” 

The study was sponsored by Innolife Pharmaceuticals and coordinated by the Baim Institute for Clinical Research in Boston. Dr. Januzzi has received grant support from Innolife. Dr. Moin declared no relevant financial relationships.

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

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

SEOUL, SOUTH KOREA – Regular testing of hydroxychloroquine levels in patients with systemic lupus erythematosus – especially those who are experiencing a disease flare – could help to identify patients who are not taking their treatment and are at risk of worse outcomes.

Data presented at an international congress on systemic lupus erythematosus showed that 7.3% of patients with SLE are severely nonadherent to their medication and have a higher risk of flare, early damage, and mortality.

Rheumatologist Nathalie Costedoat-Chalumeau, MD, PhD, professor of internal medicine at Cochin Hospital, Paris, presented data from 660 patients enrolled in the international longitudinal SLICC Inception Cohort, who had all been on hydroxychloroquine therapy for at least 3 months at baseline.

Bianca Nogrady/MDedge News

Patients’ serum hydroxychloroquine levels were measured at baseline and follow-up, and severe nonadherence was defined as below 106 ng/mL for those on 400 mg/day or 53 ng/mL for those on 200 mg/day.

Dr. Costedoat-Chalumeau said that those thresholds were chosen based on earlier work that analyzed the blood concentration of hydroxychloroquine in a group of patients and identified a group with very low concentrations corresponding to severe nonadherence.

“Since then, it has been reproduced by others with the same threshold,” she said. “When you have very low levels of hydroxychloroquine in their blood, you know that your patients don’t take their treatment.”

In the present study, the 7.3% of patients who met the criteria for severe nonadherence had a significant 3.3-fold higher risk of disease flare within a year of enrollment than did those who were adherent. They also had significantly higher mortality at 5 years after enrollment.

While the study didn’t show a significant difference in the level of damage at 5 years – defined as a worsening of their SLICC damage index – Dr. Costedoat-Chalumeau said they saw significantly greater damage occurring at 1, 2, and 3 years after enrollment among those who were severely nonadherent.

The challenge with recognizing these nonadherent patients is that they have no obvious differences at baseline from those who are adherent, Dr. Costedoat-Chalumeau said. The rates of nonadherence were similar regardless of what dose the patient was on, their ethnicity, gender, education level, or other demographic variables.

“I believe strongly that there is a benefit of testing hydroxychloroquine levels in the blood or serum to detect severe nonadherence,” she said.

At Dr. Costedoat-Chalumeau’s clinic, patients’ hydroxychloroquine levels are tested at every clinic visit, she said in an interview, and especially if they are experiencing a disease flare. “We want to know if the flare is because the patient is not taking the treatment or if it’s because the treatment is not effective, which is very different in terms of management,” she said. She recommended waiting at least 1 month after patients start treatment before measuring their hydroxychloroquine levels.

As to why some patients choose to stop taking their medication, Dr. Costedoat-Chalumeau said sometimes it was because patients were worried about side effects, but others were also unclear about why they needed to keep taking hydroxychloroquine.

“They think steroids are effective because when they take it they are better, but they don’t see the effect of hydroxychloroquine,” she said. “You have to explain that it doesn’t work the same.”

Commenting on the findings, session chair Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data show that severe nonadherence does have prognostic significance. “Many patients with SLE have low-grade disease or inflammation in the blood vessels that may not be clinically apparent and which hydroxychloroquine can help, so it might be wise to routinely get blood levels,” she said.

Dr. Costedoat-Chalumeau reported no relevant financial relationships apart from unrestricted institutional research grants from UCB and Roche.

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

A real-world study of more than 12,000 cases over 7 years has validated the predictive ability of the proposed guidelines for stratifying thrombotic risks at 1 year for patients with non–ST-elevated acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI).

In research presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions, George Dangas, MD, PhD, current SCAI president and professor of cardiology and vascular surgery at the Icahn School of Medicine at Mount Sinai, New York, reported that the European Society of Cardiology risk stratification criteria appropriately predicted risk in 12,538 patients treated from 2012 to 2019.

Icahn School of Medicine

Despite these proposed guidelines put forward by the ESC in 2020, no consensus exists on criteria for ischemic or thrombotic risk in NSTE-ACS patients, Dr. Dangas noted.

The new study shows that the 1-year major adverse cardiovascular events (MACE) risk was four times greater in patients classified as medium risk (hazard ratio, 4.31; 95% confidence interval, 2.47-7.52) and six times greater in high-risk patients (HR, 6.16; 95% CI, 3.52-10.8), compared with the low-risk group, mostly because of higher rates of all-cause death and myocardial infarction, Dr. Dangas said in an interview.

“Indeed, we found some good correlation between the three risk categories and gradation of risk that validates essentially, but with the statistical testing that we need, that this classification is meaningful if not perfect,” Dr. Dangas said. “In the future we may perform calibrations to enhance its performance.”

The study used data on consecutive patients from the Angioplasty and Stent Procedures Database of Mount Sinai, grouping them into low, medium, and high thrombotic risk based on the proposed ESC guidelines for the management of NSTE-ACS.

The guidelines included a subset of criteria to identify patients with increased thrombotic risk who may benefit from extended treatment with a second antithrombotic agent.

This study aimed to evaluate the value of the criteria to identify patients at higher risk of ischemic events. “That’s why we went to our database to see how this might work,” Dr. Dangas said.

The researchers also found that high-risk patients had about a 40% greater risk of major bleeding (HR, 1.39; 95% CI, 1.06-1.84). Bleeding risks were similar between the low- and moderate-risk groups.

The risk categories reflected the rates of all-cause death, myocardial infarction, or stroke: 5.4%, 4.1%, and 1.6% in the high-, moderate-, and low-risks groups, respectively (P < .001).

“This identification of ischemic risks worked very well for all-cause mortality,” Dr. Dangas said. “I feel this is a strength because mortality is a leader of outcomes. And of course, we’ve had some associations with all events like mortality, myocardial infarction, repeat revascularization, which are interesting and valid, but I think a study result that indicates the mortality itself is known to be unidirectional and a very good correlation makes the result more robust.”
 

Critical role

Risk prediction models such as the proposed ESC guidelines will play a critical role as individualized medicine continues to evolve, Somjot Brar, MD, MPH, director of the regional department of cardiac catheterization at Kaiser Permanente, Los Angeles Medical Center, and associate clinical professor at the University of California, Los Angeles, said in an interview.

UCLA

“This study highlights again the importance of the value for predictive and precision medicine,” Dr. Brar said. “Everything is moving in this direction where we make decisions that are more appropriate for a given patient as opposed to a population of patients.”

Study strengths are the large sample size in a real-world setting and thorough 1-year follow-up, Dr. Brar said.

A limitation is the three risk categories the guidelines proposed. “These are still pretty big boxes,” he said. “The low-, moderate- and high-risk categorization is still very, very broad and can be very vague.”

The relatively low percentage of low-risk patients – 12% versus 56% and 32% for the moderate- and high-risk groups – in this data set may also skew results, Dr. Brar said.

“As we move toward predictive analytics and medicine, we want to make these boxes smaller and smaller and smaller to be able to better understand which treatments should be administered to which patients to maximize the benefit against the risk,” he said. That would be a focus for future analyses, Dr. Brar said.

Dr. Dangas and Dr. Brar have no relevant financial disclosures.


 

BALTIMORE – Water-based personal vaginal lubricants can not only relieve vaginal dryness but also can improve dyspareunia and increase other measures of sexual satisfaction for women, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.

Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.

Southern California Center for Sexual Health and Survivorship Medicine

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

BALTIMORE – Water-based personal vaginal lubricants can not only relieve vaginal dryness but also can improve dyspareunia and increase other measures of sexual satisfaction for women, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.

Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.

Southern California Center for Sexual Health and Survivorship Medicine

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

BALTIMORE – Water-based personal vaginal lubricants can not only relieve vaginal dryness but also can improve dyspareunia and increase other measures of sexual satisfaction for women, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. In a secondary analysis also presented at the meeting, the lubricants were found not to alter the vaginal microbiome.

Using these types of lubricants during vaginal intercourse at least once a week over a 4-week period resulted in a statistically significant increase of over four points in the 36-point Female Sexual Function Index (FSFI), a self-reported measure of sexual functioning, for participants, said Michael Krychman, MD, executive director of the Southern California Center for Sexual Health and Survivorship Medicine, Newport Beach, the senior author of the study. Statistically significant improvements also were observed in individual areas such as sexual desire and arousal, orgasm, and satisfaction. Results of the study have been published in the Journal of Sexual Medicine.

Southern California Center for Sexual Health and Survivorship Medicine

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

Adding online mindfulness and self-compassion training to usual care may improve quality of life (QOL) in adults with atopic dermatitis (AD), according to results of a small randomized controlled trial in Japan.

“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
 

A bothersome disease that worsens quality of life

AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state. 

d3sign/Getty Images

Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.

“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
 

A program focused on wise, kind self-care

In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.

Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.

The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.

The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.

At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).

Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.

They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.

One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
 

Online format may give more patients access to treatment

“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.

“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.

Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.

“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.

Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.

“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.

“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”

U.S. patients can benefit from these findings

“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”

Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”

The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.

Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.

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

Adding online mindfulness and self-compassion training to usual care may improve quality of life (QOL) in adults with atopic dermatitis (AD), according to results of a small randomized controlled trial in Japan.

“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
 

A bothersome disease that worsens quality of life

AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state. 

d3sign/Getty Images

Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.

“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
 

A program focused on wise, kind self-care

In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.

Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.

The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.

The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.

At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).

Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.

They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.

One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
 

Online format may give more patients access to treatment

“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.

“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.

Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.

“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.

Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.

“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.

“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”

U.S. patients can benefit from these findings

“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”

Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”

The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.

Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.

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

Adding online mindfulness and self-compassion training to usual care may improve quality of life (QOL) in adults with atopic dermatitis (AD), according to results of a small randomized controlled trial in Japan.

“We found that skin disease–specific QOL improved over time with a large effect size,” lead study author Sanae Kishimoto, MHS, MPH, of the School of Public Health, Graduate School of Medicine at Kyoto University and colleagues write in JAMA Dermatology. “These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD.”
 

A bothersome disease that worsens quality of life

AD, a chronic, relapsing, inflammatory, multifactorial skin disease involving intense itching, affects an estimated 15%-30% of children and 2%-10% of adults, with the incidence increasing in industrialized countries, the authors state. 

d3sign/Getty Images

Measured by disability-adjusted life years, AD has the highest disease burden among skin diseases, and people with AD commonly have anxiety, depression, and sleep problems. Treatments include medications, other skin care, and lifestyle changes. New biologics appear to be effective but are expensive and need to be studied for their long-term safety, the authors add.

“Stress can make the skin worse, but at the same time the skin disease and symptoms cause stress,” Peter A. Lio, MD, who was not involved in the study, told this news organization by email. “This vicious cycle contributes greatly to impairing quality of life.”
 

A program focused on wise, kind self-care

In the SMiLE study, the authors recruited adults with moderate to severe AD and Dermatology Life Quality Index (DLQI) score above 6 from dermatology clinics and through online announcements over 1 year beginning in July 2019.

Participants averaged 36.3 years of age, 80% were women, and their mean AD duration was 26.6 years. Everyone was allowed to receive usual care during the study, except for dupilumab (a newly marketed drug when the study started), psychotherapy, or other mindfulness training.

The researchers randomly assigned 56 adults to receive mindfulness training in addition to their usual care and 51 to the wait list plus usual care. Those in the training group received eight weekly 90-minute online mindfulness and self-compassion sessions. Each group-based session was conducted at the same time and day of the week and included meditation, informal psychoeducation, inquiry, and a short lecture, along with an optional 1-day silent meditation retreat at week 7 and an optional 2-hour videoconferencing booster session at week 13.

The intervention encouraged a nonjudgmental relationship with stress using mindfulness-based stress reduction (MBSR) and emphasized a compassionate relationship with oneself during suffering using mindful self-compassion (MSC). The program was developed and taught by lead author Dr. Kishimoto, a Japanese licensed clinical psychologist who has a history of AD, the paper notes.

At 13 weeks, after completing electronic assessments, patients in the training group showed greater improvement in the DLQI score than those on the wait list (between-group difference estimate, –6.34; 95% confidence interval, –8.27 to –4.41; P < .001). The standardized effect size (Cohen’s d) at 13 weeks was –1.06 (95% CI, –1.39 to –0.74).

Patients in the training group also improved more in all secondary outcomes: severity, itch- and scratch-related visual analog scales, self-compassion, mindfulness, psychological symptoms, and adherence to dermatologist-advised treatments.

They were also more likely to follow their dermatologist’s medical treatment plans, including moisturizer and topical steroid use.

One serious adverse event, endometrial cancer in one patient, was judged to be unrelated to the intervention.
 

Online format may give more patients access to treatment

“With relatively limited data in the literature, this particularly well-done, important study is likely to positively shape thinking around this topic,” said Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago. “This study nicely demonstrates that an online approach can be effective.

“In theory, these methods or techniques could democratize treatments like this, and open them up to many more patients,” he added. He would like to see partially or entirely automated apps (free of cost), similar to meditation “apps,” to treat patients more cost-effectively.

Dr. Lio explained that excluding participants on dupilumab (Dupixent) makes the results slightly less generalizable to patients with moderate to severe AD, who may have the most serious QOL challenges and who are often candidates for dupilumab.

“However, given that we almost never have all the known variables for a study, we are generally comfortable extrapolating that the intervention would likely be helpful for patients taking dupilumab as well, despite it not being specifically evaluated in that group,” he said.

Susan Massick, MD, of the department of dermatology at the Ohio State University Wexner Medical Center in Columbus, advises clinicians to take a multipronged approach to treating the physical and behavioral components of AD and to embrace therapies beyond prescription medications.

“Self-compassion training is another tool in our toolbox toward finding the right fix for our patients,” Dr. Massick said by email. She was not involved with this research.

“I applaud the focus of this study on behavioral health training as a means toward wellness and improved mindfulness,” she added. “I was impressed by the extent to which these simple measures helped improve the quality of life for patients who used the training.”

U.S. patients can benefit from these findings

“My sense is that AD patients the world over have many similar characteristics and concerns, so I would anticipate that the results would be comparable in a U.S. population,” Dr. Lio said. “Other studies performed in the U.S. also support this line of thinking.”

Although the study involved highly motivated patients in Japan, the suffering that patients with AD experience is universal regardless of race or ethnicity, Dr. Massick said. “Americans may be even more willing to embrace mindfulness and self-compassion training as a path toward better health and wellness.”

The study was funded by the Japan Agency for Medical Research and Development and the Mental Health Okamoto Memorial Foundation, the KDDI Foundation, the Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science.

Dr. Kishimoto and several coauthors report relevant financial relationships with pharmaceutical companies. Dr. Lio reports financial relationships with Sanofi and Regeneron, the joint developers of dupilumab. Dr. Massick reports no relevant financial relationships.

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