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Hydroxyurea underused in youth with sickle cell anemia
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.
SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.
In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
Low uptake even after guideline revision
Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.
After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.
Findings were published online in JAMA Network Open.
‘A national issue’
Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”
Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.
“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.
He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”
He said often providers aren’t giving a clear and consistent message to families.
“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
Bad rap from past indications
Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.
Now it’s used in a completely different way with SCA, but the fear of the association lingers.
“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”
The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”
The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
Medicaid support critical
Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.
“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.
The authors point to interventions in clinical trials that have had some success in hydroxyurea use.
Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.
The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.
Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.
“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.
He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.
“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.
Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.
The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
FROM JAMA NETWORK OPEN
Dapagliflozin’s HFpEF benefit tied to lower filling pressure
NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.
The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.
Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.
The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
Improving a ‘specific and fundamental’ feature of HFpEF
“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.
However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.
“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.
He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.
“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
An ‘obese, cardiometabolic’ HFpEF phenotype
The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.
Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.
An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.
The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.
The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.
NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.
The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.
Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.
The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
Improving a ‘specific and fundamental’ feature of HFpEF
“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.
However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.
“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.
He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.
“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
An ‘obese, cardiometabolic’ HFpEF phenotype
The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.
Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.
An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.
The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.
The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.
NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.
The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.
Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.
The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
Improving a ‘specific and fundamental’ feature of HFpEF
“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.
However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.
“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.
He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.
“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
An ‘obese, cardiometabolic’ HFpEF phenotype
The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.
Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.
An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.
The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.
The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.
AT ACC 2023
FDA approves new Merkel cell carcinoma treatment
the agency announced.
This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.
“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”
POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.
Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).
Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.
Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.
Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.
A version of this article first appeared on Medscape.com.
the agency announced.
This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.
“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”
POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.
Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).
Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.
Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.
Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.
A version of this article first appeared on Medscape.com.
the agency announced.
This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.
“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”
POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.
Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).
Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.
Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.
Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.
A version of this article first appeared on Medscape.com.
Tyrosine kinase inhibitors – a new weapon against respiratory viruses?
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM ISCIENCE
FDA expands evinacumab approval to younger kids with HoFH
The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.
The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.
The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.
Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.
The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.
“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.
The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.
The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.
Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.
The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.
“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.
The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.
The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.
Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.
The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.
“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.
A version of this article first appeared on Medscape.com.
LAA closure device shown safe in groups omitted in trials
WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.
In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.
In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.
Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
No surprises found in real-world outcome
At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.
By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.
At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.
Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.
When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.
In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.
Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.
The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.
“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
Elderly patients benefit equally from Watchman
Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.
To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.
In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.
“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.
In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.
Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
ESRD is not Watchman contraindication
A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.
Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.
After a median follow-up of 480 days, stroke or transient ischemic attacks were observed in 3.1%, leaks > 5 mm were observed in 1.4%, and systemic emboli were observed in 0.9%. Major bleeding (BARC > 2) occurred in 13.3%.
Although the all-cause mortality over the period of follow-up was high (37.4%), most of the deaths (61.2%) were of noncardiovascular origin, according to Dr. Sulaiman. He said mortality and adverse events linked to the Watchman appeared to be roughly comparable to those seen in patients with ESRD.
“The Watchman device for patients on hemodialysis with nonvalvular atrial fibrillation is an effective and safe intervention to prevent embolic events,” he said. However, he also cautioned these the ESRD and the accompanying comorbidities place these patients at high risk of a limited life expectancy.
“Given the high mortality rate of this population, proper selection of candidates is paramount to ensure the optimal clinical benefit,” he cautioned.
Dr. Samir reported no potential conflicts of interest but stated that this study was funded by Boston Scientific. Dr. Cohen reported financial ties with Abbott Vascular, Boston Scientific, Corvia Medical, Edwards Lifesciences, Impulse Dynamics, MyoKardia, Phillips, Svelte, V-Wave, and Zoll. Dr. Sulaiman reported no potential conflicts of interest. Dr. Perez de Prado reported no potential conflicts of interest but stated that this study was funded by Boston Scientific.
WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.
In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.
In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.
Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
No surprises found in real-world outcome
At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.
By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.
At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.
Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.
When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.
In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.
Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.
The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.
“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
Elderly patients benefit equally from Watchman
Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.
To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.
In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.
“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.
In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.
Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
ESRD is not Watchman contraindication
A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.
Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.
After a median follow-up of 480 days, stroke or transient ischemic attacks were observed in 3.1%, leaks > 5 mm were observed in 1.4%, and systemic emboli were observed in 0.9%. Major bleeding (BARC > 2) occurred in 13.3%.
Although the all-cause mortality over the period of follow-up was high (37.4%), most of the deaths (61.2%) were of noncardiovascular origin, according to Dr. Sulaiman. He said mortality and adverse events linked to the Watchman appeared to be roughly comparable to those seen in patients with ESRD.
“The Watchman device for patients on hemodialysis with nonvalvular atrial fibrillation is an effective and safe intervention to prevent embolic events,” he said. However, he also cautioned these the ESRD and the accompanying comorbidities place these patients at high risk of a limited life expectancy.
“Given the high mortality rate of this population, proper selection of candidates is paramount to ensure the optimal clinical benefit,” he cautioned.
Dr. Samir reported no potential conflicts of interest but stated that this study was funded by Boston Scientific. Dr. Cohen reported financial ties with Abbott Vascular, Boston Scientific, Corvia Medical, Edwards Lifesciences, Impulse Dynamics, MyoKardia, Phillips, Svelte, V-Wave, and Zoll. Dr. Sulaiman reported no potential conflicts of interest. Dr. Perez de Prado reported no potential conflicts of interest but stated that this study was funded by Boston Scientific.
WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.
In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.
In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.
Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
No surprises found in real-world outcome
At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.
By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.
At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.
Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.
When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.
In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.
Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.
The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.
“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
Elderly patients benefit equally from Watchman
Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.
To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.
In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.
“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.
In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.
Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
ESRD is not Watchman contraindication
A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.
Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.
After a median follow-up of 480 days, stroke or transient ischemic attacks were observed in 3.1%, leaks > 5 mm were observed in 1.4%, and systemic emboli were observed in 0.9%. Major bleeding (BARC > 2) occurred in 13.3%.
Although the all-cause mortality over the period of follow-up was high (37.4%), most of the deaths (61.2%) were of noncardiovascular origin, according to Dr. Sulaiman. He said mortality and adverse events linked to the Watchman appeared to be roughly comparable to those seen in patients with ESRD.
“The Watchman device for patients on hemodialysis with nonvalvular atrial fibrillation is an effective and safe intervention to prevent embolic events,” he said. However, he also cautioned these the ESRD and the accompanying comorbidities place these patients at high risk of a limited life expectancy.
“Given the high mortality rate of this population, proper selection of candidates is paramount to ensure the optimal clinical benefit,” he cautioned.
Dr. Samir reported no potential conflicts of interest but stated that this study was funded by Boston Scientific. Dr. Cohen reported financial ties with Abbott Vascular, Boston Scientific, Corvia Medical, Edwards Lifesciences, Impulse Dynamics, MyoKardia, Phillips, Svelte, V-Wave, and Zoll. Dr. Sulaiman reported no potential conflicts of interest. Dr. Perez de Prado reported no potential conflicts of interest but stated that this study was funded by Boston Scientific.
AT CRT 2023
Liquid albuterol shortage effects reduced by alternative drugs, similar shortages may be increasingly common
The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.
The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.
Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.
Still, headlines concerning the shortage have caused “a bit of a panic” for patients with asthma and parents with asthmatic children, according to David R. Stukus, MD, professor of clinical pediatrics in the division of allergy and immunology at Nationwide Children’s, Columbus, Ohio.
Much of the media coverage has lacked context, causing unnecessary worry, he said, as the shortage only affects one type of albuterol generally reserved for inpatient and emergency use.
“The shortage has not impacted our albuterol inhalers thus far,” Dr. Stukus said in an interview. “So I certainly don’t want people with asthma to panic that they’re going to run out of their inhaler anytime soon.”
Even infants and toddlers can use inhalers
Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.
“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”
The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.
“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”
Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.
While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.
Personal preferences may also considered, he added.
“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”
One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.
“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”
She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.
“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
Generic drug shortages becoming more common
While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.
“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.
The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.
The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.
A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.
“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”
The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.
Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.
When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.
Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.
Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.
“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.
Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.
The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.
The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.
Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.
Still, headlines concerning the shortage have caused “a bit of a panic” for patients with asthma and parents with asthmatic children, according to David R. Stukus, MD, professor of clinical pediatrics in the division of allergy and immunology at Nationwide Children’s, Columbus, Ohio.
Much of the media coverage has lacked context, causing unnecessary worry, he said, as the shortage only affects one type of albuterol generally reserved for inpatient and emergency use.
“The shortage has not impacted our albuterol inhalers thus far,” Dr. Stukus said in an interview. “So I certainly don’t want people with asthma to panic that they’re going to run out of their inhaler anytime soon.”
Even infants and toddlers can use inhalers
Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.
“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”
The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.
“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”
Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.
While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.
Personal preferences may also considered, he added.
“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”
One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.
“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”
She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.
“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
Generic drug shortages becoming more common
While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.
“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.
The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.
The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.
A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.
“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”
The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.
Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.
When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.
Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.
Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.
“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.
Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.
The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.
The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.
Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.
Still, headlines concerning the shortage have caused “a bit of a panic” for patients with asthma and parents with asthmatic children, according to David R. Stukus, MD, professor of clinical pediatrics in the division of allergy and immunology at Nationwide Children’s, Columbus, Ohio.
Much of the media coverage has lacked context, causing unnecessary worry, he said, as the shortage only affects one type of albuterol generally reserved for inpatient and emergency use.
“The shortage has not impacted our albuterol inhalers thus far,” Dr. Stukus said in an interview. “So I certainly don’t want people with asthma to panic that they’re going to run out of their inhaler anytime soon.”
Even infants and toddlers can use inhalers
Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.
“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”
The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.
“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”
Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.
While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.
Personal preferences may also considered, he added.
“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”
One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.
“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”
She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.
“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
Generic drug shortages becoming more common
While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.
“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.
The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.
The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.
A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.
“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”
The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.
Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.
When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.
Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.
Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.
“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.
Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.
New hope for MDS, with AML treatments
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
Novel therapy shows promise for treating skin-predominant dermatomyositis
NEW ORLEANS – in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.
Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.
Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
Targeting an elevated cytokine
Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.
“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.
The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.
In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.
After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.
Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
Both doses better than placebo
In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.
For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.
The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.
“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.
A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.
It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.
Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.
“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.
Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.
“This is something that is definitely newsworthy,” Dr. Tsao said.
Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.
Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.
Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
Targeting an elevated cytokine
Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.
“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.
The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.
In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.
After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.
Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
Both doses better than placebo
In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.
For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.
The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.
“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.
A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.
It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.
Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.
“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.
Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.
“This is something that is definitely newsworthy,” Dr. Tsao said.
Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – in a double-blind, placebo-controlled phase 2 trial, according to results presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
“These findings support the inhibition of IFN-beta as a promising therapeutic strategy in skin-predominant disease,” said principal investigator Aaron Mangold, MD, associate professor of dermatology, Mayo Clinic, Scottsdale, Ariz.
Dermatomyositis, a rare autoimmune inflammatory condition that typically involves both skeletal muscles and skin, is a challenging disease with a diverse set of potential complications.
Immunosuppressive and immunomodulatory agents are used with mixed success for myositis, but skin manifestations, which include papular eruptions, heliotrope rash, photoerythema, burning, and pruritus, are often the most troublesome and the most difficult to control. Treatment options other than immunomodulators that target cutaneous involvement – which include steroids, emollients, and photoprotection – are generally modestly effective, according to Dr. Mangold.
Targeting an elevated cytokine
Interest in IFN-beta, which is elevated in the blood of individuals with dermatomyositis, was triggered by evidence that this cytokine plays an important role in driving the skin inflammation, Dr. Mangold explained.
“The blood concentrations of IFN-beta are positively correlated with cutaneous disease activity and severity,” he said.
The study drug, currently known as PF-06823859 (Dazukibart), “is a potent, selective humanized IgG1-neutralizing antibody directed at IFN-beta,” Dr. Mangold said. A dose-ranging phase 1 study published 2 years ago provided evidence of acceptable pharmacokinetics and safety in healthy individuals to support treatment studies for disorders associated with elevated IFN-beta levels. In addition to dermatomyositis, this includes systemic lupus erythematosus.
In this phase 2 trial, patients whose condition was not improved by at least one standard-care therapy for skin manifestations of dermatomyositis were eligible if they had moderate to severe disease as measured with the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), according to Dr. Mangold. During the study, patients were allowed to remain on a disease modifying antirheumatic drug and/or prednisone if they had been on stable doses and did not change the dose.
After a screening run-in, the trial had two blinded stages. In stage 1, 30 patients were randomly assigned either to 600 mg of PF-06823859 or to placebo, both administered intravenously every 4 weeks. A second cohort of 25 patients was randomly assigned in stage 2 to placebo, 150 mg of PF-06823859, or 600 mg of PF-06823859. The primary endpoint assessed at 12 weeks was a greater than 5-point reduction in CDASI score or greater than 40% CDASI improvement from baseline.
Both endpoints are associated with a clinically meaningful response in regard to an improved quality of life, Dr. Mangold noted.
Both doses better than placebo
In results from the stage 1 portion, the mean reduction in CDASI at 12 weeks after three doses of the assigned therapy was 18.8 points in the active-treatment group versus 3.9 points in the placebo group. In pooled data from stage 1 and 2, the reductions were 16.6 points, 19.2 points, and 2.9 points for the 150-mg, 600-mg, and placebo arms, respectively. Both doses achieved a highly significant advantage over placebo.
For both stages and doses, the response curves of the active-treatment groups and the placebo group diverged almost immediately. By 4 weeks, both measures of CDASI reductions on active therapy were significantly improved relative to placebo, and the response curves had a consistent downward slope through the end of the 12-week study, Dr. Mangold reported.
The majority of patients responded by either of the primary endpoint criteria. For a CDASI reduction of greater than 5 points, the response rates were 100% and 96% for the 150-mg and 600-mg doses of PF-06823859, respectively. The placebo response was 35.7%. For the CDASI reduction of greater than 40%, the rates were 80%, 82.1%, and 7.1% for the 150-mg, 600-mg, and placebo arms, respectively.
“There were no major safety concerns. Most of the treatment-emergent adverse events were mild, and adverse events did not have a relationship to dose,” Dr. Mangold said. Notably, there were no cases of herpes zoster, and infections of any kind were low in all study groups.
A phase 3 study is being planned with the 600-mg dose, according to Dr. Mangold, but he acknowledged that regulatory authorities have generally required endpoints for both cutaneous and muscle manifestations in previous trials of therapies for dermatomyositis.
It is not yet certain that “there will be a carve-out for skin,” he said in answer to a question about investigations moving forward. So far, studies have been focused on skin response. However, a meaningful degree of benefit against muscle involvement, which has not yet been well studied, has not been ruled out.
Even though this is a phase 2 trial with small numbers, it was controlled and blinded, and the potential of an inhibitor of IFN-beta to control the skin manifestations of dermatomyositis “is kind of a big deal,” said Paul Nghiem, MD, PhD, professor of dermatology, University of Washington, Seattle.
“There is definitely an unmet need for better therapies to control the skin involvement,” Dr. Nghiem said.
Hensin Tsao, MD, PhD, clinical director of the Melanoma and Pigmented Lesion Center at Massachusetts General Hospital, Boston, agreed. Like Dr. Nghiem, Dr. Tsao was a panelist during the late-breaker session where the study was presented, and he was impressed by the data.
“This is something that is definitely newsworthy,” Dr. Tsao said.
Dr. Mangold reports financial relationships with Actelion, Amgen, Corbus, Eli Lilly, Incyte, miRagen, Novartis, Regeneron, Solagenix, Sun Pharmaceuticals, Teva, and Pfizer, which provided funding for this trial. Both Dr. Nghiem and Dr. Tsao reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AAD 2023
Another FDA class I recall of Cardiosave Hybrid/Rescue IABPs
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.
Datascope/Getinge is recalling certain Cardiosave Hybrid and Cardiosave Rescue Intra-Aortic Balloon Pumps (IABPs) because the coiled cable connecting the display and base on some units may fail, causing an unexpected shutdown without warnings or alarms to alert the user.
The U.S. Food and Drug Administration has identified this as a class I recall, the most serious type of recall, because of the risk for serious injury or death.
The FDA warns that an unexpected pump shutdown and any interruption to therapy that occurs can lead to hemodynamic instability, organ damage, and/or death, especially in patients who are critically ill and most likely to receive therapy using these devices.
The devices are indicated for acute coronary syndrome, cardiac and noncardiac surgery, and complications of heart failure in adults.
From June 2019 to August 2022, Datascope/Getinge reported 44 complaints about damaged coiled cords resulting in unexpected shutdowns. There have been no reports of injuries or deaths related to this issue, according to the recall notice posted on the FDA’s website.
The recall includes a total of 2,300 CardioSave Hybrid or Rescue IABP units distributed prior to July 24, 2017, and/or coiled cord part number 0012-00-1801. Product model numbers for the recalled Cardiosave Hybrid and Cardiosave Rescue are available online.
The Cardiosave IABPs have previously been flagged by the FDA for subpar battery performance and fluid leaks.
To address the cable issue, Datascope/Getinge sent an urgent medical device correction letter to customers recommending that the coiled cable cord of the Cardiosave IABP be inspected for visible damage prior to use.
If an unexpected shutdown occurs, an attempt should be made to restart the Cardiosave IABP until an alternative pump is available. If the restart attempt is unsuccessful, an alternative IABP should be used. Any device that remains inoperable after a shutdown should be removed from patient care.
Customers should inspect their inventory to identify any Cardiosave Hybrid and/or Rescue IABPs that have the recalled coiled cord.
The company also asks customers to complete and sign the Medical Device Correction-Response form included with the letter and return it to Datascope/Getinge by emailing a scanned copy to [email protected] or by faxing the form to 1-877-660-5841.
Customers with questions about this recall should contact their Datascope/Getinge representative or call Datascope/Getinge technical support at 1-888-943-8872, Monday through Friday, between 8:00 AM and 6:00 PM ET.
The company has developed a hardware correction to address this issue and says a service representative will contact customers to schedule installation of the correction when the correction kit is available.
Any adverse events or suspected adverse events related to the recalled CardioSave Hybrid/Rescue IABPs should be reported to the FDA through MedWatch, its adverse event reporting program.
A version of this article first appeared on Medscape.com.