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FDA expands abemaciclib use in high-risk early breast cancer
Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.
The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.
At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.
“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.
A version of this article first appeared on Medscape.com.
Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.
The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.
At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.
“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.
A version of this article first appeared on Medscape.com.
Abemaciclib was previously approved for this group of high-risk patients with the requirement that they have a Ki-67 score of at least 20%. The new expansion removes the Ki-67 testing requirement, meaning more patients are now eligible to receive this drug. High-risk patients eligible for the CDK4/6 inhibitor can now be identified solely on the basis of nodal status, tumor size, and tumor grade.
The FDA’s decision to expand the approval was based on 4-year data from the phase 3 monarchE trial of adjuvant abemaciclib, which showed benefit in invasive disease-free survival beyond the 2-year treatment course.
At 4 years, 85.5% of patients remained recurrence free with abemaciclib plus endocrine therapy, compared with 78.6% who received endocrine therapy alone, an absolute difference in invasive disease-free survival of 6.9%.
“The initial Verzenio FDA approval in early breast cancer was practice changing and now, through this indication expansion, we have the potential to reduce the risk of breast cancer recurrence for many more patients, relying solely on commonly utilized clinicopathologic features to identify them,” Erika P. Hamilton, MD, an investigator on the monarchE clinical trial, said in a press release.
A version of this article first appeared on Medscape.com.
Celiac disease appears to double COVID-19 hospitalization risk
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
, a single-center U.S. study shows.
Vaccination against COVID-19 reduced the risk for hospitalization by almost half for both groups, however, the study finds.
“To our knowledge this is the first study that demonstrated a vaccination effect on mitigation of the risk of hospitalization in celiac disease patients with COVID-19 infection,” write Alberto Rubio-Tapia, MD, director, Celiac Disease Program, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, and colleagues.
Despite the increased risk for hospitalization among patients with celiac disease, there were no significant differences between those with and without the condition with respect to intensive care unit requirement, mortality, or thrombosis, the researchers found.
The findings suggest that celiac disease patients with COVID-19 are “not inherently at greater risk for more severe outcomes,” they wrote.
The study was published online in Clinical Gastroenterology and Hepatology.
Comparing outcomes
Although it has been shown that patients with celiac disease have increased susceptibility to viral illnesses, research to date has found similar COVID-19 incidence and outcomes, including hospitalization, between patients with celiac disease and the general population, the researchers wrote.
However, the impact of COVID-19 vaccination is less clear, so the researchers set out to compare the frequency of COVID-19–related outcomes between patients with and without celiac disease before and after vaccination.
Through an analysis of patient medical records, researchers found 171,763 patients diagnosed and treated for COVID-19 at their institution between March 1, 2020, and Jan 1, 2022. Of them, 110 adults had biopsy-proven celiac disease.
The median time from biopsy diagnosis of celiac disease to COVID-19 was 217 months, 66.3% of patients were documented to be following a gluten-free diet, and tissue transglutaminase IgA was positive in 46.2% at the time of COVID-19.
The celiac group was matched by age, ethnicity, sex, and date of COVID-19 diagnosis with a control group of 220 adults without a clinical diagnosis of celiac disease. The two cohorts had similar rates of comorbid obesity, type 2 diabetes, preexisting lung disease, and tobacco use.
Patients with celiac disease were significantly more likely to be hospitalized for COVID-19 than were the control participants, at 24% vs. 11% (hazard ratio, 2.1; P = .009), the researchers wrote.
However, hospitalized patients with celiac disease were less likely to require supplementary oxygen than were the control participants, at 63% vs. 84%.
Vaccination rates for COVID-19 were similar between the two groups, at 64.5% among patients with celiac disease and 70% in the control group. Vaccination was associated with a lower risk for hospitalization on multivariate analysis (HR, 0.53; P = .026).
There was no significant difference in hospitalization rates between vaccinated patients with celiac disease and vaccinated patients in the control group (odds ratio, 1.12; P = .79), the team reported.
The secondary outcomes of ICU requirement, mortality, and thrombosis were minimal in both groups, the researchers wrote.
Vaccination’s importance
The different findings regarding hospitalization risk among patients with celiac disease between this study and previous research are likely due to earlier studies not accounting for vaccination status, the researchers wrote.
“This study shows significantly different rates of hospitalization among patients with [celiac disease] depending on their vaccination status, with strong evidence for mitigation of hospitalization risk through vaccination,” they added.
“Vaccination against COVID-19 should be strongly recommended in patients with celiac disease,” the researchers concluded.
No funding was declared. Dr. Rubio-Tapia reported a relationship with Takeda. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
AGA offers guidance on celiac disease to help patients maintain a gluten-free diet in the AGA GI Patient Center: www.gastro.org/celiac .
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
OTC budesonide-formoterol for asthma could save lives, money
, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.
Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.
A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.
Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.
Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.
More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).
“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.
The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.
Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.
In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.
The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).
Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”
The analysis “is certainly something policy makers could take a look at,” he said.
He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).
“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”
Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.
If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.
Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.
Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.
A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.
Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.
Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.
More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).
“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.
The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.
Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.
In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.
The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).
Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”
The analysis “is certainly something policy makers could take a look at,” he said.
He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).
“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”
Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.
If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.
Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.
Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.
A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.
Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.
Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.
More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).
“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.
The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.
Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.
In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.
The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).
Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”
The analysis “is certainly something policy makers could take a look at,” he said.
He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).
“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”
Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.
If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.
Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM AAAAI 2023
Pembrolizumab before and after melanoma surgery boosts outcomes
, show results from the phase 2 SWOG S1801 trial.
The trial involved 319 patients with operable stage IIIB to stage IV melanoma. The investigators found that patients who received pembrolizumab both before and after surgery (i.e., neoadjuvant and adjuvant therapy) fared better than those who received the drug only after surgery: The 2-year event-free survival rates were 72% vs. 49%, respectively.
The research was published in the New England Journal of Medicine, but similar results had already been presented at the European Society for Medical Oncology 2022 annual Meeting.
“It’s not just what you give; it’s when you give it,” said lead author Sapna Patel, MD, in a press release issued by the University of Texas MD Anderson Cancer Center, echoing comments she gave at ESMO 2022.
The study, she continued, “demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes.”
On the basis of their findings, Dr. Patel, who is associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said that patients with high-risk melanoma “should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact.”
The mechanism of action of PD-1 blockade “relies on the presence of preexisting anti-tumor T cells attempting to attack cancer cells,” with the immunotherapy allowing the anti-tumor cells to proliferate and mediate clinical responses.
Resection of the bulk of the tumor is therefore “likely to take away some or even most of the potential anti-tumor T cells that would proliferate after PD-1 blockade,” they write.
Likely to apply also to nivolumab
Approached for comment, Jeffrey S. Weber, MD, PhD, professor of medicine, NYU Langone Medical Center, New York, said that outside of trials, both pembrolizumab and ipilimumab (Yervoy)/nivolumab (Opdivo) are already being used neoadjuvantly.
He thinks that the findings for neoadjuvant and adjuvant pembrolizumab could also apply to nivolumab because “the drugs are quite similar in efficacy.”
Dr. Weber told this news organization that, “even though the S1801 trial was not accepted as a registration trial by the FDA, I think that its results could very well change practice and confirm it for others who already use neoadjuvant therapy for palpable stage III melanoma.”
One question that is being addressed to an extent in the NADINA trial is whether adjuvant immunotherapy can be avoided all together and patients receive only neoadjuvant therapy, although Dr. Weber said, “I doubt that will be the case.”
Study details
In this study, patients were randomly assigned to either surgery followed by 18 doses of adjuvant pembrolizumab, or to receive 3 doses of neoadjuvant pembrolizumab followed by surgery and then 15 additional doses of adjuvant pembrolizumab.
After a median duration of follow-up of 14.7 months, there were 38 events in the neoadjuvant-adjuvant group and 67 in the adjuvant-only group.
“Events” were defined as disease progression, toxic effects, or complications that precluded surgery or the initiation of adjuvant therapy within 84 days of surgery, as well as the inability to fully resect the gross disease, melanoma recurrence, and death.
The team calculated that event-free survival was significantly longer in the neoadjuvant-adjuvant group (P = .004), with 2-year event-free survival at 72% vs. 49% in the adjuvant-only group.
“The benefit of neoadjuvant pembrolizumab was seen across all subgroups of patients,” the investigators note.
At the data cut-off, there were 14 deaths in the neoadjuvant-adjuvant group vs. 22 in the adjuvant-only group, which the researchers say is too few to allow “definitive comparison” in terms of overall survival.
Definitive surgery had been performed in 88% of neoadjuvant-adjuvant patients and in 95% of those assigned to adjuvant-only pembrolizumab. The most common reason for not undergoing surgery was disease progression.
Among the patients for whom safety data were available, 7% in the neoadjuvant-adjuvant group had at least one grade 3 or 4 adverse event related to pembrolizumab, whereas 7% had at least one grade 3 or 4 adverse event related to surgery.
In the adjuvant-only arm, 4% of patients had at least one grade 3 adverse event related to surgery, with no grade 4 adverse events reported.
The rates of grade 3 or 4 adverse events during adjuvant therapy were similar in the two groups, at 12% in patients assigned to neoadjuvant-adjuvant therapy and 14% in those given adjuvant-only pembrolizumab.
“Future studies can explore deescalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy,” the researchers commented.
The study was funded by the National Cancer Institute and Merck Sharp and Dohme.
Dr. Patel reports numerous relationships with industry, including with Merck, manufacturer of pembrolizumab; other coauthors also have numerous relationships with industry. Dr. Weber is a regular columnist for this news organization and lists his disclosures in his Weber on Oncology column.
A version of this article first appeared on Medscape.com.
, show results from the phase 2 SWOG S1801 trial.
The trial involved 319 patients with operable stage IIIB to stage IV melanoma. The investigators found that patients who received pembrolizumab both before and after surgery (i.e., neoadjuvant and adjuvant therapy) fared better than those who received the drug only after surgery: The 2-year event-free survival rates were 72% vs. 49%, respectively.
The research was published in the New England Journal of Medicine, but similar results had already been presented at the European Society for Medical Oncology 2022 annual Meeting.
“It’s not just what you give; it’s when you give it,” said lead author Sapna Patel, MD, in a press release issued by the University of Texas MD Anderson Cancer Center, echoing comments she gave at ESMO 2022.
The study, she continued, “demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes.”
On the basis of their findings, Dr. Patel, who is associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said that patients with high-risk melanoma “should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact.”
The mechanism of action of PD-1 blockade “relies on the presence of preexisting anti-tumor T cells attempting to attack cancer cells,” with the immunotherapy allowing the anti-tumor cells to proliferate and mediate clinical responses.
Resection of the bulk of the tumor is therefore “likely to take away some or even most of the potential anti-tumor T cells that would proliferate after PD-1 blockade,” they write.
Likely to apply also to nivolumab
Approached for comment, Jeffrey S. Weber, MD, PhD, professor of medicine, NYU Langone Medical Center, New York, said that outside of trials, both pembrolizumab and ipilimumab (Yervoy)/nivolumab (Opdivo) are already being used neoadjuvantly.
He thinks that the findings for neoadjuvant and adjuvant pembrolizumab could also apply to nivolumab because “the drugs are quite similar in efficacy.”
Dr. Weber told this news organization that, “even though the S1801 trial was not accepted as a registration trial by the FDA, I think that its results could very well change practice and confirm it for others who already use neoadjuvant therapy for palpable stage III melanoma.”
One question that is being addressed to an extent in the NADINA trial is whether adjuvant immunotherapy can be avoided all together and patients receive only neoadjuvant therapy, although Dr. Weber said, “I doubt that will be the case.”
Study details
In this study, patients were randomly assigned to either surgery followed by 18 doses of adjuvant pembrolizumab, or to receive 3 doses of neoadjuvant pembrolizumab followed by surgery and then 15 additional doses of adjuvant pembrolizumab.
After a median duration of follow-up of 14.7 months, there were 38 events in the neoadjuvant-adjuvant group and 67 in the adjuvant-only group.
“Events” were defined as disease progression, toxic effects, or complications that precluded surgery or the initiation of adjuvant therapy within 84 days of surgery, as well as the inability to fully resect the gross disease, melanoma recurrence, and death.
The team calculated that event-free survival was significantly longer in the neoadjuvant-adjuvant group (P = .004), with 2-year event-free survival at 72% vs. 49% in the adjuvant-only group.
“The benefit of neoadjuvant pembrolizumab was seen across all subgroups of patients,” the investigators note.
At the data cut-off, there were 14 deaths in the neoadjuvant-adjuvant group vs. 22 in the adjuvant-only group, which the researchers say is too few to allow “definitive comparison” in terms of overall survival.
Definitive surgery had been performed in 88% of neoadjuvant-adjuvant patients and in 95% of those assigned to adjuvant-only pembrolizumab. The most common reason for not undergoing surgery was disease progression.
Among the patients for whom safety data were available, 7% in the neoadjuvant-adjuvant group had at least one grade 3 or 4 adverse event related to pembrolizumab, whereas 7% had at least one grade 3 or 4 adverse event related to surgery.
In the adjuvant-only arm, 4% of patients had at least one grade 3 adverse event related to surgery, with no grade 4 adverse events reported.
The rates of grade 3 or 4 adverse events during adjuvant therapy were similar in the two groups, at 12% in patients assigned to neoadjuvant-adjuvant therapy and 14% in those given adjuvant-only pembrolizumab.
“Future studies can explore deescalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy,” the researchers commented.
The study was funded by the National Cancer Institute and Merck Sharp and Dohme.
Dr. Patel reports numerous relationships with industry, including with Merck, manufacturer of pembrolizumab; other coauthors also have numerous relationships with industry. Dr. Weber is a regular columnist for this news organization and lists his disclosures in his Weber on Oncology column.
A version of this article first appeared on Medscape.com.
, show results from the phase 2 SWOG S1801 trial.
The trial involved 319 patients with operable stage IIIB to stage IV melanoma. The investigators found that patients who received pembrolizumab both before and after surgery (i.e., neoadjuvant and adjuvant therapy) fared better than those who received the drug only after surgery: The 2-year event-free survival rates were 72% vs. 49%, respectively.
The research was published in the New England Journal of Medicine, but similar results had already been presented at the European Society for Medical Oncology 2022 annual Meeting.
“It’s not just what you give; it’s when you give it,” said lead author Sapna Patel, MD, in a press release issued by the University of Texas MD Anderson Cancer Center, echoing comments she gave at ESMO 2022.
The study, she continued, “demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes.”
On the basis of their findings, Dr. Patel, who is associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said that patients with high-risk melanoma “should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact.”
The mechanism of action of PD-1 blockade “relies on the presence of preexisting anti-tumor T cells attempting to attack cancer cells,” with the immunotherapy allowing the anti-tumor cells to proliferate and mediate clinical responses.
Resection of the bulk of the tumor is therefore “likely to take away some or even most of the potential anti-tumor T cells that would proliferate after PD-1 blockade,” they write.
Likely to apply also to nivolumab
Approached for comment, Jeffrey S. Weber, MD, PhD, professor of medicine, NYU Langone Medical Center, New York, said that outside of trials, both pembrolizumab and ipilimumab (Yervoy)/nivolumab (Opdivo) are already being used neoadjuvantly.
He thinks that the findings for neoadjuvant and adjuvant pembrolizumab could also apply to nivolumab because “the drugs are quite similar in efficacy.”
Dr. Weber told this news organization that, “even though the S1801 trial was not accepted as a registration trial by the FDA, I think that its results could very well change practice and confirm it for others who already use neoadjuvant therapy for palpable stage III melanoma.”
One question that is being addressed to an extent in the NADINA trial is whether adjuvant immunotherapy can be avoided all together and patients receive only neoadjuvant therapy, although Dr. Weber said, “I doubt that will be the case.”
Study details
In this study, patients were randomly assigned to either surgery followed by 18 doses of adjuvant pembrolizumab, or to receive 3 doses of neoadjuvant pembrolizumab followed by surgery and then 15 additional doses of adjuvant pembrolizumab.
After a median duration of follow-up of 14.7 months, there were 38 events in the neoadjuvant-adjuvant group and 67 in the adjuvant-only group.
“Events” were defined as disease progression, toxic effects, or complications that precluded surgery or the initiation of adjuvant therapy within 84 days of surgery, as well as the inability to fully resect the gross disease, melanoma recurrence, and death.
The team calculated that event-free survival was significantly longer in the neoadjuvant-adjuvant group (P = .004), with 2-year event-free survival at 72% vs. 49% in the adjuvant-only group.
“The benefit of neoadjuvant pembrolizumab was seen across all subgroups of patients,” the investigators note.
At the data cut-off, there were 14 deaths in the neoadjuvant-adjuvant group vs. 22 in the adjuvant-only group, which the researchers say is too few to allow “definitive comparison” in terms of overall survival.
Definitive surgery had been performed in 88% of neoadjuvant-adjuvant patients and in 95% of those assigned to adjuvant-only pembrolizumab. The most common reason for not undergoing surgery was disease progression.
Among the patients for whom safety data were available, 7% in the neoadjuvant-adjuvant group had at least one grade 3 or 4 adverse event related to pembrolizumab, whereas 7% had at least one grade 3 or 4 adverse event related to surgery.
In the adjuvant-only arm, 4% of patients had at least one grade 3 adverse event related to surgery, with no grade 4 adverse events reported.
The rates of grade 3 or 4 adverse events during adjuvant therapy were similar in the two groups, at 12% in patients assigned to neoadjuvant-adjuvant therapy and 14% in those given adjuvant-only pembrolizumab.
“Future studies can explore deescalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy,” the researchers commented.
The study was funded by the National Cancer Institute and Merck Sharp and Dohme.
Dr. Patel reports numerous relationships with industry, including with Merck, manufacturer of pembrolizumab; other coauthors also have numerous relationships with industry. Dr. Weber is a regular columnist for this news organization and lists his disclosures in his Weber on Oncology column.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
EoE: One-food elimination works as well as six-food elimination
according to a new report.
A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.
“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.
“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”
The study was published in The Lancet Gastroenterology and Hepatology.
Studying EOE and food elimination
Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.
In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.
In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.
Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).
If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.
At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.
There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.
The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.
Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.
“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
Incorporating food elimination therapy
Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.
Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.
In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.
“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”
Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.
“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.
The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
according to a new report.
A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.
“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.
“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”
The study was published in The Lancet Gastroenterology and Hepatology.
Studying EOE and food elimination
Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.
In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.
In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.
Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).
If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.
At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.
There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.
The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.
Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.
“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
Incorporating food elimination therapy
Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.
Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.
In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.
“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”
Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.
“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.
The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
according to a new report.
A one-food elimination diet (1FED) led to histologic remission in 34% of patients, as determined on the basis of eosinophil count at 6 weeks, and in 40% of patients who followed a six-food elimination diet (6FED) – a nonstatistical difference, the research team wrote.
“The takeaway message is that one-food (milk) elimination is an effective treatment and a reasonable first-line treatment for EoE,” senior study author Marc Rothenberg, MD, PhD, a professor of pediatrics and director of the allergy and immunology division at the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital Medical Center, said in an interview.
“The study was designed by the Consortium of Eosinophilic Disease Researchers (CEGIR), which includes the nation’s top institutions working with patient advocacy groups, together with the National Institutes of Health,” he said. “The group, under advice from patients, determined that it was an important question to research if one-food elimination would be effective – and how effective – compared with six-food elimination.”
The study was published in The Lancet Gastroenterology and Hepatology.
Studying EOE and food elimination
Previous studies have found that eliminating six common foods that trigger esophageal injury – milk, eggs, wheat, soy, fish, and nuts – can substantially reduce EoE symptoms. The 6FED has become a common approach to managing the disease.
In recent years, however, researchers have conducted small, nonrandomized studies of the less restrictive 1FED and have found some success.
In a multisite, randomized trial, Dr. Rothenberg and colleagues compared the 6FED with the 1FED among 129 adults aged 18-60 years with a confirmed EoE diagnosis, active EoE symptoms, and a high number of eosinophils in esophageal tissue. The participants enrolled at 1 of 10 U.S. medical centers that participate in CEGIR, which is part of the NIH-funded Rare Diseases Clinical Research Network.
Between 2016 and 2019, 67 participants were assigned to the 1FED group, which eliminated only animal milk from the diet, and 62 participants were assigned to the 6FED group, which eliminated milk, eggs, wheat, soy, fish/shellfish, and peanuts/tree nuts. After following the diet for 6 weeks, participants underwent an upper endoscopy exam and esophageal tissue biopsy. The primary endpoint was the proportion of patients with histologic remission, or a peak count of less than 15 eosinophils per high-power field (eos/hpf).
If the number of eosinophils indicated that EoE was in remission, the participant exited the study. If EoE wasn’t in remission, those who were on 1FED could proceed to 6FED, and those who were on 6FED could take fluticasone propionate 880 mcg two times per day with an unrestricted diet. Both groups followed the protocols for 6 weeks and underwent another exam with tissue biopsy.
At 6 weeks, 25 patients (40%) on 6FED and 23 patients (34%) on 1FED achieved histologic remission. The difference was not statistically significant.
There were also no significant differences between the groups at stricter thresholds for partial remission, defined as peak counts of 10 eos/hpf or less and 6 eos/hpf or less. The rate of complete remission (at a peak count of ≤ 1 eos/hpf) favored 6FED, at 19% versus 6% among 1FED.
The two diets had a similar impact across several other measures, including reduction in peak eosinophil counts, reduction in EoE symptoms, and improvement in quality of life. For 6FED versus 1FED, the mean changes from baseline in the Eosinophilic Esophagitis Histology Scoring System were –0.23 versus –0.15. In addition, the mean changes in the Eosinophilic Esophagitis Endoscopic Reference Score were 1 versus –0.6, and in the Eosinophilic Esophagitis Activity Index, they were –8.2 versus –3. None of the differences were significant.
Among the patients who didn’t respond to 1FED, 21 opted to follow 6FED in the study’s second phase. Of those patients, nine (43%) attained remission after following the more restrictive diet. Among the 11 patients who didn’t initially respond to 6FED and who opted to receive fluticasone propionate, nine patients (82%) achieved remission.
“We examined a series of validated endpoints that have not previously been examined in diet trials,” Dr. Rothenberg said. “We are surprised to see that one food was equally effective as six foods.”
Incorporating food elimination therapy
Dr. Rothenberg and colleagues are continuing their research into EoE and food-elimination diets, with a strong focus on furthering diet therapy. In particular, the research team wants to understand how to potentially add milk – and other foods – back to the diet.
Wael Sayej, MD, associate professor of pediatrics at the University of Massachusetts Baystate Regional Campus, Springfield, has found success with the one-food elimination diet among children with EoE, he said in an interview.
In a retrospective study, Dr. Sayej and colleagues found that a one-food elimination diet was an effective first-line treatment option for pediatric patients.
“Once we get past the one-food or two-food elimination, it becomes much more difficult and cumbersome for patients to follow,” said Dr. Sayej, who is also a pediatric gastroenterologist with Baystate Health in Springfield and who wasn’t involved with the CEGIR study. “Obviously, I prefer my patients to follow a strict dairy-free diet as long-term therapy, rather than have them on a medication for the rest of their life.”
Dr. Sayej advises patients to follow the one-food elimination diet in his practice. If patients aren’t responsive, he offers options for additional dietary elimination or initiation of steroid therapy.
“The most important thing about initiating dietary elimination therapy is to take the time to educate the patient and family about the disease, the risks or complications associated with untreated disease, and the pros and cons of the treatment options,” he said.
The study was cofunded by the National Institute of Allergy and Infectious Diseases, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have research, consultant, and leadership relationships with several pharmaceutical companies and organizations not related to this study. Dr. Sayej disclosed no relevant financial relationships.
FROM THE LANCET GASTROENTEROLOGY AND HEPATOLOGY
COORDINATEd effort boosts optimal therapy in patients with T2D and ASCVD
NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.
Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.
“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.
The goal is getting patients on triple therapy
The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.
Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.
Simultaneously with her report, the findings also appeared online in JAMA.
At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.
At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.
Effective interventions and the need for a champion
The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:
- Analysis of the barriers to evidence-based care at each clinic.
- Development of local interdisciplinary care pathways to address the identified barriers.
- Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
- Education of the clinic staff, including provision of educational materials.
- Auditing of clinic performance using specified metrics and feedback on the findings.
Clinics in the usual care group were given current clinical practice guidelines.
The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.
Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.
“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.
Research advances often don’t translate into management changes
“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.
“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.
“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”
The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.
The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.
COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.
NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.
Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.
“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.
The goal is getting patients on triple therapy
The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.
Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.
Simultaneously with her report, the findings also appeared online in JAMA.
At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.
At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.
Effective interventions and the need for a champion
The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:
- Analysis of the barriers to evidence-based care at each clinic.
- Development of local interdisciplinary care pathways to address the identified barriers.
- Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
- Education of the clinic staff, including provision of educational materials.
- Auditing of clinic performance using specified metrics and feedback on the findings.
Clinics in the usual care group were given current clinical practice guidelines.
The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.
Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.
“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.
Research advances often don’t translate into management changes
“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.
“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.
“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”
The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.
The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.
COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.
NEW ORLEANS – Twenty cardiology clinics successfully intensified the medical care they gave patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) after receiving a simple and scalable investigational intervention that gave the clinics’ staffs guidance on best prescribing practices and implementation and also provided quality-improvement feedback.
Within a year, these clinics quadrupled optimal medical management of these patients, compared with control clinics, in a randomized trial involving a total of 43 clinics and 1,049 patients.
“This multifaceted intervention is effective in increasing the prescription of evidence-based therapies in adults with T2D and ASCVD,” Neha J. Pagidipati, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
“The next step is to scale this intervention across cardiology practices” interested in improving the quality of care they deliver to these patients, added Dr. Pagidipati, a cardiologist specializing in cardiometabolic disease prevention at Duke University in Durham, N.C.
The goal is getting patients on triple therapy
The primary outcome of the COORDINATE-Diabetes trial was the change in the number of patients with T2D and ASCVD who received prescriptions for agents from three recommended medication classes and at recommended dosages: a high-intensity statin, a renin-angiotensin system inhibitor (RASi), and at least one agent from either of two classes that have both cardiovascular-protective and antihyperglycemic effects: the sodium-glucose cotransporter 2 (SGLT2) inhibitors, or the glucagonlike peptide 1 (GLP-1)–receptor agonists.
Among the 457 patients treated at the 20 cardiology clinics who received the quality-improvement intervention, 37.9% were on the promoted triple therapy after 12 months, compared with 14.5% of the 588 patients treated at the 23 clinics that continued with their usual care approach. This 23.4–percentage point increase in triple-class prescribing at recommended dosages represented a significant 4.4-fold increase in the goal prescribing endpoint after adjustment for possible confounders, Dr. Pagidipati reported.
Simultaneously with her report, the findings also appeared online in JAMA.
At baseline, 41%-50% of the patients were on both a high-intensity statin and a RASi, with a total of about 58%-67% on a high-intensity statin and about 70%-75% on a RASi. Fewer than 1% of patients were on SGLT2 inhibitors or GLP-1–receptor agonists at baseline. By design, no patient could be on all three categories of medication at baseline.
At their last follow-up visit (after 12 months for 97% of patients, or after 6 months for the remainder) 71% of the patients at practices that received the intervention were on a high-intensity statin, 81% were taking a RASi, and 60% were on an SGLT2 inhibitor or GLP-1–receptor agonist. Among the control patients, 58% were on a high-intensity statin, 68% on a RASi, and 36% were on one of the antihyperglycemic agents.
Effective interventions and the need for a champion
The clinics randomized to the active arm received instruction from a three-member team, either from an in-person or virtual one-time visit, on an intervention comprising several initiatives:
- Analysis of the barriers to evidence-based care at each clinic.
- Development of local interdisciplinary care pathways to address the identified barriers.
- Facilitation of care coordination among clinicians – particularly among cardiology, endocrinology, and primary care clinicians.
- Education of the clinic staff, including provision of educational materials.
- Auditing of clinic performance using specified metrics and feedback on the findings.
Clinics in the usual care group were given current clinical practice guidelines.
The investigational intervention was, by design, “low-tech and designed to be scalable,” explained Dr. Pagidipati, and once the COVID pandemic started the intervention team shifted to a virtual consultation with participating practices that was mostly front-loaded, followed by monthly phone calls to give clinics feedback on their progress.
Among the most helpful aspects of the intervention was involving the entire clinic staff, including pharmacists, nurses, and advanced care practitioners; boosting familiarity with the relevant medications and their appropriate use; and advice on navigating insurance-coverage barriers such as prior authorizations.
“What was most critical was having a local champion who took on making this effort an important part” of what the clinic was trying to do, she explained. “All it takes is passion, and the tenacity of a bulldog,” Dr. Pagidipati said.
Research advances often don’t translate into management changes
“We don’t do a great job of translating findings from trials to patient care, so any method we can use to improve that will improve practice,” commented Kristen B. Campbell, PharmD, a clinical pharmacist at Duke who was not involved in the study.
“Although the trial was not powered to look at patient outcomes, we think that patients will benefit” because all the recommended medication uses have been proven to help patients in prior trials, Dr. Campbell noted.
“A particular strength of this study was its simple design. All the interventions are low-tech and scalable.”
The low level of use of guideline-directed medical therapy in American adults with type 2 diabetes and atherosclerotic cardiovascular disease is “incredible,” said Christopher B. Granger, MD, a senior investigator on the study and a cardiologist and professor at Duke.
The researchers who ran the study are now focused on evaluating which cardiology clinics and patients had the most success from the intervention and are using that information to further refine implementation. They are also planning to encourage cardiology practices as well as other relevant medical groups to incorporate the intervention and implementation model used in the trial. The intervention program is detailed and available at no charge on the COORDINATE-Diabetes website.
COORDINATE-Diabetes received funding from Boehringer Ingelheim and Eli Lilly. Dr. Pagidipati has received personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics, and she has received research grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr. Campbell had no disclosures. Dr. Granger has received personal fees and research funding from numerous companies.
AT ACC 2023
Atorvastatin cut anthracycline cardiac dysfunction in lymphoma
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
AT ACC 2023
Bempedoic acid cuts CV events in statin-intolerant patients: CLEAR Outcomes
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
A new approach to lowering cholesterol with the use of bempedoic acid (Nexletol, Esperion) brought about a significant reduction in cardiovascular events in patients intolerant to statins in the large phase 3, placebo-controlled CLEAR Outcomes trial.
The drug lowered LDL cholesterol by 21% in the study and reduced the composite primary endpoint, including cardiovascular death, MI, stroke, or coronary revascularization, by 13%; MI was reduced by 23% and coronary revascularization, by 19%.
The drug was also well tolerated in the mixed population of primary and secondary prevention patients unable or unwilling to take statins.
“These findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin-intolerant patients,” study chair, Steven E. Nissen, MD, of the Cleveland Clinic concluded.
Dr. Nissen presented the CLEAR Outcomes trial at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
The study was simultaneously published online in the New England Journal of Medicine. Top-line results were previously reported in December 2022.
Dr. Nissen pointed out that, while in the current study bempedoic acid was studied as monotherapy, he believes the drug will mainly be used in clinical practice in combination with ezetimibe, a combination shown to reduce LDL by 38%. “I think this is how it will be used in clinical practice. So, we can get an almost 40% LDL reduction – that’s about the same as 40 mg simvastatin or 20 mg atorvastatin – without giving a statin. And I think that’s where I see the potential of this therapy,” he said.
Dr. Nissen described statin intolerance as “a vexing problem” that prevents many patients from achieving LDL cholesterol levels associated with cardiovascular benefits.
He explained that bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, inhibits hepatic cholesterol synthesis upstream of hydroxymethylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is a prodrug activated in the liver, but not in peripheral tissues, resulting in a low incidence of muscle-related adverse events. Although bempedoic acid is approved for lowering LDL cholesterol, this is the first trial to assess its effects on cardiovascular outcomes.
CLEAR Outcomes
The CLEAR Outcomes trial included 13,970 patients (48% women) from 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and who had, or were at high risk for, cardiovascular disease. They were randomly assigned to oral bempedoic acid, 180 mg daily, or placebo.
The mean LDL cholesterol level at baseline was 139 mg/dL in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg/dL (a 21.1% reduction).
The drug was also associated with a 22% reduction in high-sensitivity C-reactive protein.
After a median duration of follow-up of 40.6 months, the incidence of a primary endpoint (cardiovascular death, MI, stroke, or coronary revascularization) was significantly lower (by 13%) with bempedoic acid than with placebo (11.7% vs. 13.3%; hazard ratio, 0.87; P = .004).
The absolute risk reduction was 1.6 percentage points, and the number needed to treat for 40 months to prevent one event was 63.
The secondary composite endpoint of cardiovascular death/stroke/MI was reduced by 15% (8.2% vs. 9.5%; HR, 0.85; P = .006). Fatal or nonfatal MI was reduced by 23% (3.7% vs. 4.8%; HR, 0.77; P = .002), and coronary revascularization was reduced by 19% (6.2% vs. 7.6%; HR, 0.81; P = .001).
Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause.
Subgroup analysis showed similar results across all groups and no difference in treatment effect between men and women.
Adverse events were reported by 25% of patients in both groups, with adverse events leading to discontinuation reported by 10.8% of the bempedoic acid group and 10.4% of the placebo group.
Muscle disorders were reported in 15.0% of the bempedoic acid group versus 15.4% of the placebo group. And there was also no difference in new cases of diabetes (16.1% vs. 17.1%).
Bempedoic acid was associated with small increases in the incidence of gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%), and also small increases in serum creatinine, uric acid, and hepatic enzyme levels.
In the NEJM article, the authors pointed out that the concept of statin intolerance remains controversial. Some recent studies suggested that reported adverse effects represent an anticipation of harm, often described as the “nocebo” effect.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” they wrote.
“Management of patients unable or unwilling to take statins represents a challenging and frustrating clinical issue. Regardless whether this problem represents the ‘nocebo’ effect or actual intolerance, these high-risk patients need effective alternative therapies,” Dr. Nissen concluded. “The CLEAR Outcomes trial provides a sound rationale for use of bempedoic acid to reduce major adverse cardiovascular outcomes in patients intolerant to statins.”
‘Compelling findings’
Discussing the trial at the ACC late-breaking clinical trial session, Michelle O’Donoghue, MD, Brigham and Women’s Hospital, Boston, noted that this is the largest trial to date in statin-intolerant patients.
She pointed out that although the issue of statin intolerance remains controversial, adherence to statins is often not good, so this is an important patient population to study.
She said it was “quite remarkable” that 48% of the study were women, adding: “There is still much that we need to understand about why women appear to be less willing or able to tolerate statin therapy.”
Dr. O’Donoghue concluded that the study showed “compelling findings,” and the event reduction was in line with what would be expected from the LDL cholesterol reduction, further supporting the LDL cholesterol hypothesis.
She added: “Bempedoic acid is an important addition to our arsenal of nonstatin LDL-lowering therapies. And while it was overall well tolerated, it did not get a complete free pass, as there were some modest safety concerns.”
In an editorial accompanying the NEJM publication, John Alexander, MD, Duke Clinical Research Institute, Durham, N.C., wrote: “The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins.”
He warned, however, that it is premature to consider bempedoic acid as an alternative to statins. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects.”.
Dr. Alexander also pointed out that although bempedoic acid also reduces the LDL cholesterol level in patients taking statins, the clinical benefits of bempedoic acid added to standard statin therapy are unknown.
On the observation that bempedoic acid had no observed effect on mortality, he noted that “Many individual trials of statins have also not shown an effect of the agent on mortality; it was only through the meta-analysis of multiple clinical trials that the effects of statins on mortality became clear.”
“Bempedoic acid has now entered the list of evidence-based alternatives to statins for primary and secondary prevention in patients at high cardiovascular risk,” Dr. Alexander concluded. “The benefits of bempedoic acid are now clearer, and it is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
In a second editorial, John F. Keaney Jr., MD, Brigham and Women’s Hospital, said the lack of a clear association between bempedoic acid and muscle disorders, new-onset diabetes, or worsening hyperglycemia is “welcome news” for statin-intolerant patients.
But he cautioned that “these data must be interpreted cautiously, because bempedoic acid, when combined with a statin, appears to enhance the occurrence of muscle symptoms. Moreover, bempedoic acid has its own reported side effects, including tendon rupture, increased uric acid levels, gout, and reduced glomerular filtration rate, which are not seen with statin use.”
In terms of drug interactions, Dr. Keaney noted that bempedoic acid can increase the circulating levels of simvastatin and pravastatin, so it should not be used in patients who are receiving these agents at doses above 20 mg and 40 mg, respectively. Similarly, bempedoic acid should not be used with fibrates other than fenofibrate because of concerns regarding cholelithiasis.
“Available data clearly indicate that bempedoic acid can be used as an adjunct to statin and nonstatin therapies (except as noted above) to produce an additional 16%-26% reduction in the LDL cholesterol level,” he added. “However, it is not yet clear to what extent adjunctive bempedoic acid will further reduce the risk of cardiovascular events.”
The CLEAR Outcomes trial was supported by Esperion Therapeutics. Dr. Nissen reported receiving grants from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Esperion, Novartis, and Silence Pharmaceuticals and consultancies with Amgen and Glenmark Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM ACC 2023
Transcatheter tricuspid valve repair effective and safe for regurgitation
NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.
Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.
In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.
The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
Benefit driven by quality of life
For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).
For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).
This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).
When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.
For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.
For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.
More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).
Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
Surgery is not necessarily an option
All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.
In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.
In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”
These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.
“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.
Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”
Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.
Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.
NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.
Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.
In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.
The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
Benefit driven by quality of life
For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).
For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).
This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).
When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.
For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.
For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.
More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).
Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
Surgery is not necessarily an option
All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.
In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.
In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”
These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.
“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.
Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”
Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.
Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.
NEW ORLEANS – In the first pivotal randomized, controlled trial of a transcatheter device for the repair of severe tricuspid regurgitation, a large reduction in valve dysfunction was associated with substantial improvement in quality of life (QOL) persisting out of 1 year of follow-up, according to results of the TRILUMINATE trial.
Based on the low procedural risks of the repair, the principal investigator, Paul Sorajja, MD, called the results “very clinically meaningful” as he presented the results at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
Conducted at 65 centers in the United States, Canada, and North America, TRILUMINATE evaluated a transcatheter end-to-end (TEER) repair performed with the TriClip G4 Delivery System (Abbott). The study included two cohorts, both of which will be followed for 5 years. One included patients with very severe tricuspid regurgitation enrolled in a single arm. Data on this cohort is expected later in 2023.
In the randomized portion of the study, 350 patients enrolled with severe tricuspid regurgitation underwent TEER with a clipping device and then were followed on the guideline-directed therapy (GDMT) for heart failure they were receiving at baseline. The control group was managed on GDMT alone.
The primary composite endpoint at 1 year was a composite of death from any cause and/or tricuspid valve surgery, hospitalization for heart failure, and quality of life as measured with the Kansas City Cardiomyopathy questionnaire (KCCQ).
Benefit driven by quality of life
For the primary endpoint, the win ratio, a statistical calculation of those who did relative to those who did not benefit, was 1.48, signifying a 48% advantage (P = .02). This was driven almost entirely by the KCCQ endpoint. There was no significant difference death and/or tricuspid valve surgery, which occurred in about 10% of both groups (P = .75) or heart failure hospitalization, which was occurred in slightly more patients randomized to repair (14.9% vs. 12.1%; P = .41).
For KCCQ, the mean increase at 1 year was 12.3 points in the repair group versus 0.6 points (P < .001) in the control group. With an increase of 5-10 points typically considered to be clinically meaningful, the advantage of repair over GDMT at the threshold of 15 points or greater was highly statistically significant (49.7% vs. 26.4%; P < .0001).
This advantage was attributed to control of regurgitation. The proportion achieving moderate or less regurgitation sustained at 1 year was 87% in the repair group versus 4.8% in the GDMT group (P < .0001).
When assessed independent of treatment, KCCQ benefits at 1 year increased in a stepwise fashion as severity of regurgitation was reduced, climbing from 2 points if there was no improvement to 6 points with one grade in improvement and then to 18 points with at least a two-grade improvement.
For regurgitation, “the repair was extremely effective,” said Dr. Sorajja of Allina Health Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis. He added that the degree of regurgitation control in the TRILUMINATE trial “is the highest ever reported.” With previous trials with other transcatheter devices in development, the improvement so far has been on the order of 70%-80%.
For enrollment in TRILUMINATE, patients were required to have at least an intermediate risk of morbidity or mortality from tricuspid valve surgery. Exclusion criteria included a left ventricular ejection fraction (LVEF) less than 20% and severe pulmonary hypertension.
More than 70% of patients had the highest (torrential) or second highest (massive) category of regurgitation on a five-level scale by echocardiography. Almost all the remaining were at the third level (severe).
Of those enrolled, the average age was roughly 78 years. About 55% were women. Nearly 60% were in New York Heart Association class III or IV heart failure and most had significant comorbidities, including hypertension (> 80%), atrial fibrillation (about 90%), and renal disease (35%). Patients with diabetes (16%), chronic obstructive pulmonary disease (10%), and liver disease (7.5%) were represented in lower numbers.
Surgery is not necessarily an option
All enrolled patients were considered to be at intermediate or greater risk for mortality with surgical replacement of the tricuspid valve, but Dr. Sorajja pointed out that surgery, which involves valve replacement, is not necessarily an alternative to valve repair. Even in fit patients, the high morbidity, mortality, and extended hospital stay associated with surgical valve replacement makes this procedure unattractive.
In this trial, most patients who underwent the transcatheter procedure were discharged within a day. The safety was excellent, Dr. Sorajja said. Only three patients (1.7%) had a major adverse event. This included two cases of new-onset renal failure and one cardiovascular death. There were no cases of endocarditis requiring surgery or any other type of nonelective cardiovascular surgery, including for any device-related issue.
In the sick population enrolled, Dr. Sorajja characterized the number of adverse events over 1 year as “very low.”
These results are important, according to Kendra Grubb, MD, surgical director of the Structural Heart and Valve Center, Emory University, Atlanta. While she expressed surprise that there was no signal of benefit on hard endpoints at 1 year, she emphasized that “these patients feel terrible,” and they are frustrating to manage because surgery is often contraindicated or impractical.
“Finally, we have something for this group,” she said, noting that the mortality from valve replacement surgery even among patients who are fit enough for surgery to be considered is about 10%.
Ajay Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, was more circumspect. He agreed that the improvement in QOL was encouraging, but cautioned that QOL is a particularly soft outcome in a nonrandomized trial in which patients may feel better just knowing that there regurgitation has been controlled. He found the lack of benefit on hard outcomes not just surprising but “disappointing.”
Still, he agreed the improvement in QOL is potentially meaningful for a procedure that appears to be relatively safe.
Dr. Sorajja reported financial relationships with Boston Scientific, Edwards Lifesciences, Foldax. 4C Medical, Gore Medtronic, Phillips, Siemens, Shifamed, Vdyne, xDot, and Abbott Structural, which provided funding for this trial. Dr. Grubb reported financial relationships with Abbott Vascular, Ancora Heart, Bioventrix, Boston Scientific, Edwards Lifesciences, 4C Medical, JenaValve, and Medtronic. Dr. Kirtane reported financial relationships with Abbott Vascular, Amgen, Boston Scientific, Chiesi, Medtronic, Opsens, Phillips, ReCor, Regeneron, and Zoll.
AT ACC 2023
Beware risk of sedatives for respiratory patients
Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.
write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.
The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.
Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.
Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.
Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.
“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.
Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.
Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.
The study received no outside funding. The authors have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.
write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.
The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.
Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.
Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.
Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.
“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.
Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.
Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.
The study received no outside funding. The authors have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.
write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.
The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.
Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.
Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.
Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.
“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.
Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.
Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.
The study received no outside funding. The authors have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.