PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.

Key clinical point: Teriflunomide may be more cost effective than interferon beta-1b for relapsing MS patients.

Major finding: Over the course of 20 years, the cost of treatment with teriflunomide would cost $567,767, compared with the cost of treatment for interferon beta of $620,191 for patients in China.

Study details: A Markov cost model was developed for the study. Eleven neurologists were surveyed throughout China about costs related to treatment for RMS including acquisition and administration, patient monitoring, treating relapse, and the management of adverse events.

Disclosures: This study was funded by Sanofi China. Two study investigators reported being employees of the company.

Citation: Xu Y, et al. Clin Drug Investig. 2019 Mar;39(3):331-340. doi: 10.1007/s40261-019-00750-3.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.

Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.

Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.

Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.

Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.

Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.

Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.

Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.

Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.

Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.

Key clinical point: Polypharmacy frequency can have a negative effect on relapsing-remitting multiple sclerosis (RRMS) patients.

Major finding: The proportion of polypharmacy among patients with a secondary illness to RRMS was four times higher than in patients without a secondary illness. Patients with polypharmacy were older, had a lower level of education, and had higher comorbidities than patients without polypharmacy.

Study details: Subgroups of 145 RRMS patients were analyzed. The subgroups were patients with polypharmacy, patients without polypharmacy, patients with secondary illness, and patients without secondary illness.

Disclosures: Michael Hecker support from Bayer HealthCare, Biogen, Novartis and Teva. Uwe Klaus Zettl received support from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva. Niklas Frahm has no relevant conflicts of interest.

Citation: Frahm N, et al. PLoS One. 2019 Jan 24;14(1):e0211120. doi: 10.1371/journal.pone.0211120.

Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.

Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.

Disclosures: The investigators reported no conflicts of interest.

Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.

Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.

Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.

Disclosures: The investigators reported no conflicts of interest.

Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.

Key clinical point: Two algorithms identified in a new study can be used for future clinical research of relapsing-remitting multiple sclerosis (RRMS). Major finding: Using EHRs and the coded health care claims of 5,308 patients with possible MS, 837 and 2,271 were identified as having RRMS, respectively. There were also 779 patients identified using both algorithms.

Study details: Two different algorithms “unstructured clinical notes (EHR clinical notes-based algorithm) and structured/coded data (claims-based algorithms)” were used to identify patients with RRMS.

Disclosures: The investigators reported no conflicts of interest.

Citation: Van Le H, et al. Value Health. 2019 Jan;22(1):77-84. doi: 10.1016/j.jval.2018.06.014.

NEW ORLEANS – Up to 50% of children with asthma struggle to control their condition, yet fewer than 5% of pediatric asthma is severe and truly resistant to therapy, according to Susan Laubach, MD.

Other factors may make asthma difficult to control and may be modifiable, especially nonadherence to recommended treatment. In fact, up to 70% of patients report poor adherence to recommended treatment, Dr. Laubach said at the annual meeting of the American Academy of Pediatrics.

“Barriers to adherence may be related to the treatments themselves,” she said. “These include complex treatment schedules, lack of an immediately discernible beneficial effect, adverse effects of the medication, and prohibitive costs.”

Dr. Laubach, who directs the allergy clinic at Rady Children’s Hospital in San Diego, said that clinician-related barriers also influence patient adherence to recommended treatment, including difficulty scheduling appointments or seeing the same physician, a perceived lack of empathy, or failure to discuss the family’s concerns or answer questions. Common patient-related barriers include poor understanding of how the medication may help or how to use the inhalers.

“Some families have a lack of trust in the health care system, or certain beliefs about illness or medication that may hamper motivation to adhere,” she added. “Social issues such as poverty, lack of insurance, or a chaotic home environment may make it difficult for a patient to adhere to recommended treatment.”

In 2013, researchers led by Ted Klok, MD, PhD, of Princess Amalia Children’s Clinic in the Netherlands, explored practical ways to improve treatment adherence in children with pediatric respiratory disease (Breathe. 2013;9:268-77). One of their recommendations involves “five E’s” of ensuring optimal adherence. They include:

Ensure close and repeated follow-up to help build trust and partnership. “I’ll often follow up every month until I know a patient has gained good control of his or her asthma,” said Dr. Laubach, who was not involved in developing the recommendations. “Then I’ll follow up every 3 months.”

Explore the patient’s views, beliefs, and preferences. “You can do this by inviting questions or following up on comments or remarks made about the treatment plan,” she said. “This doesn’t have to take long. You can simply ask, ‘What are you concerned might happen if your child uses an inhaled corticosteroid?’ Or, ‘What have you heard about inhaled steroids?’ ”

Express empathy using active listening techniques tailored to the patient’s needs. Consider phrasing like, “I understand what you’re saying. In a perfect world, your child would not have to use any medications. But when he can’t sleep because he’s coughing so much, the benefit of this medication probably outweighs any potential risks.”

Exercise shared decision making. For example, if the parent of one of your patients has to leave for work very early in the morning, “maybe find a way to adjust to once-daily dosing so that appropriate doses can be given at bedtime when the parent is consistently available,” Dr. Laubach said.

Evaluate adherence in a nonjudgmental fashion. Evidence suggests that most patients with asthma miss a couple of medication doses now and then. She makes it a point to ask patients, “If you’re supposed to take 14 doses a week, how many do you think you actually take?” Their response “gives me an idea about their level of adherence and it opens a discussion into why they may miss doses, so that we can find a solution to help improve adherence.”

gpointstudio/Thinkstock

dbrunk@mdedge.com

NEW ORLEANS – Up to 50% of children with asthma struggle to control their condition, yet fewer than 5% of pediatric asthma is severe and truly resistant to therapy, according to Susan Laubach, MD.

Other factors may make asthma difficult to control and may be modifiable, especially nonadherence to recommended treatment. In fact, up to 70% of patients report poor adherence to recommended treatment, Dr. Laubach said at the annual meeting of the American Academy of Pediatrics.

“Barriers to adherence may be related to the treatments themselves,” she said. “These include complex treatment schedules, lack of an immediately discernible beneficial effect, adverse effects of the medication, and prohibitive costs.”

Dr. Laubach, who directs the allergy clinic at Rady Children’s Hospital in San Diego, said that clinician-related barriers also influence patient adherence to recommended treatment, including difficulty scheduling appointments or seeing the same physician, a perceived lack of empathy, or failure to discuss the family’s concerns or answer questions. Common patient-related barriers include poor understanding of how the medication may help or how to use the inhalers.

“Some families have a lack of trust in the health care system, or certain beliefs about illness or medication that may hamper motivation to adhere,” she added. “Social issues such as poverty, lack of insurance, or a chaotic home environment may make it difficult for a patient to adhere to recommended treatment.”

In 2013, researchers led by Ted Klok, MD, PhD, of Princess Amalia Children’s Clinic in the Netherlands, explored practical ways to improve treatment adherence in children with pediatric respiratory disease (Breathe. 2013;9:268-77). One of their recommendations involves “five E’s” of ensuring optimal adherence. They include:

Ensure close and repeated follow-up to help build trust and partnership. “I’ll often follow up every month until I know a patient has gained good control of his or her asthma,” said Dr. Laubach, who was not involved in developing the recommendations. “Then I’ll follow up every 3 months.”

Explore the patient’s views, beliefs, and preferences. “You can do this by inviting questions or following up on comments or remarks made about the treatment plan,” she said. “This doesn’t have to take long. You can simply ask, ‘What are you concerned might happen if your child uses an inhaled corticosteroid?’ Or, ‘What have you heard about inhaled steroids?’ ”

Express empathy using active listening techniques tailored to the patient’s needs. Consider phrasing like, “I understand what you’re saying. In a perfect world, your child would not have to use any medications. But when he can’t sleep because he’s coughing so much, the benefit of this medication probably outweighs any potential risks.”

Exercise shared decision making. For example, if the parent of one of your patients has to leave for work very early in the morning, “maybe find a way to adjust to once-daily dosing so that appropriate doses can be given at bedtime when the parent is consistently available,” Dr. Laubach said.

Evaluate adherence in a nonjudgmental fashion. Evidence suggests that most patients with asthma miss a couple of medication doses now and then. She makes it a point to ask patients, “If you’re supposed to take 14 doses a week, how many do you think you actually take?” Their response “gives me an idea about their level of adherence and it opens a discussion into why they may miss doses, so that we can find a solution to help improve adherence.”

gpointstudio/Thinkstock

dbrunk@mdedge.com

NEW ORLEANS – Up to 50% of children with asthma struggle to control their condition, yet fewer than 5% of pediatric asthma is severe and truly resistant to therapy, according to Susan Laubach, MD.

Other factors may make asthma difficult to control and may be modifiable, especially nonadherence to recommended treatment. In fact, up to 70% of patients report poor adherence to recommended treatment, Dr. Laubach said at the annual meeting of the American Academy of Pediatrics.

“Barriers to adherence may be related to the treatments themselves,” she said. “These include complex treatment schedules, lack of an immediately discernible beneficial effect, adverse effects of the medication, and prohibitive costs.”

Dr. Laubach, who directs the allergy clinic at Rady Children’s Hospital in San Diego, said that clinician-related barriers also influence patient adherence to recommended treatment, including difficulty scheduling appointments or seeing the same physician, a perceived lack of empathy, or failure to discuss the family’s concerns or answer questions. Common patient-related barriers include poor understanding of how the medication may help or how to use the inhalers.

“Some families have a lack of trust in the health care system, or certain beliefs about illness or medication that may hamper motivation to adhere,” she added. “Social issues such as poverty, lack of insurance, or a chaotic home environment may make it difficult for a patient to adhere to recommended treatment.”

In 2013, researchers led by Ted Klok, MD, PhD, of Princess Amalia Children’s Clinic in the Netherlands, explored practical ways to improve treatment adherence in children with pediatric respiratory disease (Breathe. 2013;9:268-77). One of their recommendations involves “five E’s” of ensuring optimal adherence. They include:

Ensure close and repeated follow-up to help build trust and partnership. “I’ll often follow up every month until I know a patient has gained good control of his or her asthma,” said Dr. Laubach, who was not involved in developing the recommendations. “Then I’ll follow up every 3 months.”

Explore the patient’s views, beliefs, and preferences. “You can do this by inviting questions or following up on comments or remarks made about the treatment plan,” she said. “This doesn’t have to take long. You can simply ask, ‘What are you concerned might happen if your child uses an inhaled corticosteroid?’ Or, ‘What have you heard about inhaled steroids?’ ”

Express empathy using active listening techniques tailored to the patient’s needs. Consider phrasing like, “I understand what you’re saying. In a perfect world, your child would not have to use any medications. But when he can’t sleep because he’s coughing so much, the benefit of this medication probably outweighs any potential risks.”

Exercise shared decision making. For example, if the parent of one of your patients has to leave for work very early in the morning, “maybe find a way to adjust to once-daily dosing so that appropriate doses can be given at bedtime when the parent is consistently available,” Dr. Laubach said.

Evaluate adherence in a nonjudgmental fashion. Evidence suggests that most patients with asthma miss a couple of medication doses now and then. She makes it a point to ask patients, “If you’re supposed to take 14 doses a week, how many do you think you actually take?” Their response “gives me an idea about their level of adherence and it opens a discussion into why they may miss doses, so that we can find a solution to help improve adherence.”

gpointstudio/Thinkstock

dbrunk@mdedge.com

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

mzoler@mdedge.com

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

mzoler@mdedge.com

PARIS – The primary endpoint of PARAGON-HF was neutral in patients with heart failure with preserved ejection fraction, but that didn’t stop some experts from seeing a practice-changing message in its findings.

Mitchel L. Zoler/MDedge News

The results of PARAGON-HF, a major trial of sacubitril/valsartan – a compound already approved for treating heart failure with reduced left ventricular ejection fraction – in patients with heart failure with preserved ejection fraction (HFpEF), showed a statistically neutral result for the study’s primary endpoint, but with an excruciatingly close near miss for statistical significance and clear benefit in a subgroup of HFpEF patients with a modestly reduced left ventricular ejection fraction. These findings seemed to convince some experts to soon try using sacubitril/valsartan (Entresto) to treat selected patients with HFpEF, driven in large part by the lack of any other agent clearly proven to benefit the large number of patients with this form of heart failure.

HFpEF is “a huge unmet need,” and data from the PARAGON-HF trial “suggest that sacubitril/valsartan may be beneficial in some patients with HFpEF, particularly those with a left ventricular ejection fraction that is not frankly reduced, but less than normal,” specifically patients with a left ventricular ejection fraction of 45%-57%, Scott D. Solomon, MD, said at the annual congress of the European Society of Cardiology as he reported the primary PARAGON-HF results.

“I’m not speaking for regulators or for guidelines, but I suspect that in this group of patients [with HFpEF and a left ventricular ejection fraction of 45%-57%] there is at least some rationale to use this treatment,” said Dr. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, both in Boston.

His suggestion, which cut against the standard rules that govern the interpretation of trial results, met a substantial level of receptivity at the congress.

Trial results “are not black and white, where a P value of .049 means the trial was totally positive, and a P of .051 means it’s totally neutral. That’s misleading, and it’s why the field is moving to different types of [statistical] analysis that give us more leeway in interpreting data,” commented Philippe Gabriel Steg, MD, professor of cardiology at the University of Paris.

“Everything in this trial points to substantial potential benefit. I’m not impressed by the P value that just missed significance. I think this is a very important advance,” said Dr. Steg, who had no involvement in the study, during a press conference at the congress.

Mitchel L. Zoler/MDedge News

“I agree. I look at the totality of evidence, and to me the PARAGON-HF results were positive in patients with an ejection fraction of 50%, which is not a normal level. The way I interpret the results is, the treatment works in patients with an ejection fraction that is ‘lowish,’ but not at the conventional level of reduced ejection fraction,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School, who also had no involvement with PARAGON-HF.

Stuart J. Connolly, MD, designated discussant for the report at the congress and professor of medicine at McMaster University, Hamilton, Ont., struck similar notes during his discussion of the report, and called the subgroup analysis by baseline ejection fraction “compelling,” and supported by several secondary findings of the study, the biological plausibility of a link between ejection fraction and treatment response, and by suggestions of a similar effect caused by related drugs in prior studies.

The argument in favor of sacubitril/valsartan’s efficacy in a subgroup of PARAGON-HF patients was also taken up by Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas. “I think it’s legitimate to say that there are HFpEF subgroups that might benefit” from sacubitril/valsartan, such as women. “I think it’s appropriate in this disease to look at subgroups because we have to find something that works for these patients,” she added in a video interview.

But Dr. Jessup also urged caution in interpreting the link between modestly reduced ejection fraction and response to sacubitril/valsartan in HFpEF patients because ejection fraction measurements by echocardiography, as done in the trial, are notoriously unreliable. “We need more precise markers of who responds to this drug and who does not,” she said.

PARAGON-HF randomized 4,796 patients at 848 sites in 43 countries who were aged at least 50 years, had signs and symptoms of heart failure with a left ventricular ejection fraction of at least 45%, had evidence on echocardiography of either left atrial enlargement or left ventricular hypertrophy, and had an elevated blood level of natriuretic peptides.

The study’s primary endpoint was the composite rate of total (both first and recurrent) hospitalizations for heart failure and cardiovascular death. That outcome occurred at a rate of 12.8 events/100 patient-years in patients treated with sacubitril/valsartan and a rate of 14.6 events/100 patient-years in control patients treated with the angiotensin receptor blocking drug valsartan alone. Those results yielded a relative risk reduction by sacubitril/valsartan of 13% with a P value of .059, just missing statistical significance. Concurrently with Dr. Solomon’s report the results appeared in an article online and then subsequently in print (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The primary endpoint was driven primarily by a 15% relative risk reduction in hospitalizations for heart failure; the two treatment arms showed nearly identical rates of cardiovascular disease death.

Notable secondary findings that reached statistical significance included a 16% relative decrease in total heart failure hospitalizations, cardiovascular deaths, and urgent heart failure visits with sacubitril/valsartan treatment, as well as a 16% reduction in all investigator-reported events. Other significant benefits linked with sacubitril/valsartan treatment were a 45% relative improvement in functional class, a 30% relative improvement in patients achieving a meaningful increase in a quality of life measure, and a halving of the incidence of worsening renal function with sacubitril/valsartan.

The safety profile of sacubitril/valsartan in the study matched previous reports on the drug in patients with heart failure with reduced ejection fraction, an approved indication since 2015.

The key subgroup analysis detailed by Dr. Solomon was the incidence of the primary endpoint by baseline ejection fraction. Among the 2,495 patients (52% of the study population) with a left ventricular ejection fraction of 57% or less when they entered the study, treatment with sacubitril/valsartan cut the primary endpoint incidence by 22%, compared with valsartan alone, a statistically significant difference. Among patients with a baseline ejection fraction of 58% or greater, treatment with sacubitril/valsartan had no effect on the primary endpoint, compared with control patients. Dr. Solomon also reported a statistically significant 22% relative improvement in the primary endpoint among the 2,479 women in the study (52% of the total study cohort) while the drug had no discernible impact among men, but he did not highlight any immediate implication of this finding.

Despite how suggestive the finding related to ejection fraction may be for practice, a major impediment to prescribing sacubitril/valsartan to HFpEF patients may come from pharmacy managers, suggested Douglas L. Mann, MD, a heart failure specialist and professor of medicine at Washington University, St. Louis.

“The study did not hit its primary endpoint, so pharmacy managers will face no moral issue by withholding the drug” from HFpEF patients, Dr. Mann said in an interview. Because sacubitril/valsartan is substantially costlier than other renin-angiotensin system inhibitor drugs, which are mostly generic, patients may often find it difficult to pay for sacubitril/valsartan themselves if it receives no insurance coverage.

“It’s heartbreaking that the endpoint missed for a disease with no proven treatment. The study may have narrowly missed, but it still missed, and a lot of us had hoped it would be positive. It’s a slippery slope” when investigators try to qualify a trial result that failed to meet the study’s prespecified definition of a statistically significant effect. “The primary endpoint is the primary endpoint, and we should not overinterpret the data,” Dr. Mann warned.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). Dr. Solomon has been a consultant to and has received research funding from Novartis and from several other companies. Dr. Steg has received personal fees from Novartis and has received personal fees and research funding from several other companies. Dr. Bhatt has been a consultant to and received research funding from several companies but has had no recent relationship with Novartis. Dr. Connolly and Dr. Jessup had no disclosures. Dr. Mann has been a consultant to Novartis, as well as Bristol-Myers Squibb, LivaNova, and Tenaya Therapeutics.

mzoler@mdedge.com

Background: Current AFib management guidelines recommend ischemic stroke risk stratification with CHA₂DS₂-VASc score; however, emerging studies have highlighted limitations of this score.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Current AFib management guidelines recommend ischemic stroke risk stratification with CHA₂DS₂-VASc score; however, emerging studies have highlighted limitations of this score.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Current AFib management guidelines recommend ischemic stroke risk stratification with CHA₂DS₂-VASc score; however, emerging studies have highlighted limitations of this score.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.