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AHA reviews impact of aggressive LDL lowering on the brain
“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.
The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.
The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.
They reached four main conclusions:
- First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
- Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
- Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
- Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.
The research had no commercial funding. A list of disclosures for the writing group is available with the original article.
A version of this article appeared on Medscape.com.
“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.
The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.
The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.
They reached four main conclusions:
- First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
- Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
- Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
- Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.
The research had no commercial funding. A list of disclosures for the writing group is available with the original article.
A version of this article appeared on Medscape.com.
“The brain is the body’s most cholesterol-rich organ, and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes,” the writing group, led by Larry Goldstein, MD, chair, department of neurology, University of Kentucky, Lexington, points out.
The 39-page AHA scientific statement, titled “Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke,” was published online in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
The objective was to evaluate contemporary evidence that either supports or refutes the conclusion that aggressive LDL-C lowering or lipid lowering exerts toxic effects on the brain, leading to cognitive impairment or dementia or hemorrhagic stroke.
The eight-member writing group used literature reviews, references to published clinical and epidemiology studies, clinical and public health guidelines, authoritative statements, and expert opinion to summarize the latest evidence and identify gaps in current knowledge.
They reached four main conclusions:
- First, the available data “consistently” show that LDL-C lowering reduces the risk of atherosclerotic cardiovascular disease-related events in high-risk groups.
- Second, although some older retrospective, case-control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the “preponderance” of observational studies and data from randomized trials do not support this conclusion, at least among trials with median follow-up of up to 6 years. The group says additional studies are needed to ensure cognitive safety over longer periods of time. For now, contemporary guidelines recommending the risk-stratified attainment of lipid-lowering goals are “reasonable,” they conclude.
- Third, the risk for hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is “small and consistently nonsignificant.” They found no evidence that PCSK9 inhibitors or ezetimibe (Zetia) increases bleeding risk. Further, there is “no indication” that patients or populations with lifelong low LDL-C have enhanced vulnerability to hemorrhagic stroke, and there is “little evidence” that achieving very low levels of LDL-C increases that risk. What is clear, the writing group says, is that lower LDL-C levels correlate with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke. “Concern about hemorrhagic stroke risk should not deter a clinician from treating LDL-C to guideline-recommended risk-stratified targets,” the writing group says.
- Fourth, the group notes that data reflecting the risk of hemorrhagic stroke with statin therapy among patients with a history of hemorrhagic stroke are not robust. PCSK9 inhibitors have not been adequately tested in patients with prior intracerebral hemorrhage. Lipid lowering in these populations requires more focused study.
The research had no commercial funding. A list of disclosures for the writing group is available with the original article.
A version of this article appeared on Medscape.com.
FROM ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY
Fish oil labels make health claims, despite lack of data
Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘Vague statements’
To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.
The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.
QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.
An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”
By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”
Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”
Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.
The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).
Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.
“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”
Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
Enthusiasm vs. evidence
“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.
“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.
The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.
A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.
Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.
Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”
No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.
A version of this article first appeared on Medscape.com.
Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘Vague statements’
To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.
The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.
QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.
An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”
By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”
Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”
Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.
The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).
Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.
“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”
Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
Enthusiasm vs. evidence
“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.
“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.
The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.
A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.
Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.
Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”
No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.
A version of this article first appeared on Medscape.com.
Overall, about 74% of more than 2,800 supplements that were examined had labels that made at least one health claim, and only 19% included a U.S. Food and Drug Administration–reviewed qualified health claim (QHC).
The authors say “additional regulation” of the claims may be needed to prevent consumer misinformation. Notably, 20% of adults older than 60 years take fish oil supplements for heart health despite the fact that multiple randomized trials show no cardiovascular benefit.
“Based on what I’ve seen personally in the grocery store and pharmacy, I was not surprised to find such high rates of health claims on fish oil supplements,” lead author Joanna Assadourian, BSA, of UT Southwestern Medical Center, Dallas, said in an interview. “What was surprising, though, was just how broad the types of claims being made were – from heart and brain health to joint health, eye health, and immune function.”
Principal author Ann Marie Navar, MD, PhD, also of UT Southwestern, added, “As a preventive cardiologist, I tell my patients that if they are taking fish oil to try to avoid heart disease, then they can stop taking it because it’s not helping them. Their money would be better spent on something that will actually prevent a heart attack, like more fresh vegetables, their blood pressure or cholesterol medication, or a gym membership.”
The study was published online in JAMA Cardiology.
‘Vague statements’
To evaluate health claims made on fish oil supplement labels in the United States and to examine doses of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in commonly available formulations, the investigators analyzed labels on supplements obtained from the National Institutes of Health Dietary Supplement Label Database.
The main outcomes were the frequency and types of health claims made on the labels, including use of an FDA-reviewed QHC versus a structure/function claim and the organ system referenced, as well as the total daily doses in combined EPA and DHA supplements from leading manufacturers and retailers.
QHCs are statements regarding a supplement’s or food’s potential to treatment or prevent disease. Such claims undergo evidence review by the FDA and include qualifying language that reflects lack of scientific consensus or uncertainty.
An example: “Consuming EPA and DHA combined may reduce the risk of CHD [coronary heart disease] by lowering blood pressure. However, FDA has concluded that the evidence is inconsistent and inconclusive. One serving of [name of the food or dietary supplement] provides [ ] gram(s) of EPA and DHA.”
By contrast, structure/function claims “describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans” but do not state that the supplement prevents, treats, or cures any disease. Such a claim “does not require any mitigating language regarding potential scientific uncertainty of the statement.”
Structure/function claims commonly state that the supplement “maintains,” “supports,” or “promotes” the function of certain organs. Examples are “promotes heart health” and “supports heart, mind and mood.”
Among 2,819 fish oil supplements, 2,082 (73.9%) made at least one health claim. Of these, only 399 (19.2%) used a QHC; the rest made only structure/function claims. In addition to heart-health claims, many fish oil supplements also have labels that make claims implying benefit to other organ systems, such as brain/mental health, joint health, and eye health – despite a lack of data from randomized clinical trials that support benefit.
The dose analysis of 255 fish oil supplements across 16 major brands found “substantial variability” in the daily dose of EPA (median interquartile range, 340 [135-647] mg/d), DHA (median IQR, 270 [140-500] mg/d), and total EPA+DHA (median IQR, 600 [300-1,100] mg/d).
Twenty-four (9.4%) of the supplements contained a daily dose of 2 g or more EPA+DHA.
“Significant heterogeneity exists in the daily dose of EPA+DHA in available supplements, leading to potential variability in safety and efficacy between supplements,” the authors conclude. “Increasing regulation of dietary supplement labeling may be needed to prevent consumer misinformation.”
Dr. Navar added, “We now need to understand what consumers are taking away from vague statements like ‘promotes brain health’ or ‘supports joint function’ – and test what language we can use to accurately describe the state of the science around fish oil and heart health.”
Enthusiasm vs. evidence
“I agree with these concerns and think that the enthusiasm for these supplements outpaces the evidence from rigorous randomized clinical trials,” JoAnn E. Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, Boston, said in an interview. “Results of the observational studies have tended to be much more favorable than the randomized clinical trials.
“The labels can be very misleading to the general public,” she noted. “People are confronted with a dizzying array of dietary supplements, many of which include structure/function claims that require minimal, if any, evidence of efficacy. Clinicians should emphasize with patients that a dietary supplement will never be a substitute for a heart-healthy diet and that many supplements are not helpful for people who already follow a healthy diet,” she said.
The VITAL trial, for which Dr. Manson was principal investigator, showed that supplementation with n-3 fatty acids did not lead to a lower incidence of major cardiovascular events or cancer, compared with placebo.
A subgroup analysis showed that 1 g/d conferred a 20% reduction in major events only for participants who ate less than 1.5 servings of fish per week, Dr. Manson said.
Regarding supplement labels, clinicians should recommend that patients look for a U.S. Pharmacopoeia seal or a seal from the National Science Foundation or ConsumerLab, she advised. These seals ensure that the product has been audited for purity and consistency of content and that the dose in the capsule is consistent with what is on the label.
Dr. Manson also would like to see labels explain that most of the products have not been reviewed by the FDA. “Many members of the general public are misled by these labels into thinking that they’re going to receive health benefits. They’re spending a lot of money on supplements that likely provide no benefit and may even be associated with increased risks.”
No funding for the study was reported. Dr. Navar has received grants from BMS, Esperion, Amgen, and Janssen and personal fees from AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Esperion, Janssen, Eli Lilly, Merck, Silence Therapeutics, Novo Nordisk, Novartis, New Amsterdam, and Pfizer outside the submitted work and serves as deputy editor for equity, diversity, and inclusion at JAMA Cardiology.
A version of this article first appeared on Medscape.com.
FROM JAMA CARDIOLOGY
Should clinic BP be routinely measured lying down?
new preliminary research suggests.
An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.
“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.
Mr. Giao presented the findings at the Hypertension Scientific Sessions.
Take seated and supine BP in clinic?
Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.
To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.
As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.
The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.
Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).
The results did not differ by antihypertensive medication use (P > .05).
For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.
“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.
“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
Busy clinical practice
In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”
She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”
The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.
However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.
“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.
The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new preliminary research suggests.
An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.
“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.
Mr. Giao presented the findings at the Hypertension Scientific Sessions.
Take seated and supine BP in clinic?
Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.
To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.
As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.
The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.
Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).
The results did not differ by antihypertensive medication use (P > .05).
For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.
“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.
“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
Busy clinical practice
In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”
She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”
The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.
However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.
“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.
The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new preliminary research suggests.
An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.
“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.
Mr. Giao presented the findings at the Hypertension Scientific Sessions.
Take seated and supine BP in clinic?
Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.
To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.
As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.
The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.
Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).
The results did not differ by antihypertensive medication use (P > .05).
For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.
“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.
“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
Busy clinical practice
In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”
She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”
The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.
However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.
“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.
The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION 2023
Sotatercept tied to disease modification in pulmonary arterial hypertension
MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.
The STELLAR trial: A milestone in PAH research
PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.
Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.
Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
Disease modification in PAH
In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”
“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.
“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
Unmasking hemodynamic impact
Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:
- A small increase in systemic blood pressure and systemic vascular resistance.
- No changes in systolic and diastolic volumes of the left ventricle (lv).
- A small but significant reduction in lv ejection fraction.
- A great reduction in the mean pulmonary artery pressure (mPAP).
- No change in cardiac output.
- An improvement in pulmonary artery compliance.
- A reduction in the right ventricle work and in right atrial pressure.
- An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.
“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
A new course in PAH treatment?
Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. ,” he told this news organization.
Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.
“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
Further insights into sotatercept
The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.
Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.
A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.
Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.
A version of this article first appeared on Medscape.com.
MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.
The STELLAR trial: A milestone in PAH research
PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.
Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.
Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
Disease modification in PAH
In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”
“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.
“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
Unmasking hemodynamic impact
Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:
- A small increase in systemic blood pressure and systemic vascular resistance.
- No changes in systolic and diastolic volumes of the left ventricle (lv).
- A small but significant reduction in lv ejection fraction.
- A great reduction in the mean pulmonary artery pressure (mPAP).
- No change in cardiac output.
- An improvement in pulmonary artery compliance.
- A reduction in the right ventricle work and in right atrial pressure.
- An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.
“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
A new course in PAH treatment?
Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. ,” he told this news organization.
Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.
“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
Further insights into sotatercept
The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.
Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.
A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.
Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.
A version of this article first appeared on Medscape.com.
MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.
The STELLAR trial: A milestone in PAH research
PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.
Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.
Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
Disease modification in PAH
In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”
“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.
“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
Unmasking hemodynamic impact
Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:
- A small increase in systemic blood pressure and systemic vascular resistance.
- No changes in systolic and diastolic volumes of the left ventricle (lv).
- A small but significant reduction in lv ejection fraction.
- A great reduction in the mean pulmonary artery pressure (mPAP).
- No change in cardiac output.
- An improvement in pulmonary artery compliance.
- A reduction in the right ventricle work and in right atrial pressure.
- An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.
“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
A new course in PAH treatment?
Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. ,” he told this news organization.
Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.
“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
Further insights into sotatercept
The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.
Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.
A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.
Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.
A version of this article first appeared on Medscape.com.
AT ERS 2023
Blood transfusions linked to intracerebral hemorrhage risk
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From JAMA
Lead exposure still a global health burden
TOPLINE:
Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.
METHODOLOGY:
- Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
- Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
- Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.
TAKEAWAY:
- Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
- The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
- These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
- The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.
IN PRACTICE:
Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.
STUDY DETAILS:
The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.
LIMITATIONS:
- Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
- Certain income projections and income losses are uncertain.
- Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.
DISCLOSURES:
The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.
METHODOLOGY:
- Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
- Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
- Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.
TAKEAWAY:
- Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
- The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
- These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
- The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.
IN PRACTICE:
Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.
STUDY DETAILS:
The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.
LIMITATIONS:
- Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
- Certain income projections and income losses are uncertain.
- Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.
DISCLOSURES:
The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
TOPLINE:
Globally, lead exposure is linked to more than 5.5 million adult cardiovascular deaths in 2019, as well as loss of 765 million intelligence quotient (IQ) points in children younger than 5 years, which cost U.S. $6 trillion in lost productivity, new research suggests.
METHODOLOGY:
- Global lead exposure has declined substantially since leaded gasoline was phased out, but several sources of lead remain, resulting in adverse health and economic effects, particularly in low- and middle-income countries (LMICs).
- Estimates of cardiovascular disease (CVD) deaths from lead exposure have been limited to effects of increased blood pressure, but studies show that lead exposure has cardiovascular impacts through mechanisms other than hypertension.
- Drawing from various sources and studies, researchers estimated global blood lead levels and the impact of lead exposure on CVD mortality in 2019 among adults aged 25 years or older, IQ loss in children younger than 5 years, and the related economic costs.
TAKEAWAY:
- Researchers estimated that there were 5,545,000 (95% confidence interval, 2,305,000-8,271,000) cardiovascular deaths in adults from lead exposure in 2019, with as many as 90.2% of these deaths in LMICs; however, this estimate may be incomplete because it does not include the effect of lead exposure on CVD mortality mediated through hypertension.
- The estimated global IQ loss in children younger than 5 years due to lead exposure was 765 million (95% CI, 443 million-1,098 million) IQ points in 2019, 95.3% of which occurred in LMICs.
- These estimates place lead exposure on a par with ambient particulate matter and household air pollution combined, and ahead of unsafe household drinking water, sanitation, and handwashing, as an environmental risk factor.
- The estimated global cost of lead exposure from CVD mortality and IQ loss combined is U.S. $6.0 trillion (range, $2.6 trillion-9.0 trillion) in 2019, equivalent to 6.9% of the 2019 global gross domestic product.
IN PRACTICE:
Given the magnitude of the estimated health effects of lead exposure, particularly in LMICs, “it is imperative that nationally representative periodic blood lead level measurements be institutionalized,” write the authors, adding that these measurements could be incorporated into existing household surveys.
STUDY DETAILS:
The study was conducted by Bjorn Larsen, PhD, environmental economist and consultant to the World Bank, and Ernesto Sánchez-Triana. It was published online in The Lancet Planetary Health.
LIMITATIONS:
- Global blood lead level estimates may be inaccurate, given that measurements are absent for many countries.
- Certain income projections and income losses are uncertain.
- Because the study does not capture the detrimental effects of lead exposure other than IQ loss and CVD mortality, the estimates of global costs are conservative.
DISCLOSURES:
The study received support from the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program. The authors have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Cold weather may challenge blood pressure control
A review of electronic health records of more than 60,000 U.S. adults being treated for hypertension found that on average, systolic BP rose by up to 1.7 mm Hg in the cold winter months, compared with the hot summer months.
On a population level, BP control rates decreased by up to 5% during the cold winter months, compared with control rates in the warm summer months.
“Some patients may benefit from increased pharmacological intervention to keep blood pressure controlled during the winter,” Robert Barrett, with the American Medical Association, Greenville, S.C., told this news organization.
“Individuals with hypertension or values near the range of hypertension may benefit from periodic blood pressure monitoring and improvements in physical activity and nutritional patterns during winter months to offset adverse effects from seasonal blood pressure changes,” Mr. Barrett added in a news release.
Mr. Barrett presented the study findings at the American Heart Association Hypertension Scientific Sessions 2023 in Boston.
Supportive data
Mr. Barrett explained that seasonal variation in BP has been previously documented, and as part of the evaluation for the AMA MAP Hypertension program, he and colleagues were interested in the effect of this variation on population control rates under standard metrics (visits with BP < 140/90 mm Hg).
They analyzed data from 60,676 men and women (mean age, 62 years) with hypertension from six health care organizations in the southeastern and midwestern United States that were participating in the quality improvement program.
During the roughly 5-year assessment period, none of the patients had changes in their antihypertensive medication, and all had at least one visit in each temperate season. The researchers estimated the seasonal effect on average systolic BP and BP control (defined as < 140/90 mm Hg).
Across a total of 453,787 visits, systolic BP during the winter averaged 0.47 mm Hg higher (95% confidence interval, 0.364-0.573) than the yearly average, with a significantly lower odds ratio for BP control (OR, 0.92; 95% CI, 0.91-0.94), the researchers report.
In contrast, average systolic BP was 0.92 mm Hg lower during the summer, with a higher likelihood of BP control (OR ,1.10; 95% CI, 1.07-1.12).
“Seasonal variation in blood pressure has a substantial effect on hypertension control, often defined as blood pressure < 140/90,” Barrett told this news organization.
“Patients with hypertension are less likely to have their blood pressure controlled during winter than summer months. If the blood pressure is very well controlled, for example to < 130/80, then seasonal variation will have little effect on control to < 140/90,” Mr. Barrett noted.
“However, if blood pressure is not well controlled, then patients near the 140/90 level could benefit from monitoring their blood pressure regularly, closer medical follow-up, and avoiding decreased physical activity and increased weight toward year end,” he added.
Wanpen Vongpatanasin, MD, clinical chair for the conference, said that it’s “well known that BP tends to lower during summer months and patients may be susceptible to dehydration and acute kidney injury when BP is too low, particularly when treated with certain medication such as diuretics.”
On the flip side, “cold weather predisposes to vasoconstriction as our blood vessel constrict to maintain core temperature and it could be challenging to manage BP. That’s why it is important for high BP patients to monitor home BP regularly,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center, Dallas.
The study had no commercial funding. Mr. Barrett and Dr. Vongpatanasin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
A review of electronic health records of more than 60,000 U.S. adults being treated for hypertension found that on average, systolic BP rose by up to 1.7 mm Hg in the cold winter months, compared with the hot summer months.
On a population level, BP control rates decreased by up to 5% during the cold winter months, compared with control rates in the warm summer months.
“Some patients may benefit from increased pharmacological intervention to keep blood pressure controlled during the winter,” Robert Barrett, with the American Medical Association, Greenville, S.C., told this news organization.
“Individuals with hypertension or values near the range of hypertension may benefit from periodic blood pressure monitoring and improvements in physical activity and nutritional patterns during winter months to offset adverse effects from seasonal blood pressure changes,” Mr. Barrett added in a news release.
Mr. Barrett presented the study findings at the American Heart Association Hypertension Scientific Sessions 2023 in Boston.
Supportive data
Mr. Barrett explained that seasonal variation in BP has been previously documented, and as part of the evaluation for the AMA MAP Hypertension program, he and colleagues were interested in the effect of this variation on population control rates under standard metrics (visits with BP < 140/90 mm Hg).
They analyzed data from 60,676 men and women (mean age, 62 years) with hypertension from six health care organizations in the southeastern and midwestern United States that were participating in the quality improvement program.
During the roughly 5-year assessment period, none of the patients had changes in their antihypertensive medication, and all had at least one visit in each temperate season. The researchers estimated the seasonal effect on average systolic BP and BP control (defined as < 140/90 mm Hg).
Across a total of 453,787 visits, systolic BP during the winter averaged 0.47 mm Hg higher (95% confidence interval, 0.364-0.573) than the yearly average, with a significantly lower odds ratio for BP control (OR, 0.92; 95% CI, 0.91-0.94), the researchers report.
In contrast, average systolic BP was 0.92 mm Hg lower during the summer, with a higher likelihood of BP control (OR ,1.10; 95% CI, 1.07-1.12).
“Seasonal variation in blood pressure has a substantial effect on hypertension control, often defined as blood pressure < 140/90,” Barrett told this news organization.
“Patients with hypertension are less likely to have their blood pressure controlled during winter than summer months. If the blood pressure is very well controlled, for example to < 130/80, then seasonal variation will have little effect on control to < 140/90,” Mr. Barrett noted.
“However, if blood pressure is not well controlled, then patients near the 140/90 level could benefit from monitoring their blood pressure regularly, closer medical follow-up, and avoiding decreased physical activity and increased weight toward year end,” he added.
Wanpen Vongpatanasin, MD, clinical chair for the conference, said that it’s “well known that BP tends to lower during summer months and patients may be susceptible to dehydration and acute kidney injury when BP is too low, particularly when treated with certain medication such as diuretics.”
On the flip side, “cold weather predisposes to vasoconstriction as our blood vessel constrict to maintain core temperature and it could be challenging to manage BP. That’s why it is important for high BP patients to monitor home BP regularly,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center, Dallas.
The study had no commercial funding. Mr. Barrett and Dr. Vongpatanasin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
A review of electronic health records of more than 60,000 U.S. adults being treated for hypertension found that on average, systolic BP rose by up to 1.7 mm Hg in the cold winter months, compared with the hot summer months.
On a population level, BP control rates decreased by up to 5% during the cold winter months, compared with control rates in the warm summer months.
“Some patients may benefit from increased pharmacological intervention to keep blood pressure controlled during the winter,” Robert Barrett, with the American Medical Association, Greenville, S.C., told this news organization.
“Individuals with hypertension or values near the range of hypertension may benefit from periodic blood pressure monitoring and improvements in physical activity and nutritional patterns during winter months to offset adverse effects from seasonal blood pressure changes,” Mr. Barrett added in a news release.
Mr. Barrett presented the study findings at the American Heart Association Hypertension Scientific Sessions 2023 in Boston.
Supportive data
Mr. Barrett explained that seasonal variation in BP has been previously documented, and as part of the evaluation for the AMA MAP Hypertension program, he and colleagues were interested in the effect of this variation on population control rates under standard metrics (visits with BP < 140/90 mm Hg).
They analyzed data from 60,676 men and women (mean age, 62 years) with hypertension from six health care organizations in the southeastern and midwestern United States that were participating in the quality improvement program.
During the roughly 5-year assessment period, none of the patients had changes in their antihypertensive medication, and all had at least one visit in each temperate season. The researchers estimated the seasonal effect on average systolic BP and BP control (defined as < 140/90 mm Hg).
Across a total of 453,787 visits, systolic BP during the winter averaged 0.47 mm Hg higher (95% confidence interval, 0.364-0.573) than the yearly average, with a significantly lower odds ratio for BP control (OR, 0.92; 95% CI, 0.91-0.94), the researchers report.
In contrast, average systolic BP was 0.92 mm Hg lower during the summer, with a higher likelihood of BP control (OR ,1.10; 95% CI, 1.07-1.12).
“Seasonal variation in blood pressure has a substantial effect on hypertension control, often defined as blood pressure < 140/90,” Barrett told this news organization.
“Patients with hypertension are less likely to have their blood pressure controlled during winter than summer months. If the blood pressure is very well controlled, for example to < 130/80, then seasonal variation will have little effect on control to < 140/90,” Mr. Barrett noted.
“However, if blood pressure is not well controlled, then patients near the 140/90 level could benefit from monitoring their blood pressure regularly, closer medical follow-up, and avoiding decreased physical activity and increased weight toward year end,” he added.
Wanpen Vongpatanasin, MD, clinical chair for the conference, said that it’s “well known that BP tends to lower during summer months and patients may be susceptible to dehydration and acute kidney injury when BP is too low, particularly when treated with certain medication such as diuretics.”
On the flip side, “cold weather predisposes to vasoconstriction as our blood vessel constrict to maintain core temperature and it could be challenging to manage BP. That’s why it is important for high BP patients to monitor home BP regularly,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center, Dallas.
The study had no commercial funding. Mr. Barrett and Dr. Vongpatanasin have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION 2023
Steady VKA therapy beats switch to NOAC in frail AFib patients: FRAIL-AF
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.
The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.
“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.
“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”
Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.
Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.
“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
Frailty a clinical syndrome
Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”
Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.
NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.
The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.
So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.
This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.
Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m2 or with valvular AFib were excluded.
Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.
A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.
Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.
After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.
Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.
Completely different patients
Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”
Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.
That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.
The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”
The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.
The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.
“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”
NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”
The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
‘New dawn’ for aldosterone as drug target in hypertension?
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.
Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.
“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”
Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
Aldosterone’s contribution ‘vastly underappreciated’
Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.
Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).
The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.
The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.
Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).
In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.
Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.
Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.
Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.
A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat.
No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.
The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”
A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
‘New dawn’ for therapies targeting aldosterone
The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”
“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.
The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION 2023
Is AFib ablation the fifth pillar in heart failure care? CASTLE-HTx
Recorded Aug. 28, 2023. This transcript has been edited for clarity.
John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.
Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.
Christian, why don’t you tell us the top-line results and what you found.
CASTLE-HTx key findings
Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.
Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.
Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?
Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.
If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.
I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.
Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?
Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.
If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
How can AFib ablation have such big, early effects?
Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?
Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.
The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.
Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?
Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.
It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.
We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.
Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?
Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.
We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.
I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
Rhythm control
Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?
Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.
It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.
Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.
I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.
Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?
Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.
Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.
If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.
Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?
Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.
Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.
Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.
A version of this article first appeared on Medscape.com.
Recorded Aug. 28, 2023. This transcript has been edited for clarity.
John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.
Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.
Christian, why don’t you tell us the top-line results and what you found.
CASTLE-HTx key findings
Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.
Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.
Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?
Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.
If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.
I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.
Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?
Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.
If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
How can AFib ablation have such big, early effects?
Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?
Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.
The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.
Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?
Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.
It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.
We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.
Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?
Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.
We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.
I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
Rhythm control
Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?
Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.
It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.
Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.
I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.
Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?
Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.
Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.
If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.
Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?
Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.
Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.
Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.
A version of this article first appeared on Medscape.com.
Recorded Aug. 28, 2023. This transcript has been edited for clarity.
John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.
Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.
Christian, why don’t you tell us the top-line results and what you found.
CASTLE-HTx key findings
Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.
Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.
Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?
Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.
If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.
I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.
Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?
Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.
If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
How can AFib ablation have such big, early effects?
Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?
Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.
The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.
Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?
Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.
It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.
We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.
Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?
Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.
We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.
I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
Rhythm control
Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?
Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.
It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.
Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.
I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.
Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?
Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.
Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.
If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.
Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?
Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.
Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.
Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.
A version of this article first appeared on Medscape.com.