Pulmonology

Greater adherence to the Dietary Approaches to Stop Hypertension (DASH) diet was associated with a significantly reduced risk of chronic obstructive pulmonary disease (COPD) and improved lung function, based on data from more than 28,000 individuals in the United States.

Diet is a modifiable risk factor for COPD and other chronic diseases, but the effects of specific diet models such as the DASH diet and Mediterranean diet on COPD in particular has not been well studied, Jingli Wen, MD, of Nanjing Medical University, Jiangsu, China, and colleagues wrote.

In a study published in Frontiers in Nutrition, the researchers reviewed data from 28,605 adult participants in the National Health and Nutrition Examination Survey from 1999 to 2018.

The study population included 2,488 individuals with COPD participants and 25,607 individuals without COPD; the mean ages of the COPD and non-COPD groups were 60.2 years and 56.9 years, and the proportion of women was 63.7% and 51.4%, respectively. The primary outcome was the prevalence of COPD, defined as self-reports of a diagnosis of chronic bronchitis or emphysema. DASH diet scores were based on consumption of nine target nutrients: saturated fat, total fat, protein, cholesterol, fiber, magnesium, calcium, potassium, and sodium. Scores for compliance with the Mediterranean diet were based on intake of eight food categories: fruits, vegetables, legumes, fish, red meat, dairy products, alcohol, and olive oil.

Overall, a higher score for adherence to the DASH diet was significantly associated with a lower COPD risk (odds ratio, 0.83; P = .021). This association remained significant in subgroups of younger adults (OR, 0.74), men (OR, 0.73), and smokers (OR, 0.82).

By contrast, adherence to the Mediterranean diet was not significantly associated with COPD prevalence (OR, 1.03; P = .697).

The researchers also found a correlation between DASH diet adherence and improved lung function, especially among individuals without COPD. The risk of FEV₁: forced vital capacity decrease, as well as dyspnea, cough, and expectoration, were negatively associated with greater adherence to the DASH diet, but greater adherence to the Mediterranean diet was only negatively associated with cough risk.

The relationship between the DASH diet and reduced COPD risk persisted after adjusting for occupational exposure and excluding participants with cardiovascular disease, cancer, or diabetes.

The current study is the first known to focus on the association between DASH diet and the risk of COPD among adults in the United States, the researchers wrote. The lack of effect of the Mediterranean diet on COPD, in contrast to some studies in other countries, “suggests that regional differences in diet may affect the role of diet in the development of COPD.”

The study findings were limited by several factors including the cross-sectional design that prevented conclusions of causality, the researchers noted. Other limitations included the lack of data of the impact of poor living habits, such as smoking, on food decisions, the use of short-term 24-hour dietary recall, and the reliance of self-reports for a diagnosis of COPD.

However, the results support the role of diet in COPD pathogenesis and expand the knowledge of relationships between the DASH diet and major chronic diseases, the researchers said. More prospective studies and clinical intervention studies are needed, but the findings should encourage clinicians to consider the potential role of a healthy diet in promoting lung health.

The study was supported by the Department of Health, Jiangsu Province, China. The researchers had no financial conflicts to disclose.

Greater adherence to the Dietary Approaches to Stop Hypertension (DASH) diet was associated with a significantly reduced risk of chronic obstructive pulmonary disease (COPD) and improved lung function, based on data from more than 28,000 individuals in the United States.

Diet is a modifiable risk factor for COPD and other chronic diseases, but the effects of specific diet models such as the DASH diet and Mediterranean diet on COPD in particular has not been well studied, Jingli Wen, MD, of Nanjing Medical University, Jiangsu, China, and colleagues wrote.

In a study published in Frontiers in Nutrition, the researchers reviewed data from 28,605 adult participants in the National Health and Nutrition Examination Survey from 1999 to 2018.

The study population included 2,488 individuals with COPD participants and 25,607 individuals without COPD; the mean ages of the COPD and non-COPD groups were 60.2 years and 56.9 years, and the proportion of women was 63.7% and 51.4%, respectively. The primary outcome was the prevalence of COPD, defined as self-reports of a diagnosis of chronic bronchitis or emphysema. DASH diet scores were based on consumption of nine target nutrients: saturated fat, total fat, protein, cholesterol, fiber, magnesium, calcium, potassium, and sodium. Scores for compliance with the Mediterranean diet were based on intake of eight food categories: fruits, vegetables, legumes, fish, red meat, dairy products, alcohol, and olive oil.

Overall, a higher score for adherence to the DASH diet was significantly associated with a lower COPD risk (odds ratio, 0.83; P = .021). This association remained significant in subgroups of younger adults (OR, 0.74), men (OR, 0.73), and smokers (OR, 0.82).

By contrast, adherence to the Mediterranean diet was not significantly associated with COPD prevalence (OR, 1.03; P = .697).

The researchers also found a correlation between DASH diet adherence and improved lung function, especially among individuals without COPD. The risk of FEV₁: forced vital capacity decrease, as well as dyspnea, cough, and expectoration, were negatively associated with greater adherence to the DASH diet, but greater adherence to the Mediterranean diet was only negatively associated with cough risk.

The relationship between the DASH diet and reduced COPD risk persisted after adjusting for occupational exposure and excluding participants with cardiovascular disease, cancer, or diabetes.

The current study is the first known to focus on the association between DASH diet and the risk of COPD among adults in the United States, the researchers wrote. The lack of effect of the Mediterranean diet on COPD, in contrast to some studies in other countries, “suggests that regional differences in diet may affect the role of diet in the development of COPD.”

The study findings were limited by several factors including the cross-sectional design that prevented conclusions of causality, the researchers noted. Other limitations included the lack of data of the impact of poor living habits, such as smoking, on food decisions, the use of short-term 24-hour dietary recall, and the reliance of self-reports for a diagnosis of COPD.

However, the results support the role of diet in COPD pathogenesis and expand the knowledge of relationships between the DASH diet and major chronic diseases, the researchers said. More prospective studies and clinical intervention studies are needed, but the findings should encourage clinicians to consider the potential role of a healthy diet in promoting lung health.

The study was supported by the Department of Health, Jiangsu Province, China. The researchers had no financial conflicts to disclose.

Greater adherence to the Dietary Approaches to Stop Hypertension (DASH) diet was associated with a significantly reduced risk of chronic obstructive pulmonary disease (COPD) and improved lung function, based on data from more than 28,000 individuals in the United States.

Diet is a modifiable risk factor for COPD and other chronic diseases, but the effects of specific diet models such as the DASH diet and Mediterranean diet on COPD in particular has not been well studied, Jingli Wen, MD, of Nanjing Medical University, Jiangsu, China, and colleagues wrote.

In a study published in Frontiers in Nutrition, the researchers reviewed data from 28,605 adult participants in the National Health and Nutrition Examination Survey from 1999 to 2018.

The study population included 2,488 individuals with COPD participants and 25,607 individuals without COPD; the mean ages of the COPD and non-COPD groups were 60.2 years and 56.9 years, and the proportion of women was 63.7% and 51.4%, respectively. The primary outcome was the prevalence of COPD, defined as self-reports of a diagnosis of chronic bronchitis or emphysema. DASH diet scores were based on consumption of nine target nutrients: saturated fat, total fat, protein, cholesterol, fiber, magnesium, calcium, potassium, and sodium. Scores for compliance with the Mediterranean diet were based on intake of eight food categories: fruits, vegetables, legumes, fish, red meat, dairy products, alcohol, and olive oil.

Overall, a higher score for adherence to the DASH diet was significantly associated with a lower COPD risk (odds ratio, 0.83; P = .021). This association remained significant in subgroups of younger adults (OR, 0.74), men (OR, 0.73), and smokers (OR, 0.82).

By contrast, adherence to the Mediterranean diet was not significantly associated with COPD prevalence (OR, 1.03; P = .697).

The researchers also found a correlation between DASH diet adherence and improved lung function, especially among individuals without COPD. The risk of FEV₁: forced vital capacity decrease, as well as dyspnea, cough, and expectoration, were negatively associated with greater adherence to the DASH diet, but greater adherence to the Mediterranean diet was only negatively associated with cough risk.

The relationship between the DASH diet and reduced COPD risk persisted after adjusting for occupational exposure and excluding participants with cardiovascular disease, cancer, or diabetes.

The current study is the first known to focus on the association between DASH diet and the risk of COPD among adults in the United States, the researchers wrote. The lack of effect of the Mediterranean diet on COPD, in contrast to some studies in other countries, “suggests that regional differences in diet may affect the role of diet in the development of COPD.”

The study findings were limited by several factors including the cross-sectional design that prevented conclusions of causality, the researchers noted. Other limitations included the lack of data of the impact of poor living habits, such as smoking, on food decisions, the use of short-term 24-hour dietary recall, and the reliance of self-reports for a diagnosis of COPD.

However, the results support the role of diet in COPD pathogenesis and expand the knowledge of relationships between the DASH diet and major chronic diseases, the researchers said. More prospective studies and clinical intervention studies are needed, but the findings should encourage clinicians to consider the potential role of a healthy diet in promoting lung health.

The study was supported by the Department of Health, Jiangsu Province, China. The researchers had no financial conflicts to disclose.

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.

Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.

Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.

In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.

“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.

Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.

The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.

The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.

The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.

However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.

“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

As a lifeguard during college and then a physician assistant in emergency medicine for almost 3 decades, people often ask how I deal with emergency situations. I tell them the emotions turn off; skills and training take over. That is exactly what happened one day while I was surfing.

There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.

In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.

I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.

I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.

Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.

The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.

At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.

The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”

The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.

Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.

By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.

We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.

The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.

For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!

While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”

A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.

The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.

Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered. 

When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”

He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.

I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”

Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.

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

As a lifeguard during college and then a physician assistant in emergency medicine for almost 3 decades, people often ask how I deal with emergency situations. I tell them the emotions turn off; skills and training take over. That is exactly what happened one day while I was surfing.

There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.

In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.

I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.

I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.

Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.

The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.

At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.

The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”

The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.

Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.

By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.

We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.

The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.

For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!

While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”

A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.

The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.

Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered. 

When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”

He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.

I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”

Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.

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

As a lifeguard during college and then a physician assistant in emergency medicine for almost 3 decades, people often ask how I deal with emergency situations. I tell them the emotions turn off; skills and training take over. That is exactly what happened one day while I was surfing.

There’s a famous surf spot called Old Man’s on San Onofre beach in north San Diego County. It has nice, gentle waves that people say are similar to Waikiki in Hawaii. Since the waves are so forgiving, a lot of older people surf there. I taught my boys and some friends how to surf there. Everyone enjoys the water. It’s just a really fun vibe.

In September of 2008, I was at Old Man’s surfing with friends. After a while, I told them I was going to catch the next wave in. When I rode the wave to the beach, I saw an older guy waving his arms above his head, trying to get the lifeguard’s attention. His friend was lying on the sand at the water’s edge, unconscious. The lifeguards were about 200 yards away in their truck. Since it was off-season, they weren’t in the nearby towers.

I threw my board down on the sand and ran over. The guy was blue in the face and had some secretions around his mouth. He wasn’t breathing and had no pulse. I told his friend to get the lifeguards.

I gave two rescue breaths, and then started CPR. The waves were still lapping against his feet. I could sense people gathering around, so I said, “Okay, we’re going to be hooking him up to electricity, let’s get him out of the water.” I didn’t want him in contact with the water that could potentially transmit that electricity to anyone else.

Many hands reached in and we dragged him up to dry sand. When we pulled down his wetsuit, I saw an old midline sternotomy incision on his chest and I thought: “Oh man, he’s got a cardiac history.” I said, “I need a towel,” and suddenly there was a towel in my hand. I dried him off and continued doing CPR.

The lifeguard truck pulled up and in my peripheral vision I saw two lifeguards running over with their first aid kit. While doing compressions, I yelled over my shoulder: “Bring your AED! Get your oxygen!” They ran back to the truck.

At that point, a young woman came up and said: “I’m a nuclear medicine tech. What can I do?” I asked her to help me keep his airway open. I positioned her at his head, and she did a chin lift.

The two lifeguards came running back. One was very experienced, and he started getting the AED ready and putting the pads on. The other lifeguard was younger. He was nervous and shaking, trying to figure out how to turn on the oxygen tank. I told him: “Buddy, you better figure that out real fast.”

The AED said there was a shockable rhythm so it delivered a shock. I started compressions again. The younger lifeguard finally figured out how to turn on the oxygen tank. Now we had oxygen, a bag valve mask, and an AED. We let our training take over and quickly melded together as an efficient team.

Two minutes later the AED analyzed the rhythm and administered another shock. More compressions. Then another shock and compressions. I had so much adrenaline going through my body that I wasn’t even getting tired.

By then I had been doing compressions for a good 10 minutes. Finally, I asked: “Hey, when are the paramedics going to get here?” And the lifeguard said: “They’re on their way.” But we were all the way down on a very remote section of beach.

We did CPR on him for what seemed like eternity, probably only 15-20 minutes. Sometimes he would get a pulse back and pink up, and we could stop and get a break. But then I would see him become cyanotic. His pulse would become thready, so I would start again.

The paramedics finally arrived and loaded him into the ambulance. He was still blue in the face, and I honestly thought he would probably not survive. I said a quick prayer for him as they drove off.

For the next week, I wondered what happened to him. The next time I was at the beach, I approached some older guys and said: “Hey, I was doing CPR on a guy here last week. Do you know what happened to him?” They gave me a thumbs up sign and said: “He’s doing great!” I was amazed!

While at the beach, I saw the nuclear med tech who helped with the airway and oxygen. She told me she’d called her hospital after the incident and asked if they had received a full arrest from the beach. They said: “Yes, he was sitting up, awake and talking when he came through the door.”

A few weeks later, the local paper called and wanted to do an interview and get some photos on the beach. We set up a time to meet, and I told the reporter that if he ever found out who the guy was, I would love to meet him. I had two reasons: First, because I had done mouth-to-mouth on him and I wanted to make sure he didn’t have any communicable diseases. Second, and this is a little weirder, I wanted to find out if he had an out-of-body experience. They fascinate me.

The reporter called back a few minutes later and said: “You’ll never believe this – while I was talking to you, my phone beeped with another call. The person left a message, and it was the guy. He wants to meet you.” I was amazed at the coincidence that he would call at exactly the same time.

Later that day, we all met at the beach. I gave him a big hug and told him he looked a lot better than the last time I saw him. He now had a pacemaker/defibrillator. I found out he was married and had three teenage boys (who still have a father). He told me on the day of the incident he developed chest pain, weakness, and shortness of breath while surfing, so he came in and sat down at the water’s edge to catch his breath. That was the last thing he remembered. 

When I told him I did mouth-to-mouth on him, he laughed and reassured me that he didn’t have any contagious diseases. Then I asked him about an out-of-body experience, like hovering above his body and watching the CPR. “Did you see us doing that?” I asked. He said: “No, nothing but black. The next thing I remember is waking up in the back of the ambulance, and the paramedic asked me, ‘how does it feel to come back from the dead?’ ” He answered: “I think I have to throw up.”

He was cleared to surf 6 weeks later, and I thought it would be fun to surf with him. But when he started paddling out, he said his defibrillator went off, so he has now retired to golf.

I’ve been a PA in the emergency room for 28 years. I’ve done CPR for so long it’s instinctive for me. It really saves lives, especially with the AED. When people say: “You saved his life,” I say: “No, I didn’t. I just kept him alive and let the AED do its job.”

Ms. Westbrook-May is an emergency medicine physician assistant in Newport Beach, Calif.

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

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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