Federal Practitioner

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

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

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

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

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

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

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

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

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

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

Much has changed in the 10 years since Medscape’s first survey on what physicians would do when faced with painful choices in patient care.

A new report, Ethics 2020: Life, Death, and Painful Dilemmas, shows that physicians’ value judgments have shifted in many respects, sometimes as a result of increased regulations and fears of litigation.
 

 End-of-life decisions

Several of the questions in the survey revolved around end-of-life decisions, and in some cases, the differences seen in just a decade were striking. One example concerned life support decisions in the context of a family’s choices.

Age also seemed to play a role in the 2020 answers to that question: Physicians younger than 45 were more likely (28%) to answer “yes” (that they would withdraw life support in that instance) than were those 45 and older (16%).

A critical care physician said, “If the family appears to have an underlying motivation that may not be in the patient’s best interest, I might be inclined to pursue a legal decision prior to withdrawing support.”

A cardiologist had a more pointed response to the question: “To me, that would be murder.”

Another example of how perspectives have changed over the past 10 years concerns whether physician-aided dying should be legal for terminally ill patients. The practice is now mandated by law in eight states and the District of Columbia, and it is mandated by court ruling in two additional states.

In 2010, 41% said “no.” That number dropped to 28% in 2020.

On legalization, a psychiatrist said, “Yes, when there is truly no hope and the quality of remaining life is too poor. We show more compassion to our sick animals than we do to our human population.”

Conversely, a neurologist answered, “No, I see younger physicians already becoming comfortable with the idea of deciding ASAP whether there is a reasonable chance of survival and then pressing for the right code status. This change would make things worse.”
 

Assisted death and incurable suffering

Far fewer physicians supported physician-assisted death for those who had years to live but faced incurable suffering: Thirty-seven percent said “yes,” 34% said “no,” and 29% said “it depends.”

However, support was significantly higher than it was just 2 years ago, in 2018, when only 27% supported the concept, the report authors noted.

“The shift reflects movements by many states to legalize assisted dying for the terminally ill,” Arthur Caplan, PhD, director of the division of medical ethics, New York University, said in the report. “Legalization has not been abused, so some doctors are more willing to press further beyond terminal illness as a trigger to suffering.”

Conversely, many more physicians (44% vs. 24% a decade ago) said they would provide life-sustaining therapy if the family requested it, even if the physician thought it was futile.

“Concerns over a malpractice lawsuit and potential negative patient/family online reviews are factors that play into this change,” the survey authors wrote.

Shared decision making also increased in the past decade.
 

Would you undertreat pain?

Primary care physicians fear the consequences of what they consider adequate pain management more than specialists do (24% vs. 17%), the survey authors noted.

Ten years ago, Medscape asked physicians whether they would undertreat a patient’s pain because of fear of repercussions or the patient’s becoming addicted: Eighty-four percent said “no,” and 6% said “yes.” The rest said “it depends.”

In 2020, the question was asked slightly differently: “Would you undertreat a patient’s pain for fear of addiction or Drug Enforcement Administration or medical board scrutiny?” This year, three times as many said “yes” (18%); 63% said “no.”

“Respondents this year talked about investigations and reprimands by medical boards, and how much they wanted to avoid that,” the survey authors wrote.
 

Should physicians be required to treat COVID-19 patients?

Some questions were new this year, including one on whether physicians should be required to treat COVID-19 patients. Fewer than half (47%) answered “yes,” 24% said “no,” and 29% answered “it depends.”

Doctors’ answers to this question differed slightly by gender: Fifty percent of men and 43% of women said “yes.” In their responses, many physicians said consideration should be given to risk factors, such as age, underlying conditions, risk of family members, and availability of personal protective equipment (PPE).

Another pandemic-related question asked whether physicians felt they should correct physicians who post misinformation about the pandemic on social media. Half (50%) said “yes,” 19% said “no,” and 31% said “it depends.”
 

Speaking out against the workplace

This year, many physicians have felt betrayed when they didn’t have adequate PPE during the pandemic.

Asked, “Is it right to speak out against your hospital or workplace when they don’t give you what you need?” 53% of physicians said “yes,” 8% said “no,” and 40% said “it depends.”

A cardiologist made the value judgment this way: “Speaking out just because you had an argument with your boss is inappropriate. Bringing to the public repeated failures to correct situations that have been brought through the proper channels is necessary to incite change.”
 

Random drug testing for physicians?

Another question in the survey asked whether physicians should be subjected to random drug testing for alcohol and drug abuse. About one-third (34%) said yes, 43% said no, and 23% said “it depends.” A study found that between 10% and 15% of physicians have abused a substance at some point in their careers.

The subject continues to hit a nerve in medicine.

A family physician wrote, “This should not be done unless a particular physician had a problem with drug or alcohol abuse and shows signs of impairment.”

An internist took a different view, saying, “Military service men and women, police, firefighters, airline pilots, and other professions that have responsibilities affecting people’s lives are subject to testing; why not physicians?”
 

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

There is a link between liver injury and a tendency toward excessive clotting in patients with COVID-19, and the organ’s own blood vessels could be responsible, new research shows.

Cells that line the liver’s blood vessels produce high levels of factor VIII, a coagulation factor, when they are exposed to interleukin-6, an inflammatory molecule associated with COVID-19.

These findings “center the liver in global coagulopathy of COVID-19 and define a mechanism for increased coagulation factor levels that may be treatment targets,” said investigator Matthew McConnell, MD, from the Yale University, New Haven, Conn.

The effect of IL-6 on the liver sinusoidal endothelial cells lining the liver blood vessels creates a prothrombotic environment that includes the release of factor VIII, said Dr. McConnell, who presented the results at the virtual annual meeting of the American Association for the Study of Liver Diseases.

These associations offer insights into why COVID-19 patients with underlying liver disease can experience “devastating complications” related to improper blood vessel function in the organ, he added.

For their study, Dr. McConnell and colleagues analyzed data on ALT and hypercoagulability from 68 adults treated at the Yale–New Haven Hospital. The liver and coagulation tests were administered within 5 days of each other.

The team set the ALT cutoff for liver injury at three times the upper limit of normal. Patients with two or more parameters indicating excessive clotting were considered to have a hypercoagulable profile, which Dr. McConnell called “a signature clinical finding of COVID-19 infection.”

Patients with high levels of ALT also experienced elevations in clotting-related factors, such as fibrinogen levels and the activity of factor VIII and factor II. Furthermore, liver injury was significantly associated with hypercoagulability (P < .05).

Because COVID-19 is linked to the proinflammatory IL-6, the investigators examined how this cytokine and its receptor affect human liver sinusoidal cells. Cells exposed to IL-6 and its receptor pumped out factor VIII at levels that were significantly higher than in unexposed cells (P < .01). Exposed cells also produced significantly more von Willebrand factor (P < .05), another prothrombotic molecule, and showed increased expression of genes that induce the expression of factor VIII.

“As we learn more about COVID-19, we find that it is as much a coagulatory as a respiratory disease,” said Tien Dong, MD, PhD, from the University of California, Los Angeles, who was not involved in the study.

These findings are in line with a lot of other COVID-19-related research that suggests a link between hepatocyte injury and clotting disorders, he added.

One important factor is existing liver disease, said Dr. Dong. “If you have COVID-19 on top of that, you’re probably at risk of developing acute liver injury from the infection itself.”

That said, it’s still a good idea to check liver function in patients with COVID-19 and no known liver disease, he advised. Staying on top of these measures will keep the odds of long-term problems “a lot lower.”

There is utility in the findings beyond COVID-19, said Dr. McConnell. They provide “insights into complications of critical illness, in general, in the liver blood vessels” of patients with underlying liver disease.

Dr. McConnell and Dr. Dong have disclosed no relevant financial relationships.

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

There is a link between liver injury and a tendency toward excessive clotting in patients with COVID-19, and the organ’s own blood vessels could be responsible, new research shows.

Cells that line the liver’s blood vessels produce high levels of factor VIII, a coagulation factor, when they are exposed to interleukin-6, an inflammatory molecule associated with COVID-19.

These findings “center the liver in global coagulopathy of COVID-19 and define a mechanism for increased coagulation factor levels that may be treatment targets,” said investigator Matthew McConnell, MD, from the Yale University, New Haven, Conn.

The effect of IL-6 on the liver sinusoidal endothelial cells lining the liver blood vessels creates a prothrombotic environment that includes the release of factor VIII, said Dr. McConnell, who presented the results at the virtual annual meeting of the American Association for the Study of Liver Diseases.

These associations offer insights into why COVID-19 patients with underlying liver disease can experience “devastating complications” related to improper blood vessel function in the organ, he added.

For their study, Dr. McConnell and colleagues analyzed data on ALT and hypercoagulability from 68 adults treated at the Yale–New Haven Hospital. The liver and coagulation tests were administered within 5 days of each other.

The team set the ALT cutoff for liver injury at three times the upper limit of normal. Patients with two or more parameters indicating excessive clotting were considered to have a hypercoagulable profile, which Dr. McConnell called “a signature clinical finding of COVID-19 infection.”

Patients with high levels of ALT also experienced elevations in clotting-related factors, such as fibrinogen levels and the activity of factor VIII and factor II. Furthermore, liver injury was significantly associated with hypercoagulability (P < .05).

Because COVID-19 is linked to the proinflammatory IL-6, the investigators examined how this cytokine and its receptor affect human liver sinusoidal cells. Cells exposed to IL-6 and its receptor pumped out factor VIII at levels that were significantly higher than in unexposed cells (P < .01). Exposed cells also produced significantly more von Willebrand factor (P < .05), another prothrombotic molecule, and showed increased expression of genes that induce the expression of factor VIII.

“As we learn more about COVID-19, we find that it is as much a coagulatory as a respiratory disease,” said Tien Dong, MD, PhD, from the University of California, Los Angeles, who was not involved in the study.

These findings are in line with a lot of other COVID-19-related research that suggests a link between hepatocyte injury and clotting disorders, he added.

One important factor is existing liver disease, said Dr. Dong. “If you have COVID-19 on top of that, you’re probably at risk of developing acute liver injury from the infection itself.”

That said, it’s still a good idea to check liver function in patients with COVID-19 and no known liver disease, he advised. Staying on top of these measures will keep the odds of long-term problems “a lot lower.”

There is utility in the findings beyond COVID-19, said Dr. McConnell. They provide “insights into complications of critical illness, in general, in the liver blood vessels” of patients with underlying liver disease.

Dr. McConnell and Dr. Dong have disclosed no relevant financial relationships.

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

There is a link between liver injury and a tendency toward excessive clotting in patients with COVID-19, and the organ’s own blood vessels could be responsible, new research shows.

Cells that line the liver’s blood vessels produce high levels of factor VIII, a coagulation factor, when they are exposed to interleukin-6, an inflammatory molecule associated with COVID-19.

These findings “center the liver in global coagulopathy of COVID-19 and define a mechanism for increased coagulation factor levels that may be treatment targets,” said investigator Matthew McConnell, MD, from the Yale University, New Haven, Conn.

The effect of IL-6 on the liver sinusoidal endothelial cells lining the liver blood vessels creates a prothrombotic environment that includes the release of factor VIII, said Dr. McConnell, who presented the results at the virtual annual meeting of the American Association for the Study of Liver Diseases.

These associations offer insights into why COVID-19 patients with underlying liver disease can experience “devastating complications” related to improper blood vessel function in the organ, he added.

For their study, Dr. McConnell and colleagues analyzed data on ALT and hypercoagulability from 68 adults treated at the Yale–New Haven Hospital. The liver and coagulation tests were administered within 5 days of each other.

The team set the ALT cutoff for liver injury at three times the upper limit of normal. Patients with two or more parameters indicating excessive clotting were considered to have a hypercoagulable profile, which Dr. McConnell called “a signature clinical finding of COVID-19 infection.”

Patients with high levels of ALT also experienced elevations in clotting-related factors, such as fibrinogen levels and the activity of factor VIII and factor II. Furthermore, liver injury was significantly associated with hypercoagulability (P < .05).

Because COVID-19 is linked to the proinflammatory IL-6, the investigators examined how this cytokine and its receptor affect human liver sinusoidal cells. Cells exposed to IL-6 and its receptor pumped out factor VIII at levels that were significantly higher than in unexposed cells (P < .01). Exposed cells also produced significantly more von Willebrand factor (P < .05), another prothrombotic molecule, and showed increased expression of genes that induce the expression of factor VIII.

“As we learn more about COVID-19, we find that it is as much a coagulatory as a respiratory disease,” said Tien Dong, MD, PhD, from the University of California, Los Angeles, who was not involved in the study.

These findings are in line with a lot of other COVID-19-related research that suggests a link between hepatocyte injury and clotting disorders, he added.

One important factor is existing liver disease, said Dr. Dong. “If you have COVID-19 on top of that, you’re probably at risk of developing acute liver injury from the infection itself.”

That said, it’s still a good idea to check liver function in patients with COVID-19 and no known liver disease, he advised. Staying on top of these measures will keep the odds of long-term problems “a lot lower.”

There is utility in the findings beyond COVID-19, said Dr. McConnell. They provide “insights into complications of critical illness, in general, in the liver blood vessels” of patients with underlying liver disease.

Dr. McConnell and Dr. Dong have disclosed no relevant financial relationships.

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

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

[email protected]

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

[email protected]

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.