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‘Very doable’ low-dose workout enough to treat knee OA
Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.
A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.
Both high and low doses of exercise reduced pain and improved function and quality of life.
The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.
“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
What’s the right dose?
Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.
The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.
Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.
The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.
The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.
“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported
High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.
Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.
“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”
All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.
Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.
“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.
The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.
A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.
Both high and low doses of exercise reduced pain and improved function and quality of life.
The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.
“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
What’s the right dose?
Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.
The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.
Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.
The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.
The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.
“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported
High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.
Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.
“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”
All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.
Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.
“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.
The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Exercise helps patients with knee osteoarthritis, but more isn’t necessarily better, new research shows.
A low-dose exercise regimen helped patients with knee OA about as much as a more intense workout plan, according to trial results published online in Annals of Internal Medicine.
Both high and low doses of exercise reduced pain and improved function and quality of life.
The improvements with the lower-dose plan and its 98% adherence rate are encouraging, said Nick Trasolini, MD, assistant professor of orthopedic surgery at Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, N.C.
“This is a very doable amount of medical exercise therapy for patients with knee osteoarthritis, and one that makes a big difference in patient-reported symptoms,” Dr. Trasolini, who was not involved in the study, said in an interview.
What’s the right dose?
Exercise is a go-to treatment for knee OA, but the precise dose to recommend has been unclear. To study this question, Tom Arild Torstensen, MSc, RPT, with Karolinska Institutet, Huddinge, Sweden, and Holten Institute, Stockholm, and colleagues conducted a trial at four centers in Sweden and Norway.
The study included 189 men and women with knee OA. Participants were randomly assigned to low- or high-dose exercise plans, which they performed three times per week for 12 weeks under the supervision of a physiotherapist.
Participants in the high-dose group performed 11 exercises during each session, which lasted 70-90 minutes.
The low-dose regimen consisted of five exercises – cycling, squats, step-ups, step-downs, and knee extensions – performed for 20–30 minutes.
The researchers measured outcomes using the Knee Injury and Osteoarthritis Outcome Score, which assesses pain, other symptoms, function in daily living, function in sports and recreation, and knee-related quality of life.
“Patients in both groups improved significantly over time, but high-dose exercise was not superior to low-dose exercise in most comparisons,” the study investigators reported
High-dose exercise was associated with better function in sports and recreational activity and knee-related quality of life at 6 months. Those differences did not persist at 1 year, however. The researchers reported no safety concerns with either intervention.
Adherence was “nearly perfect” in the low-dose group. It was slightly lower in the high-dose group, the researchers said.
“Interestingly, it seems that high-dose treatment could be preferable to low-dose treatment in the long run for people who lead active lives,” they wrote. “This should be the subject of future studies.”
All clinical practice guidelines for knee OA recommend exercise, but “we do not know the optimal dose,” Kim Bennell, PhD, a research physiotherapist at the University of Melbourne, said in an interview.
Dose has components, including number of times per week, number of exercises, sets and repetitions, intensity, and duration of exercise sessions, Dr. Bennell said.
“These results suggest that an exercise program that involves less time and fewer exercises can still offer benefits and may be easier for patients to undertake and stick at than one that involves greater time and effort,” she said.
The study was supported by the Swedish Rheumatic Fund. Dr. Trasolini and Dr. Bennell have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Depression guidelines fall short in characterizing withdrawal
Previous research suggests that approximately half of patients who discontinue or decrease dosage of antidepressants experience withdrawal symptoms, wrote Anders Sørensen, MD, of Copenhagen University Hospital, and colleagues. These symptoms are diverse and may include flulike symptoms, fatigue, anxiety, and sensations of electric shock, they noted. Most withdrawal effects last for a few weeks, but some persist for months or years, sometimes described as persistent postwithdrawal disorder, they added.
“Symptoms of withdrawal and depression overlap considerably but constitute two fundamentally different clinical conditions, which makes it important to distinguish between the two,” the researchers emphasized.
In a study published in the Journal of Affective Disorders, the researchers identified 21 clinical practice guidelines (CPGs) for depression published between 1998 and 2022. The guidelines were published in the United Kingdom, the United States, Canada, Australia, Singapore, Ireland, and New Zealand. They compared descriptions of withdrawal from antidepressants and calculated the proportion of CPGs with different information.
Overall, 15 of the 21 studies in the review (71%) noted that antidepressants are associated with withdrawal symptoms, but less than half (43%) used the term “withdrawal symptoms,” or similar. Of the nine guidelines that mentioned withdrawal symptoms, five used the term interchangeably with “discontinuation symptoms” and six used the term “discontinuation symptoms” only when discussing antidepressant withdrawal. In addition, six CPGs specifically stated that patients who stop antidepressants can experience withdrawal symptoms, and five stated that these symptoms also can occur in patients who are reducing or tapering their doses.
The type of withdrawal symptoms was mentioned in 10 CPGs, and the other 11 had no information on potential withdrawal symptoms, the researchers noted. Of the CPGs that mentioned symptoms specifically associated with withdrawal, the number of potential symptoms ranged from 4 to 39.
“None of the CPGs provided an exhaustive list of the potential withdrawal symptoms identified in the research literature,” the researchers wrote in their discussion.
Only four of the guidelines (19%) mentioned the overlap in symptoms between withdrawal from antidepressants and depression relapse, and only one provided guidance on distinguishing between the two conditions. Most of the symptoms of withdrawal, when described, were characterized as mild, brief, or self-limiting, the researchers noted.
“Being in withdrawal is a fundamentally different clinical situation than experiencing relapse, requiring two distinctly different treatment approaches,” the researchers emphasized. “Withdrawal reactions that are more severe and longer lasting than currently defined in the CPGs could risk getting misinterpreted as relapse, potentially leading to resumed unnecessary long-term antidepressant treatment in some patients,” they added.
The findings were limited by several factors including the inclusion only of guidelines from English-speaking countries, which may limit generalizability, the researchers noted. Other potential limitations include the subjective judgments involved in creating different guidelines, they said.
However, the results support the need for improved CPGs that help clinicians distinguish potential withdrawal reactions from depression relapse, and the need for more research on optimal dose reduction strategies for antidepressants, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Previous research suggests that approximately half of patients who discontinue or decrease dosage of antidepressants experience withdrawal symptoms, wrote Anders Sørensen, MD, of Copenhagen University Hospital, and colleagues. These symptoms are diverse and may include flulike symptoms, fatigue, anxiety, and sensations of electric shock, they noted. Most withdrawal effects last for a few weeks, but some persist for months or years, sometimes described as persistent postwithdrawal disorder, they added.
“Symptoms of withdrawal and depression overlap considerably but constitute two fundamentally different clinical conditions, which makes it important to distinguish between the two,” the researchers emphasized.
In a study published in the Journal of Affective Disorders, the researchers identified 21 clinical practice guidelines (CPGs) for depression published between 1998 and 2022. The guidelines were published in the United Kingdom, the United States, Canada, Australia, Singapore, Ireland, and New Zealand. They compared descriptions of withdrawal from antidepressants and calculated the proportion of CPGs with different information.
Overall, 15 of the 21 studies in the review (71%) noted that antidepressants are associated with withdrawal symptoms, but less than half (43%) used the term “withdrawal symptoms,” or similar. Of the nine guidelines that mentioned withdrawal symptoms, five used the term interchangeably with “discontinuation symptoms” and six used the term “discontinuation symptoms” only when discussing antidepressant withdrawal. In addition, six CPGs specifically stated that patients who stop antidepressants can experience withdrawal symptoms, and five stated that these symptoms also can occur in patients who are reducing or tapering their doses.
The type of withdrawal symptoms was mentioned in 10 CPGs, and the other 11 had no information on potential withdrawal symptoms, the researchers noted. Of the CPGs that mentioned symptoms specifically associated with withdrawal, the number of potential symptoms ranged from 4 to 39.
“None of the CPGs provided an exhaustive list of the potential withdrawal symptoms identified in the research literature,” the researchers wrote in their discussion.
Only four of the guidelines (19%) mentioned the overlap in symptoms between withdrawal from antidepressants and depression relapse, and only one provided guidance on distinguishing between the two conditions. Most of the symptoms of withdrawal, when described, were characterized as mild, brief, or self-limiting, the researchers noted.
“Being in withdrawal is a fundamentally different clinical situation than experiencing relapse, requiring two distinctly different treatment approaches,” the researchers emphasized. “Withdrawal reactions that are more severe and longer lasting than currently defined in the CPGs could risk getting misinterpreted as relapse, potentially leading to resumed unnecessary long-term antidepressant treatment in some patients,” they added.
The findings were limited by several factors including the inclusion only of guidelines from English-speaking countries, which may limit generalizability, the researchers noted. Other potential limitations include the subjective judgments involved in creating different guidelines, they said.
However, the results support the need for improved CPGs that help clinicians distinguish potential withdrawal reactions from depression relapse, and the need for more research on optimal dose reduction strategies for antidepressants, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Previous research suggests that approximately half of patients who discontinue or decrease dosage of antidepressants experience withdrawal symptoms, wrote Anders Sørensen, MD, of Copenhagen University Hospital, and colleagues. These symptoms are diverse and may include flulike symptoms, fatigue, anxiety, and sensations of electric shock, they noted. Most withdrawal effects last for a few weeks, but some persist for months or years, sometimes described as persistent postwithdrawal disorder, they added.
“Symptoms of withdrawal and depression overlap considerably but constitute two fundamentally different clinical conditions, which makes it important to distinguish between the two,” the researchers emphasized.
In a study published in the Journal of Affective Disorders, the researchers identified 21 clinical practice guidelines (CPGs) for depression published between 1998 and 2022. The guidelines were published in the United Kingdom, the United States, Canada, Australia, Singapore, Ireland, and New Zealand. They compared descriptions of withdrawal from antidepressants and calculated the proportion of CPGs with different information.
Overall, 15 of the 21 studies in the review (71%) noted that antidepressants are associated with withdrawal symptoms, but less than half (43%) used the term “withdrawal symptoms,” or similar. Of the nine guidelines that mentioned withdrawal symptoms, five used the term interchangeably with “discontinuation symptoms” and six used the term “discontinuation symptoms” only when discussing antidepressant withdrawal. In addition, six CPGs specifically stated that patients who stop antidepressants can experience withdrawal symptoms, and five stated that these symptoms also can occur in patients who are reducing or tapering their doses.
The type of withdrawal symptoms was mentioned in 10 CPGs, and the other 11 had no information on potential withdrawal symptoms, the researchers noted. Of the CPGs that mentioned symptoms specifically associated with withdrawal, the number of potential symptoms ranged from 4 to 39.
“None of the CPGs provided an exhaustive list of the potential withdrawal symptoms identified in the research literature,” the researchers wrote in their discussion.
Only four of the guidelines (19%) mentioned the overlap in symptoms between withdrawal from antidepressants and depression relapse, and only one provided guidance on distinguishing between the two conditions. Most of the symptoms of withdrawal, when described, were characterized as mild, brief, or self-limiting, the researchers noted.
“Being in withdrawal is a fundamentally different clinical situation than experiencing relapse, requiring two distinctly different treatment approaches,” the researchers emphasized. “Withdrawal reactions that are more severe and longer lasting than currently defined in the CPGs could risk getting misinterpreted as relapse, potentially leading to resumed unnecessary long-term antidepressant treatment in some patients,” they added.
The findings were limited by several factors including the inclusion only of guidelines from English-speaking countries, which may limit generalizability, the researchers noted. Other potential limitations include the subjective judgments involved in creating different guidelines, they said.
However, the results support the need for improved CPGs that help clinicians distinguish potential withdrawal reactions from depression relapse, and the need for more research on optimal dose reduction strategies for antidepressants, they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM THE JOURNAL OF AFFECTIVE DISORDERS
Mastocytosis: Rare, underdiagnosed, potentially fatal
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
PCSK9 inhibitors for severe COVID? Pilot trial signals of benefit
PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.
In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).
Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published in the Journal of the American College of Cardiology.
Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
PCSK9 inhibitors as anti-inflammatories
Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.
and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.
The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.
Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”
If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.
In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.
But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
A single injection
The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.
They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.
Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.
Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.
The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.
Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).
A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.
Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”
Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.
In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).
Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published in the Journal of the American College of Cardiology.
Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
PCSK9 inhibitors as anti-inflammatories
Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.
and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.
The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.
Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”
If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.
In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.
But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
A single injection
The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.
They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.
Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.
Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.
The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.
Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).
A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.
Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”
Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.
In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).
Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published in the Journal of the American College of Cardiology.
Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
PCSK9 inhibitors as anti-inflammatories
Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.
and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.
The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.
Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”
If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.
In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.
But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
A single injection
The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.
They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.
Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.
Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.
The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.
Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).
A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.
Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”
Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Guidelines recommend CBT alone for mild acute depression, more options for more severe cases
The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.
These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.
More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.
In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.
Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”
This analysis yielded three pieces of clinical advice.
First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.
Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.
“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.
The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.
“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.
The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.
“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.
Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.
A timely update
“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”
Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.
“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.
“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”
Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.
He went on to offer some more detailed steps forward.
“If someone chooses to be treated with an SGA alone and has not had much response at all to an initial SGA, usually a selective serotonin reuptake inhibitor, I’ll usually switch to a different SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) and/or add CBT,” Dr. Skolnik said. “If they have had a partial response, I’ll often encourage CBT and consider the addition of augmentation with an additional medication as discussed in the guidelines.”
Valuable despite the gaps
Other experts expressed mixed impressions of the update, noting both highs and lows.
“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.
Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.
“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.
They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”
After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”
Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.
“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.
This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.
“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”
Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.
The other key gap they pointed out relates to withdrawal.
Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.
“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.
Financial costs remain unclear
Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.
In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.
For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.
“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”
When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.
The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.
The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.
These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.
More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.
In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.
Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”
This analysis yielded three pieces of clinical advice.
First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.
Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.
“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.
The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.
“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.
The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.
“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.
Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.
A timely update
“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”
Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.
“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.
“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”
Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.
He went on to offer some more detailed steps forward.
“If someone chooses to be treated with an SGA alone and has not had much response at all to an initial SGA, usually a selective serotonin reuptake inhibitor, I’ll usually switch to a different SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) and/or add CBT,” Dr. Skolnik said. “If they have had a partial response, I’ll often encourage CBT and consider the addition of augmentation with an additional medication as discussed in the guidelines.”
Valuable despite the gaps
Other experts expressed mixed impressions of the update, noting both highs and lows.
“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.
Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.
“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.
They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”
After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”
Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.
“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.
This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.
“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”
Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.
The other key gap they pointed out relates to withdrawal.
Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.
“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.
Financial costs remain unclear
Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.
In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.
For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.
“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”
When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.
The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.
The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.
These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.
More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.
In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.
Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”
This analysis yielded three pieces of clinical advice.
First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.
Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.
“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.
The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.
“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.
The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.
“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.
Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.
A timely update
“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”
Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.
“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.
“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”
Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.
He went on to offer some more detailed steps forward.
“If someone chooses to be treated with an SGA alone and has not had much response at all to an initial SGA, usually a selective serotonin reuptake inhibitor, I’ll usually switch to a different SSRI or serotonin and norepinephrine reuptake inhibitor (SNRI) and/or add CBT,” Dr. Skolnik said. “If they have had a partial response, I’ll often encourage CBT and consider the addition of augmentation with an additional medication as discussed in the guidelines.”
Valuable despite the gaps
Other experts expressed mixed impressions of the update, noting both highs and lows.
“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.
Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.
“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.
They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”
After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”
Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.
“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.
This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.
“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”
Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.
The other key gap they pointed out relates to withdrawal.
Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.
“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.
Financial costs remain unclear
Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.
In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.
For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.
“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”
When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.
The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE
FDA approves new type 2 diabetes drug bexagliflozin
The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m2.
Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m2).
In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.
In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.
“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.
“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”
As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.
Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.
Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m2.
Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m2).
In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.
In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.
“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.
“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”
As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.
Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.
Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m2.
Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m2).
In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.
In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.
“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.
“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”
As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.
Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.
Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.
A version of this article first appeared on Medscape.com.
Highly anticipated HIV vaccine fails in large trial
officials announced Wednesday.
The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.
Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.
“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”
No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.
There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.
A version of this article first appeared on WebMD.com.
officials announced Wednesday.
The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.
Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.
“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”
No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.
There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.
A version of this article first appeared on WebMD.com.
officials announced Wednesday.
The vaccine had been in development since 2019 and was given to 3,900 study participants through October 2022, but data shows it does not protect against HIV compared with a placebo, according to developer Janssen Pharmaceutical.
Experts estimate the failure means there won’t be another potential vaccine on the horizon for 3 to 5 years, the New York Times reported.
“It’s obviously disappointing,” Anthony Fauci, MD, former head of the National Institute of Allergy and Infectious Diseases, told MSNBC, noting that other areas of HIV treatment research are promising. “I don’t think that people should give up on the field of the HIV vaccine.”
No safety issues had been identified with the vaccine during the trial, which studied the experimental treatment in men who have sex with men or with transgender people.
There is no cure for HIV, but disease progression can be managed with existing treatments. HIV attacks the body’s immune system and destroys white blood cells, increasing the risk of other infections. More than 1.5 million people worldwide were infected with HIV in 2021 and 38.4 million people are living with the virus, according to UNAIDS.
A version of this article first appeared on WebMD.com.
Physician sues AMA for defamation over 2022 election controversy
If Willarda Edwards, MD, MBA, had won her 2022 campaign for president-elect of the American Medical Association (AMA), she would have been the second Black woman to head the group.
The lawsuit sheds light on the power dynamics of a politically potent organization that has more than 271,000 members and holds assets of $1.2 billion. The AMA president is one of the most visible figures in American medicine.
“The AMA impugned Dr. Edwards with these false charges, which destroyed her candidacy and irreparably damaged her reputation,” according to the complaint, which was filed Nov. 9, 2022, in Baltimore County Circuit Court. The case was later moved to federal court.
The AMA “previously rejected our attempt to resolve this matter without litigation,” Dr. Edwards’ attorney, Timothy Maloney, told this news organization. An AMA spokesman said the organization had no comment on Dr. Edwards’ suit.
Dr. Edwards is a past president of the National Medical Association, MedChi, the Baltimore City Medical Society, the Monumental City Medical Society, and the Sickle Cell Disease Association of America. She joined the AMA in 1994 and has served as a trustee since 2016.
As chair of the AMA Task Force on Health Equity, “she helped lead the way in consensus building and driving action that in 2019 resulted in the AMA House of Delegates establishing the AMA Center on Health Equity,” according to her AMA bio page.
‘Quid pro quo’ alleged
In June 2022, Dr. Edwards was one of three individuals running to be AMA president-elect.
According to Dr. Edwards’ complaint, she was “incorrectly advised by colleagues” that Virginia urologist William Reha, MD, had decided not to seek the AMA vice-speakership in 2023. This was important because both Dr. Edwards and Dr. Reha were in the Southeastern delegation. It could be in Dr. Edwards’ favor if Dr. Reha was not running, as it would mean one less leadership candidate from the same region.
Dr. Edwards called Dr. Reha on June 6 to discuss the matter. When they talked, Dr. Reha allegedly recorded the call without Dr. Edwards’ knowledge or permission – a felony in Maryland – and also steered her toward discussions about how his decision could benefit her campaign, according to the complaint.
The suit alleges that Dr. Reha’s questions were “clearly calculated to draw some statements by Dr. Edwards that he could use later to thwart her candidacy and to benefit her opponent.”
On June 10, at the AMA’s House of Delegates meeting in Chicago, Dr. Edwards was taken aside and questioned by members of the AMA’s Election Campaign Committee, according to the complaint. They accused her of “vote trading” but did not provide any evidence or a copy of a complaint they said had been filed against her, the suit said.
Dr. Edwards was given no opportunity to produce her own evidence or rebut the accusations, the suit alleges.
Just before the delegates started formal business on June 13, House Speaker Bruce Scott, MD, read a statement to the assembly saying that a complaint of a possible campaign violation had been filed against Dr. Edwards.
Dr. Scott told the delegates that “committee members interviewed the complainant and multiple other individuals said to have knowledge of the circumstances. In addition to conducting multiple interviews, the committee reviewed evidence that was deemed credible and corroborated that a campaign violation did in fact occur,” according to the complaint.
The supposed violation: A “quid pro quo” in which an unnamed delegation would support Dr. Edwards’ current candidacy, and the Southeastern delegation would support a future candidate from that other unnamed delegation.
Dr. Edwards was given a short opportunity to speak, in which she denied any violations.
According to a news report, Dr. Edwards said, “I’ve been in the House of Delegates for 30 years, and you know me as a process person – a person who truly believes in the process and trying to follow the complexities of our election campaign.”
The lawsuit alleges that “this defamatory conduct was repeated the next day to more than 600 delegates just minutes prior to the casting of votes, when Dr Scott repeated these allegations.”
Dr. Edwards lost the election.
AMA: Nothing more to add
The suit alleges that neither the Election Campaign Committee nor the AMA itself has made any accusers or complaints available to Dr. Edwards and that it has not provided any audio or written evidence of her alleged violation.
In July, the AMA’s Southeastern delegation told its membership, “We continue to maintain that Willarda was ‘set up’ ... The whole affair lacked any reasonable semblance of due process.”
The delegation has filed a counter claim against the AMA seeking “to address this lack of due process as well as the reputational harm” to the delegation.
The AMA said that it has nothing it can produce. “The Speaker of the House presented a verbal report to the attending delegates,” said a spokesman. “The Speaker’s report remains the only remarks from an AMA officer, and no additional remarks can be expected at this time.”
He added that there “is no official transcript of the Speaker’s report.”
A version of this article first appeared on Medscape.com.
If Willarda Edwards, MD, MBA, had won her 2022 campaign for president-elect of the American Medical Association (AMA), she would have been the second Black woman to head the group.
The lawsuit sheds light on the power dynamics of a politically potent organization that has more than 271,000 members and holds assets of $1.2 billion. The AMA president is one of the most visible figures in American medicine.
“The AMA impugned Dr. Edwards with these false charges, which destroyed her candidacy and irreparably damaged her reputation,” according to the complaint, which was filed Nov. 9, 2022, in Baltimore County Circuit Court. The case was later moved to federal court.
The AMA “previously rejected our attempt to resolve this matter without litigation,” Dr. Edwards’ attorney, Timothy Maloney, told this news organization. An AMA spokesman said the organization had no comment on Dr. Edwards’ suit.
Dr. Edwards is a past president of the National Medical Association, MedChi, the Baltimore City Medical Society, the Monumental City Medical Society, and the Sickle Cell Disease Association of America. She joined the AMA in 1994 and has served as a trustee since 2016.
As chair of the AMA Task Force on Health Equity, “she helped lead the way in consensus building and driving action that in 2019 resulted in the AMA House of Delegates establishing the AMA Center on Health Equity,” according to her AMA bio page.
‘Quid pro quo’ alleged
In June 2022, Dr. Edwards was one of three individuals running to be AMA president-elect.
According to Dr. Edwards’ complaint, she was “incorrectly advised by colleagues” that Virginia urologist William Reha, MD, had decided not to seek the AMA vice-speakership in 2023. This was important because both Dr. Edwards and Dr. Reha were in the Southeastern delegation. It could be in Dr. Edwards’ favor if Dr. Reha was not running, as it would mean one less leadership candidate from the same region.
Dr. Edwards called Dr. Reha on June 6 to discuss the matter. When they talked, Dr. Reha allegedly recorded the call without Dr. Edwards’ knowledge or permission – a felony in Maryland – and also steered her toward discussions about how his decision could benefit her campaign, according to the complaint.
The suit alleges that Dr. Reha’s questions were “clearly calculated to draw some statements by Dr. Edwards that he could use later to thwart her candidacy and to benefit her opponent.”
On June 10, at the AMA’s House of Delegates meeting in Chicago, Dr. Edwards was taken aside and questioned by members of the AMA’s Election Campaign Committee, according to the complaint. They accused her of “vote trading” but did not provide any evidence or a copy of a complaint they said had been filed against her, the suit said.
Dr. Edwards was given no opportunity to produce her own evidence or rebut the accusations, the suit alleges.
Just before the delegates started formal business on June 13, House Speaker Bruce Scott, MD, read a statement to the assembly saying that a complaint of a possible campaign violation had been filed against Dr. Edwards.
Dr. Scott told the delegates that “committee members interviewed the complainant and multiple other individuals said to have knowledge of the circumstances. In addition to conducting multiple interviews, the committee reviewed evidence that was deemed credible and corroborated that a campaign violation did in fact occur,” according to the complaint.
The supposed violation: A “quid pro quo” in which an unnamed delegation would support Dr. Edwards’ current candidacy, and the Southeastern delegation would support a future candidate from that other unnamed delegation.
Dr. Edwards was given a short opportunity to speak, in which she denied any violations.
According to a news report, Dr. Edwards said, “I’ve been in the House of Delegates for 30 years, and you know me as a process person – a person who truly believes in the process and trying to follow the complexities of our election campaign.”
The lawsuit alleges that “this defamatory conduct was repeated the next day to more than 600 delegates just minutes prior to the casting of votes, when Dr Scott repeated these allegations.”
Dr. Edwards lost the election.
AMA: Nothing more to add
The suit alleges that neither the Election Campaign Committee nor the AMA itself has made any accusers or complaints available to Dr. Edwards and that it has not provided any audio or written evidence of her alleged violation.
In July, the AMA’s Southeastern delegation told its membership, “We continue to maintain that Willarda was ‘set up’ ... The whole affair lacked any reasonable semblance of due process.”
The delegation has filed a counter claim against the AMA seeking “to address this lack of due process as well as the reputational harm” to the delegation.
The AMA said that it has nothing it can produce. “The Speaker of the House presented a verbal report to the attending delegates,” said a spokesman. “The Speaker’s report remains the only remarks from an AMA officer, and no additional remarks can be expected at this time.”
He added that there “is no official transcript of the Speaker’s report.”
A version of this article first appeared on Medscape.com.
If Willarda Edwards, MD, MBA, had won her 2022 campaign for president-elect of the American Medical Association (AMA), she would have been the second Black woman to head the group.
The lawsuit sheds light on the power dynamics of a politically potent organization that has more than 271,000 members and holds assets of $1.2 billion. The AMA president is one of the most visible figures in American medicine.
“The AMA impugned Dr. Edwards with these false charges, which destroyed her candidacy and irreparably damaged her reputation,” according to the complaint, which was filed Nov. 9, 2022, in Baltimore County Circuit Court. The case was later moved to federal court.
The AMA “previously rejected our attempt to resolve this matter without litigation,” Dr. Edwards’ attorney, Timothy Maloney, told this news organization. An AMA spokesman said the organization had no comment on Dr. Edwards’ suit.
Dr. Edwards is a past president of the National Medical Association, MedChi, the Baltimore City Medical Society, the Monumental City Medical Society, and the Sickle Cell Disease Association of America. She joined the AMA in 1994 and has served as a trustee since 2016.
As chair of the AMA Task Force on Health Equity, “she helped lead the way in consensus building and driving action that in 2019 resulted in the AMA House of Delegates establishing the AMA Center on Health Equity,” according to her AMA bio page.
‘Quid pro quo’ alleged
In June 2022, Dr. Edwards was one of three individuals running to be AMA president-elect.
According to Dr. Edwards’ complaint, she was “incorrectly advised by colleagues” that Virginia urologist William Reha, MD, had decided not to seek the AMA vice-speakership in 2023. This was important because both Dr. Edwards and Dr. Reha were in the Southeastern delegation. It could be in Dr. Edwards’ favor if Dr. Reha was not running, as it would mean one less leadership candidate from the same region.
Dr. Edwards called Dr. Reha on June 6 to discuss the matter. When they talked, Dr. Reha allegedly recorded the call without Dr. Edwards’ knowledge or permission – a felony in Maryland – and also steered her toward discussions about how his decision could benefit her campaign, according to the complaint.
The suit alleges that Dr. Reha’s questions were “clearly calculated to draw some statements by Dr. Edwards that he could use later to thwart her candidacy and to benefit her opponent.”
On June 10, at the AMA’s House of Delegates meeting in Chicago, Dr. Edwards was taken aside and questioned by members of the AMA’s Election Campaign Committee, according to the complaint. They accused her of “vote trading” but did not provide any evidence or a copy of a complaint they said had been filed against her, the suit said.
Dr. Edwards was given no opportunity to produce her own evidence or rebut the accusations, the suit alleges.
Just before the delegates started formal business on June 13, House Speaker Bruce Scott, MD, read a statement to the assembly saying that a complaint of a possible campaign violation had been filed against Dr. Edwards.
Dr. Scott told the delegates that “committee members interviewed the complainant and multiple other individuals said to have knowledge of the circumstances. In addition to conducting multiple interviews, the committee reviewed evidence that was deemed credible and corroborated that a campaign violation did in fact occur,” according to the complaint.
The supposed violation: A “quid pro quo” in which an unnamed delegation would support Dr. Edwards’ current candidacy, and the Southeastern delegation would support a future candidate from that other unnamed delegation.
Dr. Edwards was given a short opportunity to speak, in which she denied any violations.
According to a news report, Dr. Edwards said, “I’ve been in the House of Delegates for 30 years, and you know me as a process person – a person who truly believes in the process and trying to follow the complexities of our election campaign.”
The lawsuit alleges that “this defamatory conduct was repeated the next day to more than 600 delegates just minutes prior to the casting of votes, when Dr Scott repeated these allegations.”
Dr. Edwards lost the election.
AMA: Nothing more to add
The suit alleges that neither the Election Campaign Committee nor the AMA itself has made any accusers or complaints available to Dr. Edwards and that it has not provided any audio or written evidence of her alleged violation.
In July, the AMA’s Southeastern delegation told its membership, “We continue to maintain that Willarda was ‘set up’ ... The whole affair lacked any reasonable semblance of due process.”
The delegation has filed a counter claim against the AMA seeking “to address this lack of due process as well as the reputational harm” to the delegation.
The AMA said that it has nothing it can produce. “The Speaker of the House presented a verbal report to the attending delegates,” said a spokesman. “The Speaker’s report remains the only remarks from an AMA officer, and no additional remarks can be expected at this time.”
He added that there “is no official transcript of the Speaker’s report.”
A version of this article first appeared on Medscape.com.
Interval FITs could cut colonoscopies in those at above-average risk
In a new retrospective analysis of patients with above-average risk of colorectal cancer, multiple negative fecal immunohistochemical tests (FITs) were associated with a lower risk of advanced neoplasia. The findings suggest that multiple negative FITs could potentially identify individuals in high-risk surveillance who aren’t truly high risk, which could in turn ease the logjam of colonoscopies and free resources for truly high-risk individuals.
The study, conducted in Australia, was published online in Clinical Gastroenterology and Hepatology. It included patients who completed at least two FIT exams between surveillance colonoscopies and had no neoplasia or nonadvanced adenoma at prior colonoscopy. Above-average risk was defined as a family history or by findings at surveillance colonoscopy.
The study has some limitations. It is a retrospective analysis between the years 2008 and 2019, and colonoscopy guidelines in the United States have since changed, with a recommendation of surveillance colonoscopy at 7-10 years following 1-2 adenomas discovered at surveillance colonoscopy, and the current study includes follow-up colonoscopy at 5 years. “These data are informative for patients up to 5 years, but they’re not really informative afterwards. They just don’t have those data yet,” said Reed Ness, MD, who was asked to comment on the study.
The authors also don’t describe what they mean by a family history of colorectal cancer risk. “My take was that it’s an interesting result which would seem to support the possibility of returning some patients with a family history or adenoma history to a noncolonoscopy screening regimen after a negative surveillance colonoscopy. We’ll need to see where the data lead us in the future,” said Dr. Ness, who is an associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.
“We’re letting people go 10 years now, and some people are uncomfortable with allowing patients to go 10 years. So you could think of a scenario where you use FIT to try to find people that might have higher-risk lesions that need to come back for colonoscopy within that 10 years,” said Dr. Ness. That issue is particularly relevant given the wide range of adenoma detection rates among gastroenterologists, because FIT could detect a polyp that was missed during a colonoscopy.
The study included two groups with increased risk – those with a family history of colon cancer, and those with previously detected adenomas. The family history cohort may be useful for clinical practice, according to Priyanka Kanth, MD, who was also asked to comment on the study. “Some people may not need [a colonoscopy] at 5 years if they have no polyps found and negative FIT,” said Dr. Kanth, who is an associate professor of gastroenterology at Georgetown University, Washington.
She feels less certain about the group with previously detected adenomas, given the change in U.S. guidelines. “We have already changed that, so I don’t think we need to really do FIT intervals for that cohort,” said Dr. Kanth. “I think this is a good study that has a lot of information and also reassures us that we don’t need such frequent colonoscopy surveillance,” she added.
Steve Serrao, MD, PhD, who was also asked for comment, emphasized the importance of high-quality colonoscopies that reach the cecum 95% of the time, and achieving high adenoma-detection rates. The system can get overwhelmed conducting colonoscopies on patients with good insurance coverage who have already undergone high-quality colonoscopies. “That pushes out patients that haven’t necessarily had a colonoscopy or a FIT. People who don’t have access are kind of crowded out by these false-positive tests. The best modality is actually to do a high-quality colonoscopy and then to have a really well-directed strategy following that colonoscopy,” said Dr. Serrao, who is division chief of gastroenterology and hepatology at Riverside University Health System, Moreno Valley, Calif.
The researchers analyzed data from 4,021 surveillance intervals and 3,369 participants. A total of 1,436 had no neoplasia at the prior colonoscopy, 1,704 had nonadvanced adenoma, and 880 had advanced adenoma. Participants completed no or one to four FIT tests between colonoscopies, with the final colonoscopy performed within 2 years of FIT tests. The median age was 63.9 years; 53.6% were female; 71.1% had a prior adenoma; and 28.9% had a family history of colorectal cancer. A total of 29.4% of participants had one negative FIT; 6.9% had four negative FITs during the interval period; and 31.0% did not complete any FIT tests.
Of follow-up colonoscopies, 9.9% revealed advanced adenomas. Among the patients with no prior neoplasia, those with one negative FIT had a cumulative index function for advanced neoplasia at 5 years of 8.5% (95% confidence interval, 4.9%-13.3%). This was higher than for those with three negative FITs (4.5%; 95% CI, 2.0%-8.6%) or four negative FITs (1.9%; 95% CI, 0.5%-5.0%). The association held for individuals with prior nonadvanced adenoma but not those with advanced adenoma.
Over the 5-year interval, three or more negative FIT tests were associated with a 50%-70% reduction in advanced neoplasia risk at follow-up colonoscopy (P < .001). There was no significant association over a 3-year interval. Dr. Kanth, Dr. Serrao, and Dr. Ness have no relevant financial disclosures.
In a new retrospective analysis of patients with above-average risk of colorectal cancer, multiple negative fecal immunohistochemical tests (FITs) were associated with a lower risk of advanced neoplasia. The findings suggest that multiple negative FITs could potentially identify individuals in high-risk surveillance who aren’t truly high risk, which could in turn ease the logjam of colonoscopies and free resources for truly high-risk individuals.
The study, conducted in Australia, was published online in Clinical Gastroenterology and Hepatology. It included patients who completed at least two FIT exams between surveillance colonoscopies and had no neoplasia or nonadvanced adenoma at prior colonoscopy. Above-average risk was defined as a family history or by findings at surveillance colonoscopy.
The study has some limitations. It is a retrospective analysis between the years 2008 and 2019, and colonoscopy guidelines in the United States have since changed, with a recommendation of surveillance colonoscopy at 7-10 years following 1-2 adenomas discovered at surveillance colonoscopy, and the current study includes follow-up colonoscopy at 5 years. “These data are informative for patients up to 5 years, but they’re not really informative afterwards. They just don’t have those data yet,” said Reed Ness, MD, who was asked to comment on the study.
The authors also don’t describe what they mean by a family history of colorectal cancer risk. “My take was that it’s an interesting result which would seem to support the possibility of returning some patients with a family history or adenoma history to a noncolonoscopy screening regimen after a negative surveillance colonoscopy. We’ll need to see where the data lead us in the future,” said Dr. Ness, who is an associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.
“We’re letting people go 10 years now, and some people are uncomfortable with allowing patients to go 10 years. So you could think of a scenario where you use FIT to try to find people that might have higher-risk lesions that need to come back for colonoscopy within that 10 years,” said Dr. Ness. That issue is particularly relevant given the wide range of adenoma detection rates among gastroenterologists, because FIT could detect a polyp that was missed during a colonoscopy.
The study included two groups with increased risk – those with a family history of colon cancer, and those with previously detected adenomas. The family history cohort may be useful for clinical practice, according to Priyanka Kanth, MD, who was also asked to comment on the study. “Some people may not need [a colonoscopy] at 5 years if they have no polyps found and negative FIT,” said Dr. Kanth, who is an associate professor of gastroenterology at Georgetown University, Washington.
She feels less certain about the group with previously detected adenomas, given the change in U.S. guidelines. “We have already changed that, so I don’t think we need to really do FIT intervals for that cohort,” said Dr. Kanth. “I think this is a good study that has a lot of information and also reassures us that we don’t need such frequent colonoscopy surveillance,” she added.
Steve Serrao, MD, PhD, who was also asked for comment, emphasized the importance of high-quality colonoscopies that reach the cecum 95% of the time, and achieving high adenoma-detection rates. The system can get overwhelmed conducting colonoscopies on patients with good insurance coverage who have already undergone high-quality colonoscopies. “That pushes out patients that haven’t necessarily had a colonoscopy or a FIT. People who don’t have access are kind of crowded out by these false-positive tests. The best modality is actually to do a high-quality colonoscopy and then to have a really well-directed strategy following that colonoscopy,” said Dr. Serrao, who is division chief of gastroenterology and hepatology at Riverside University Health System, Moreno Valley, Calif.
The researchers analyzed data from 4,021 surveillance intervals and 3,369 participants. A total of 1,436 had no neoplasia at the prior colonoscopy, 1,704 had nonadvanced adenoma, and 880 had advanced adenoma. Participants completed no or one to four FIT tests between colonoscopies, with the final colonoscopy performed within 2 years of FIT tests. The median age was 63.9 years; 53.6% were female; 71.1% had a prior adenoma; and 28.9% had a family history of colorectal cancer. A total of 29.4% of participants had one negative FIT; 6.9% had four negative FITs during the interval period; and 31.0% did not complete any FIT tests.
Of follow-up colonoscopies, 9.9% revealed advanced adenomas. Among the patients with no prior neoplasia, those with one negative FIT had a cumulative index function for advanced neoplasia at 5 years of 8.5% (95% confidence interval, 4.9%-13.3%). This was higher than for those with three negative FITs (4.5%; 95% CI, 2.0%-8.6%) or four negative FITs (1.9%; 95% CI, 0.5%-5.0%). The association held for individuals with prior nonadvanced adenoma but not those with advanced adenoma.
Over the 5-year interval, three or more negative FIT tests were associated with a 50%-70% reduction in advanced neoplasia risk at follow-up colonoscopy (P < .001). There was no significant association over a 3-year interval. Dr. Kanth, Dr. Serrao, and Dr. Ness have no relevant financial disclosures.
In a new retrospective analysis of patients with above-average risk of colorectal cancer, multiple negative fecal immunohistochemical tests (FITs) were associated with a lower risk of advanced neoplasia. The findings suggest that multiple negative FITs could potentially identify individuals in high-risk surveillance who aren’t truly high risk, which could in turn ease the logjam of colonoscopies and free resources for truly high-risk individuals.
The study, conducted in Australia, was published online in Clinical Gastroenterology and Hepatology. It included patients who completed at least two FIT exams between surveillance colonoscopies and had no neoplasia or nonadvanced adenoma at prior colonoscopy. Above-average risk was defined as a family history or by findings at surveillance colonoscopy.
The study has some limitations. It is a retrospective analysis between the years 2008 and 2019, and colonoscopy guidelines in the United States have since changed, with a recommendation of surveillance colonoscopy at 7-10 years following 1-2 adenomas discovered at surveillance colonoscopy, and the current study includes follow-up colonoscopy at 5 years. “These data are informative for patients up to 5 years, but they’re not really informative afterwards. They just don’t have those data yet,” said Reed Ness, MD, who was asked to comment on the study.
The authors also don’t describe what they mean by a family history of colorectal cancer risk. “My take was that it’s an interesting result which would seem to support the possibility of returning some patients with a family history or adenoma history to a noncolonoscopy screening regimen after a negative surveillance colonoscopy. We’ll need to see where the data lead us in the future,” said Dr. Ness, who is an associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.
“We’re letting people go 10 years now, and some people are uncomfortable with allowing patients to go 10 years. So you could think of a scenario where you use FIT to try to find people that might have higher-risk lesions that need to come back for colonoscopy within that 10 years,” said Dr. Ness. That issue is particularly relevant given the wide range of adenoma detection rates among gastroenterologists, because FIT could detect a polyp that was missed during a colonoscopy.
The study included two groups with increased risk – those with a family history of colon cancer, and those with previously detected adenomas. The family history cohort may be useful for clinical practice, according to Priyanka Kanth, MD, who was also asked to comment on the study. “Some people may not need [a colonoscopy] at 5 years if they have no polyps found and negative FIT,” said Dr. Kanth, who is an associate professor of gastroenterology at Georgetown University, Washington.
She feels less certain about the group with previously detected adenomas, given the change in U.S. guidelines. “We have already changed that, so I don’t think we need to really do FIT intervals for that cohort,” said Dr. Kanth. “I think this is a good study that has a lot of information and also reassures us that we don’t need such frequent colonoscopy surveillance,” she added.
Steve Serrao, MD, PhD, who was also asked for comment, emphasized the importance of high-quality colonoscopies that reach the cecum 95% of the time, and achieving high adenoma-detection rates. The system can get overwhelmed conducting colonoscopies on patients with good insurance coverage who have already undergone high-quality colonoscopies. “That pushes out patients that haven’t necessarily had a colonoscopy or a FIT. People who don’t have access are kind of crowded out by these false-positive tests. The best modality is actually to do a high-quality colonoscopy and then to have a really well-directed strategy following that colonoscopy,” said Dr. Serrao, who is division chief of gastroenterology and hepatology at Riverside University Health System, Moreno Valley, Calif.
The researchers analyzed data from 4,021 surveillance intervals and 3,369 participants. A total of 1,436 had no neoplasia at the prior colonoscopy, 1,704 had nonadvanced adenoma, and 880 had advanced adenoma. Participants completed no or one to four FIT tests between colonoscopies, with the final colonoscopy performed within 2 years of FIT tests. The median age was 63.9 years; 53.6% were female; 71.1% had a prior adenoma; and 28.9% had a family history of colorectal cancer. A total of 29.4% of participants had one negative FIT; 6.9% had four negative FITs during the interval period; and 31.0% did not complete any FIT tests.
Of follow-up colonoscopies, 9.9% revealed advanced adenomas. Among the patients with no prior neoplasia, those with one negative FIT had a cumulative index function for advanced neoplasia at 5 years of 8.5% (95% confidence interval, 4.9%-13.3%). This was higher than for those with three negative FITs (4.5%; 95% CI, 2.0%-8.6%) or four negative FITs (1.9%; 95% CI, 0.5%-5.0%). The association held for individuals with prior nonadvanced adenoma but not those with advanced adenoma.
Over the 5-year interval, three or more negative FIT tests were associated with a 50%-70% reduction in advanced neoplasia risk at follow-up colonoscopy (P < .001). There was no significant association over a 3-year interval. Dr. Kanth, Dr. Serrao, and Dr. Ness have no relevant financial disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Adverse events reported in one-quarter of inpatient admissions
as indicated from data from 2,809 admissions at 11 hospitals.
The 1991 Harvard Medical Practice Study, which focused on medical injury and litigation, documented an adverse event rate of 3.7 events per 100 admissions; 28% of those events were attributed to negligence, write David W. Bates, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
Although patient safety has changed significantly since 1991, documenting improvements has been challenging, the researchers say. Several reports have shown a decrease in health care–associated infections. However, other aspects of safety – notably, adverse drug events, defined as injuries resulting from drugs taken – are not easily measured and tracked, the researchers say.
“We have not had good estimates of how much harm is being caused by care in hospitals in an ongoing way that looked across all types of adverse events,” and the current review is therefore important, Dr. Bates said in an interview.
In a study recently published in the New England Journal of Medicine, the researchers analyzed a random sample of 2,809 hospital admissions from 11 hospitals in Massachusetts during the 2018 calendar year. The hospitals ranged in size from fewer than 100 beds to more than 700 beds; all patients were aged 18 years and older. A panel of nine nurses reviewed the admissions records to identify potential adverse events, and eight physicians reviewed the adverse event summaries and either agreed or disagreed with the adverse event type. The severity of each event was ranked using a general severity scale into categories of significant, serious, life-threatening, or fatal.
Overall, at least one adverse event was identified in 23.6% of the hospital admissions. A total of 978 adverse events were deemed to have occurred during the index admission, and 222 of these (22.7%) were deemed preventable. Among the preventable adverse events, 19.7% were classified as serious, 3.3% as life-threatening, and 0.5% as fatal.
A total of 523 admissions (18.6%) involved at least one significant adverse event, defined as an event that caused unnecessary harm but from which recovery was rapid. A total of 211 admissions involved a serious adverse event, defined as harm resulting in substantial intervention or prolonged recovery; 34 included at least one life-threatening event; and seven admissions involved a fatal adverse event.
A total of 191 admissions involved at least one adverse event deemed preventable. Of those, 29 involved at least one preventable adverse event that was serious, life-threatening, or fatal, the researchers write. Of the seven deaths in the study population, one was deemed preventable.
The most common adverse events were adverse drug events, which accounted for 39.0% of the adverse events; surgical or other procedural events accounted for 30.4%; patient care events (including falls and pressure ulcers) accounted for 15.0%; and health care–associated infections accounted for 11.9%.
Overcoming barriers to better safety
“The overall level of harm, with nearly 1 in 4 patients suffering an adverse event, was higher than I expected it might be,” Dr. Bates told this news organization. However, techniques for identifying adverse events have improved, and “it is easier to find them in electronic records than in paper records,” he noted.
“Hospitals have many issues they are currently dealing with since COVID, and one issue is simply prioritization,” Dr. Bates said. “But it is now possible to measure harm for all patients using electronic tools, and if hospitals know how much harm they are having in specific areas, they can make choices about which ones to focus on.”
“We now have effective prevention strategies for most of the main kinds of harm,” he said. Generally, rates of harm are high because these strategies are not being used effectively, he said. “In addition, there are new tools that can be used – for example, to identify patients who are decompensating earlier,” he noted.
As for additional research, some specific types of harm that have been resistant to interventions, such as pressure ulcers, deserve more attention, said Dr. Bates. “In addition, diagnostic errors appear to cause a great deal of harm, but we don’t yet have good strategies for preventing these,” he said.
The study findings were limited by several factors, including the use of data from hospitals that might not represent hospitals at large and by the inclusion mainly of patients with private insurance, the researchers write. Other limitations include the likelihood that some adverse events were missed and the level of agreement on adverse events between adjudicators was only fair.
However, the findings serve as a reminder to health care professionals of the need for continued attention to improving patient safety, and measuring adverse events remains a critical part of guiding these improvements, the researchers conclude.
Timely reassessment and opportunities to improve
In the decades since the publication of the report, “To Err Is Human,” by the National Academies in 2000, significant attention has been paid to improving patient safety during hospitalizations, and health care systems have increased in both system and disease complexity, Said Suman Pal, MBBS, a specialist in hospital medicine at the University of New Mexico, Albuquerque, said in an interview. “Therefore, this study is important in reassessing the safety of inpatient care at the current time,” he said.
“The findings of this study showing preventable adverse events in approximately 7% of all admissions; while concerning, is not surprising, as it is consistent with other studies over time, as the authors have also noted in their discussion,” said Dr. Pal. The current findings “underscore the importance of continuous quality improvement efforts to increase the safety of patient care for hospitalized patients,” he noted.
“The increasing complexity of medical care, fragmentation of health care, structural inequities of health systems, and more recent widespread public health challenges such as the COVID-19 pandemic have been, in my opinion, barriers to improving patient safety,” Dr. Pal said. “The use of innovation and an interdisciplinary approach to patient safety and quality improvement in hospital-based care, such as the use of machine learning to monitor trends and predict the individualized risk of harm, could be a potential way out” to help reduce barriers and improve safety, he said.
“Additional research is needed to understand the key drivers of preventable harm for hospitalized patients in the United States,” said Dr. Pal. “When planning for change, keen attention must be paid to understanding how these [drivers] may differ for patients who have been historically marginalized or are otherwise underserved so as to not exacerbate health care inequities,” he added.
The study was funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions. Dr. Bates owns stock options with AESOP, Clew, FeelBetter, Guided Clinical Solutions, MDClone, and ValeraHealth and has grants/contracts from IBM Watson and EarlySense. He has also served as a consultant for CDI Negev. Dr. Pal has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
as indicated from data from 2,809 admissions at 11 hospitals.
The 1991 Harvard Medical Practice Study, which focused on medical injury and litigation, documented an adverse event rate of 3.7 events per 100 admissions; 28% of those events were attributed to negligence, write David W. Bates, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
Although patient safety has changed significantly since 1991, documenting improvements has been challenging, the researchers say. Several reports have shown a decrease in health care–associated infections. However, other aspects of safety – notably, adverse drug events, defined as injuries resulting from drugs taken – are not easily measured and tracked, the researchers say.
“We have not had good estimates of how much harm is being caused by care in hospitals in an ongoing way that looked across all types of adverse events,” and the current review is therefore important, Dr. Bates said in an interview.
In a study recently published in the New England Journal of Medicine, the researchers analyzed a random sample of 2,809 hospital admissions from 11 hospitals in Massachusetts during the 2018 calendar year. The hospitals ranged in size from fewer than 100 beds to more than 700 beds; all patients were aged 18 years and older. A panel of nine nurses reviewed the admissions records to identify potential adverse events, and eight physicians reviewed the adverse event summaries and either agreed or disagreed with the adverse event type. The severity of each event was ranked using a general severity scale into categories of significant, serious, life-threatening, or fatal.
Overall, at least one adverse event was identified in 23.6% of the hospital admissions. A total of 978 adverse events were deemed to have occurred during the index admission, and 222 of these (22.7%) were deemed preventable. Among the preventable adverse events, 19.7% were classified as serious, 3.3% as life-threatening, and 0.5% as fatal.
A total of 523 admissions (18.6%) involved at least one significant adverse event, defined as an event that caused unnecessary harm but from which recovery was rapid. A total of 211 admissions involved a serious adverse event, defined as harm resulting in substantial intervention or prolonged recovery; 34 included at least one life-threatening event; and seven admissions involved a fatal adverse event.
A total of 191 admissions involved at least one adverse event deemed preventable. Of those, 29 involved at least one preventable adverse event that was serious, life-threatening, or fatal, the researchers write. Of the seven deaths in the study population, one was deemed preventable.
The most common adverse events were adverse drug events, which accounted for 39.0% of the adverse events; surgical or other procedural events accounted for 30.4%; patient care events (including falls and pressure ulcers) accounted for 15.0%; and health care–associated infections accounted for 11.9%.
Overcoming barriers to better safety
“The overall level of harm, with nearly 1 in 4 patients suffering an adverse event, was higher than I expected it might be,” Dr. Bates told this news organization. However, techniques for identifying adverse events have improved, and “it is easier to find them in electronic records than in paper records,” he noted.
“Hospitals have many issues they are currently dealing with since COVID, and one issue is simply prioritization,” Dr. Bates said. “But it is now possible to measure harm for all patients using electronic tools, and if hospitals know how much harm they are having in specific areas, they can make choices about which ones to focus on.”
“We now have effective prevention strategies for most of the main kinds of harm,” he said. Generally, rates of harm are high because these strategies are not being used effectively, he said. “In addition, there are new tools that can be used – for example, to identify patients who are decompensating earlier,” he noted.
As for additional research, some specific types of harm that have been resistant to interventions, such as pressure ulcers, deserve more attention, said Dr. Bates. “In addition, diagnostic errors appear to cause a great deal of harm, but we don’t yet have good strategies for preventing these,” he said.
The study findings were limited by several factors, including the use of data from hospitals that might not represent hospitals at large and by the inclusion mainly of patients with private insurance, the researchers write. Other limitations include the likelihood that some adverse events were missed and the level of agreement on adverse events between adjudicators was only fair.
However, the findings serve as a reminder to health care professionals of the need for continued attention to improving patient safety, and measuring adverse events remains a critical part of guiding these improvements, the researchers conclude.
Timely reassessment and opportunities to improve
In the decades since the publication of the report, “To Err Is Human,” by the National Academies in 2000, significant attention has been paid to improving patient safety during hospitalizations, and health care systems have increased in both system and disease complexity, Said Suman Pal, MBBS, a specialist in hospital medicine at the University of New Mexico, Albuquerque, said in an interview. “Therefore, this study is important in reassessing the safety of inpatient care at the current time,” he said.
“The findings of this study showing preventable adverse events in approximately 7% of all admissions; while concerning, is not surprising, as it is consistent with other studies over time, as the authors have also noted in their discussion,” said Dr. Pal. The current findings “underscore the importance of continuous quality improvement efforts to increase the safety of patient care for hospitalized patients,” he noted.
“The increasing complexity of medical care, fragmentation of health care, structural inequities of health systems, and more recent widespread public health challenges such as the COVID-19 pandemic have been, in my opinion, barriers to improving patient safety,” Dr. Pal said. “The use of innovation and an interdisciplinary approach to patient safety and quality improvement in hospital-based care, such as the use of machine learning to monitor trends and predict the individualized risk of harm, could be a potential way out” to help reduce barriers and improve safety, he said.
“Additional research is needed to understand the key drivers of preventable harm for hospitalized patients in the United States,” said Dr. Pal. “When planning for change, keen attention must be paid to understanding how these [drivers] may differ for patients who have been historically marginalized or are otherwise underserved so as to not exacerbate health care inequities,” he added.
The study was funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions. Dr. Bates owns stock options with AESOP, Clew, FeelBetter, Guided Clinical Solutions, MDClone, and ValeraHealth and has grants/contracts from IBM Watson and EarlySense. He has also served as a consultant for CDI Negev. Dr. Pal has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
as indicated from data from 2,809 admissions at 11 hospitals.
The 1991 Harvard Medical Practice Study, which focused on medical injury and litigation, documented an adverse event rate of 3.7 events per 100 admissions; 28% of those events were attributed to negligence, write David W. Bates, MD, of Brigham and Women’s Hospital, Boston, and colleagues.
Although patient safety has changed significantly since 1991, documenting improvements has been challenging, the researchers say. Several reports have shown a decrease in health care–associated infections. However, other aspects of safety – notably, adverse drug events, defined as injuries resulting from drugs taken – are not easily measured and tracked, the researchers say.
“We have not had good estimates of how much harm is being caused by care in hospitals in an ongoing way that looked across all types of adverse events,” and the current review is therefore important, Dr. Bates said in an interview.
In a study recently published in the New England Journal of Medicine, the researchers analyzed a random sample of 2,809 hospital admissions from 11 hospitals in Massachusetts during the 2018 calendar year. The hospitals ranged in size from fewer than 100 beds to more than 700 beds; all patients were aged 18 years and older. A panel of nine nurses reviewed the admissions records to identify potential adverse events, and eight physicians reviewed the adverse event summaries and either agreed or disagreed with the adverse event type. The severity of each event was ranked using a general severity scale into categories of significant, serious, life-threatening, or fatal.
Overall, at least one adverse event was identified in 23.6% of the hospital admissions. A total of 978 adverse events were deemed to have occurred during the index admission, and 222 of these (22.7%) were deemed preventable. Among the preventable adverse events, 19.7% were classified as serious, 3.3% as life-threatening, and 0.5% as fatal.
A total of 523 admissions (18.6%) involved at least one significant adverse event, defined as an event that caused unnecessary harm but from which recovery was rapid. A total of 211 admissions involved a serious adverse event, defined as harm resulting in substantial intervention or prolonged recovery; 34 included at least one life-threatening event; and seven admissions involved a fatal adverse event.
A total of 191 admissions involved at least one adverse event deemed preventable. Of those, 29 involved at least one preventable adverse event that was serious, life-threatening, or fatal, the researchers write. Of the seven deaths in the study population, one was deemed preventable.
The most common adverse events were adverse drug events, which accounted for 39.0% of the adverse events; surgical or other procedural events accounted for 30.4%; patient care events (including falls and pressure ulcers) accounted for 15.0%; and health care–associated infections accounted for 11.9%.
Overcoming barriers to better safety
“The overall level of harm, with nearly 1 in 4 patients suffering an adverse event, was higher than I expected it might be,” Dr. Bates told this news organization. However, techniques for identifying adverse events have improved, and “it is easier to find them in electronic records than in paper records,” he noted.
“Hospitals have many issues they are currently dealing with since COVID, and one issue is simply prioritization,” Dr. Bates said. “But it is now possible to measure harm for all patients using electronic tools, and if hospitals know how much harm they are having in specific areas, they can make choices about which ones to focus on.”
“We now have effective prevention strategies for most of the main kinds of harm,” he said. Generally, rates of harm are high because these strategies are not being used effectively, he said. “In addition, there are new tools that can be used – for example, to identify patients who are decompensating earlier,” he noted.
As for additional research, some specific types of harm that have been resistant to interventions, such as pressure ulcers, deserve more attention, said Dr. Bates. “In addition, diagnostic errors appear to cause a great deal of harm, but we don’t yet have good strategies for preventing these,” he said.
The study findings were limited by several factors, including the use of data from hospitals that might not represent hospitals at large and by the inclusion mainly of patients with private insurance, the researchers write. Other limitations include the likelihood that some adverse events were missed and the level of agreement on adverse events between adjudicators was only fair.
However, the findings serve as a reminder to health care professionals of the need for continued attention to improving patient safety, and measuring adverse events remains a critical part of guiding these improvements, the researchers conclude.
Timely reassessment and opportunities to improve
In the decades since the publication of the report, “To Err Is Human,” by the National Academies in 2000, significant attention has been paid to improving patient safety during hospitalizations, and health care systems have increased in both system and disease complexity, Said Suman Pal, MBBS, a specialist in hospital medicine at the University of New Mexico, Albuquerque, said in an interview. “Therefore, this study is important in reassessing the safety of inpatient care at the current time,” he said.
“The findings of this study showing preventable adverse events in approximately 7% of all admissions; while concerning, is not surprising, as it is consistent with other studies over time, as the authors have also noted in their discussion,” said Dr. Pal. The current findings “underscore the importance of continuous quality improvement efforts to increase the safety of patient care for hospitalized patients,” he noted.
“The increasing complexity of medical care, fragmentation of health care, structural inequities of health systems, and more recent widespread public health challenges such as the COVID-19 pandemic have been, in my opinion, barriers to improving patient safety,” Dr. Pal said. “The use of innovation and an interdisciplinary approach to patient safety and quality improvement in hospital-based care, such as the use of machine learning to monitor trends and predict the individualized risk of harm, could be a potential way out” to help reduce barriers and improve safety, he said.
“Additional research is needed to understand the key drivers of preventable harm for hospitalized patients in the United States,” said Dr. Pal. “When planning for change, keen attention must be paid to understanding how these [drivers] may differ for patients who have been historically marginalized or are otherwise underserved so as to not exacerbate health care inequities,” he added.
The study was funded by the Controlled Risk Insurance Company and the Risk Management Foundation of the Harvard Medical Institutions. Dr. Bates owns stock options with AESOP, Clew, FeelBetter, Guided Clinical Solutions, MDClone, and ValeraHealth and has grants/contracts from IBM Watson and EarlySense. He has also served as a consultant for CDI Negev. Dr. Pal has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE