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Four commonly abused drugs linked with atrial fibrillation
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.
While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.
“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.
Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.
The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.
Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.
“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”
In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.
At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).
“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.
Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
Causal mechanisms deserve a closer look
Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.
“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”
Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.
Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.
“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”
Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.
“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”
Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.
“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”
The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.
FROM EUROPEAN HEART JOURNAL
More data suggest preexisting statin use improves COVID outcomes
Compared with patients who didn’t take statins, statin users had better health outcomes. For those who used these medications, the researchers saw lower mortality, lower clinical severity, and shorter hospital stays, aligning with previous observational studies, said lead author Ettore Crimi, MD, of the University of Central Florida, Orlando, and colleagues in their abstract, which was part of the agenda for the Anesthesiology annual meeting.
They attributed these clinical improvements to the pleiotropic – non–cholesterol lowering – effects of statins.
“[These] benefits of statins have been reported since the 1990s,” Dr. Crimi said in an interview. “Statin treatment has been associated with a marked reduction of markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), interleukin-6 (IL-6), ferritin, and white blood cell count, among others.”
He noted that these effects have been studied in an array of conditions, including cancer, autoimmune diseases, chronic inflammatory disease, and in the perioperative setting, and with infectious diseases, including COVID-19.
In those previous studies, “preexisting statin use was protective among hospitalized COVID-19 patients, but a large, multicenter cohort study has not been reported in the United States,” Dr. Crimi and his colleagues wrote in their abstract.
To address this knowledge gap, they turned to electronic medical records from 38,875 patients hospitalized with COVID-19 from January to September 2020. Almost one-third of the population (n = 11,533) were using statins prior to hospitalization, while the remainder (n = 27,342) were nonusers.
The primary outcome was all-cause mortality. Secondary outcomes included death from COVID-19, along with a variety of severe complications. While the analysis did account for a range of potentially confounding variables, the effects of different SARS-CoV-2 variants and new therapeutics were not considered. Vaccines were not yet available at the time the data were collected.
Statin users had a 31% lower rate of all-cause mortality (odds ratio, 0.69; 95% confidence interval, 0.64-0.75; P = .001) and a 37% reduced rate of death from COVID-19 (OR, 0.63; 95% CI, 0.58-0.69; P = .001).
A litany of other secondary variables also favored statin users, including reduced rates of discharge to hospice (OR, 0.79), ICU admission (OR, 0.69), severe acute respiratory distress syndrome (ARDs; OR, 0.72), critical ARDs (OR, 0.57), mechanical ventilation (OR, 0.60), severe sepsis with septic shock (OR, 0.66), and thrombosis (OR, 0.46). Statin users also had, on average, shorter hospital stays and briefer mechanical ventilation.
“Our study showed a strong association between preexisting statin use and reduced mortality and morbidity rates in hospitalized COVID-19 patients,” the investigators concluded. “Pleiotropic benefits of statins could be repurposed for COVID-19 illness.”
Prospective studies needed before practice changes
How to best use statins against COVID-19, if at all, remains unclear, Dr. Crimi said, as initiation upon infection has generated mixed results in other studies, possibly because of statin pharmacodynamics. Cholesterol normalization can take about 6 weeks, so other benefits may track a similar timeline.
“The delayed onset of statins’ pleiotropic effects may likely fail to keep pace with the rapidly progressive, devastating COVID-19 disease,” Dr. Crimi said. “Therefore, initiating statins for an acute disease may not be an ideal first-line treatment.”
Stronger data are on the horizon, he added, noting that 19 federally funded prospective trials are underway to better understand the relationship between statins and COVID-19.
Daniel Rader, MD, of the University of Pennsylvania, Philadelphia, said the present findings are “not especially notable” because they “mostly confirm previous studies, but in a large U.S. cohort.”
Dr. Rader, who wrote about the potential repurposing of statins for COVID-19 back in the first year of the pandemic (Cell Metab. 2020 Aug 4;32[2]:145-7), agreed with the investigators that recommending changes to clinical practice would be imprudent until randomized controlled data confirm the benefits of initiating statins in patients with active COVID-19.
“More research on the impact of cellular cholesterol metabolism on SARS-CoV-2 infection of cells and generation of inflammation would also be of interest,” he added.
The investigators disclosed no competing interests. Dr. Rader disclosed relationships with Novartis, Pfizer, Verve, and others.
Compared with patients who didn’t take statins, statin users had better health outcomes. For those who used these medications, the researchers saw lower mortality, lower clinical severity, and shorter hospital stays, aligning with previous observational studies, said lead author Ettore Crimi, MD, of the University of Central Florida, Orlando, and colleagues in their abstract, which was part of the agenda for the Anesthesiology annual meeting.
They attributed these clinical improvements to the pleiotropic – non–cholesterol lowering – effects of statins.
“[These] benefits of statins have been reported since the 1990s,” Dr. Crimi said in an interview. “Statin treatment has been associated with a marked reduction of markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), interleukin-6 (IL-6), ferritin, and white blood cell count, among others.”
He noted that these effects have been studied in an array of conditions, including cancer, autoimmune diseases, chronic inflammatory disease, and in the perioperative setting, and with infectious diseases, including COVID-19.
In those previous studies, “preexisting statin use was protective among hospitalized COVID-19 patients, but a large, multicenter cohort study has not been reported in the United States,” Dr. Crimi and his colleagues wrote in their abstract.
To address this knowledge gap, they turned to electronic medical records from 38,875 patients hospitalized with COVID-19 from January to September 2020. Almost one-third of the population (n = 11,533) were using statins prior to hospitalization, while the remainder (n = 27,342) were nonusers.
The primary outcome was all-cause mortality. Secondary outcomes included death from COVID-19, along with a variety of severe complications. While the analysis did account for a range of potentially confounding variables, the effects of different SARS-CoV-2 variants and new therapeutics were not considered. Vaccines were not yet available at the time the data were collected.
Statin users had a 31% lower rate of all-cause mortality (odds ratio, 0.69; 95% confidence interval, 0.64-0.75; P = .001) and a 37% reduced rate of death from COVID-19 (OR, 0.63; 95% CI, 0.58-0.69; P = .001).
A litany of other secondary variables also favored statin users, including reduced rates of discharge to hospice (OR, 0.79), ICU admission (OR, 0.69), severe acute respiratory distress syndrome (ARDs; OR, 0.72), critical ARDs (OR, 0.57), mechanical ventilation (OR, 0.60), severe sepsis with septic shock (OR, 0.66), and thrombosis (OR, 0.46). Statin users also had, on average, shorter hospital stays and briefer mechanical ventilation.
“Our study showed a strong association between preexisting statin use and reduced mortality and morbidity rates in hospitalized COVID-19 patients,” the investigators concluded. “Pleiotropic benefits of statins could be repurposed for COVID-19 illness.”
Prospective studies needed before practice changes
How to best use statins against COVID-19, if at all, remains unclear, Dr. Crimi said, as initiation upon infection has generated mixed results in other studies, possibly because of statin pharmacodynamics. Cholesterol normalization can take about 6 weeks, so other benefits may track a similar timeline.
“The delayed onset of statins’ pleiotropic effects may likely fail to keep pace with the rapidly progressive, devastating COVID-19 disease,” Dr. Crimi said. “Therefore, initiating statins for an acute disease may not be an ideal first-line treatment.”
Stronger data are on the horizon, he added, noting that 19 federally funded prospective trials are underway to better understand the relationship between statins and COVID-19.
Daniel Rader, MD, of the University of Pennsylvania, Philadelphia, said the present findings are “not especially notable” because they “mostly confirm previous studies, but in a large U.S. cohort.”
Dr. Rader, who wrote about the potential repurposing of statins for COVID-19 back in the first year of the pandemic (Cell Metab. 2020 Aug 4;32[2]:145-7), agreed with the investigators that recommending changes to clinical practice would be imprudent until randomized controlled data confirm the benefits of initiating statins in patients with active COVID-19.
“More research on the impact of cellular cholesterol metabolism on SARS-CoV-2 infection of cells and generation of inflammation would also be of interest,” he added.
The investigators disclosed no competing interests. Dr. Rader disclosed relationships with Novartis, Pfizer, Verve, and others.
Compared with patients who didn’t take statins, statin users had better health outcomes. For those who used these medications, the researchers saw lower mortality, lower clinical severity, and shorter hospital stays, aligning with previous observational studies, said lead author Ettore Crimi, MD, of the University of Central Florida, Orlando, and colleagues in their abstract, which was part of the agenda for the Anesthesiology annual meeting.
They attributed these clinical improvements to the pleiotropic – non–cholesterol lowering – effects of statins.
“[These] benefits of statins have been reported since the 1990s,” Dr. Crimi said in an interview. “Statin treatment has been associated with a marked reduction of markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), interleukin-6 (IL-6), ferritin, and white blood cell count, among others.”
He noted that these effects have been studied in an array of conditions, including cancer, autoimmune diseases, chronic inflammatory disease, and in the perioperative setting, and with infectious diseases, including COVID-19.
In those previous studies, “preexisting statin use was protective among hospitalized COVID-19 patients, but a large, multicenter cohort study has not been reported in the United States,” Dr. Crimi and his colleagues wrote in their abstract.
To address this knowledge gap, they turned to electronic medical records from 38,875 patients hospitalized with COVID-19 from January to September 2020. Almost one-third of the population (n = 11,533) were using statins prior to hospitalization, while the remainder (n = 27,342) were nonusers.
The primary outcome was all-cause mortality. Secondary outcomes included death from COVID-19, along with a variety of severe complications. While the analysis did account for a range of potentially confounding variables, the effects of different SARS-CoV-2 variants and new therapeutics were not considered. Vaccines were not yet available at the time the data were collected.
Statin users had a 31% lower rate of all-cause mortality (odds ratio, 0.69; 95% confidence interval, 0.64-0.75; P = .001) and a 37% reduced rate of death from COVID-19 (OR, 0.63; 95% CI, 0.58-0.69; P = .001).
A litany of other secondary variables also favored statin users, including reduced rates of discharge to hospice (OR, 0.79), ICU admission (OR, 0.69), severe acute respiratory distress syndrome (ARDs; OR, 0.72), critical ARDs (OR, 0.57), mechanical ventilation (OR, 0.60), severe sepsis with septic shock (OR, 0.66), and thrombosis (OR, 0.46). Statin users also had, on average, shorter hospital stays and briefer mechanical ventilation.
“Our study showed a strong association between preexisting statin use and reduced mortality and morbidity rates in hospitalized COVID-19 patients,” the investigators concluded. “Pleiotropic benefits of statins could be repurposed for COVID-19 illness.”
Prospective studies needed before practice changes
How to best use statins against COVID-19, if at all, remains unclear, Dr. Crimi said, as initiation upon infection has generated mixed results in other studies, possibly because of statin pharmacodynamics. Cholesterol normalization can take about 6 weeks, so other benefits may track a similar timeline.
“The delayed onset of statins’ pleiotropic effects may likely fail to keep pace with the rapidly progressive, devastating COVID-19 disease,” Dr. Crimi said. “Therefore, initiating statins for an acute disease may not be an ideal first-line treatment.”
Stronger data are on the horizon, he added, noting that 19 federally funded prospective trials are underway to better understand the relationship between statins and COVID-19.
Daniel Rader, MD, of the University of Pennsylvania, Philadelphia, said the present findings are “not especially notable” because they “mostly confirm previous studies, but in a large U.S. cohort.”
Dr. Rader, who wrote about the potential repurposing of statins for COVID-19 back in the first year of the pandemic (Cell Metab. 2020 Aug 4;32[2]:145-7), agreed with the investigators that recommending changes to clinical practice would be imprudent until randomized controlled data confirm the benefits of initiating statins in patients with active COVID-19.
“More research on the impact of cellular cholesterol metabolism on SARS-CoV-2 infection of cells and generation of inflammation would also be of interest,” he added.
The investigators disclosed no competing interests. Dr. Rader disclosed relationships with Novartis, Pfizer, Verve, and others.
FROM ANESTHESIOLOGY 2022
JAK inhibitors show no excess cardiovascular safety signal in French nationwide cohort
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF THE RHEUMATIC DISEASES
Apixaban outmatches rivaroxaban in patients with AFib and valvular heart disease
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
Compared with rivaroxaban, apixaban cut risks nearly in half, suggesting that clinicians should consider these new data when choosing an anticoagulant, reported lead author Ghadeer K. Dawwas, PhD, of the University of Pennsylvania, Philadelphia, and colleagues.
In the new retrospective study involving almost 20,000 patients, Dr. Dawwas and her colleagues “emulated a target trial” using private insurance claims from Optum’s deidentified Clinformatics Data Mart Database. The cohort was narrowed from a screened population of 58,210 patients with concurrent AFib and VHD to 9,947 new apixaban users who could be closely matched with 9,947 new rivaroxaban users. Covariates included provider specialty, type of VHD, demographic characteristics, measures of health care use, baseline use of medications, and baseline comorbidities.
The primary effectiveness outcome was a composite of systemic embolism and ischemic stroke, while the primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
“Although several ongoing trials aim to compare apixaban with warfarin in patients with AFib and VHD, none of these trials will directly compare apixaban and rivaroxaban,” the investigators wrote. Their report is in Annals of Internal Medicine.
Dr. Dawwas and colleagues previously showed that direct oral anticoagulants (DOACs) were safer and more effective than warfarin in the same patient population. Comparing apixaban and rivaroxaban – the two most common DOACs – was the next logical step, Dr. Dawwas said in an interview.
Study results
Compared with rivaroxaban, patients who received apixaban had a 43% reduced risk of stroke or embolism (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40-0.80). Apixaban’s ability to protect against bleeding appeared even more pronounced, with a 49% reduced risk over rivaroxaban (HR, 0.51; 95% CI, 0.41-0.62).
Comparing the two agents on an absolute basis, apixaban reduced risk of embolism or stroke by 0.2% within the first 6 months of treatment initiation, and 1.1% within the first year of initiation. At the same time points, absolute risk reductions for bleeding were 1.2% and 1.9%, respectively.
The investigators noted that their results held consistent in an alternative analysis that considered separate types of VHD.
“Based on the results from our analysis, we showed that apixaban is effective and safe in patients with atrial fibrillation and valvular heart diseases,” Dr. Dawwas said.
Head-to-head trial needed to change practice
Christopher M. Bianco, DO, associate professor of medicine at West Virginia University Heart and Vascular Institute, Morgantown, said the findings “add to the growing body of literature,” but “a head-to-head trial would be necessary to make a definitive change to clinical practice.”
Dr. Bianco, who recently conducted a retrospective analysis of apixaban and rivaroxaban that found no difference in safety and efficacy among a different patient population, said these kinds of studies are helpful in generating hypotheses, but they can’t account for all relevant clinical factors.
“There are just so many things that go into the decision-making process of [prescribing] apixaban and rivaroxaban,” he said. “Even though [Dr. Dawwas and colleagues] used propensity matching, you’re never going to be able to sort that out with a retrospective analysis.”
Specifically, Dr. Bianco noted that the findings did not include dose data. This is a key gap, he said, considering how often real-world datasets have shown that providers underdose DOACs for a number of unaccountable reasons, and how frequently patients exhibit poor adherence.
The study also lacked detail concerning the degree of renal dysfunction, which can determine drug eligibility, Dr. Bianco said. Furthermore, attempts to stratify patients based on thrombosis and bleeding risk were likely “insufficient,” he added.
Dr. Bianco also cautioned that the investigators defined valvular heart disease as any valve-related disease of any severity. In contrast, previous studies have generally restricted valvular heart disease to patients with mitral stenosis or prosthetic valves.
“This is definitely not the traditional definition of valvular heart disease, so the title is a little bit misleading in that sense, although they certainly do disclose that in the methods,” Dr. Bianco said.
On a more positive note, he highlighted the size of the patient population, and the real-world data, which included many patients who would be excluded from clinical trials.
More broadly, the study helps drive research forward, Dr. Bianco concluded; namely, by attracting financial support for a more powerful head-to-head trial that drug makers are unlikely to fund due to inherent market risk.
This study was supported by the National Institutes of Health. The investigators disclosed additional relationships with Takeda, Spark, Sanofi, and others. Dr. Bianco disclosed no conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE
Increased body temperature triggers flares in rare autoinflammatory disorder
Increased core body temperature is a likely trigger of disease flares in the rare genetic autoinflammatory disorder mevalonate kinase deficiency (MKD), based on a study involving new mouse models.
The study also uncovered potential strategies for treating MKD, lead author Marcia A. Munoz, PhD, of the Garvan Institute of Medical Research and the University of New South Wales, Sydney, and colleagues reported in Journal of Clinical Investigation.
“MKD encompasses a severe manifestation – mevalonic aciduria, and a milder form – a periodic fever syndrome known as hyperimmunoglobulinemia D syndrome,” the investigators wrote.
They noted that severity inversely correlates with the amount of mevalonate kinase in the body. To date, however, it’s been unclear why reduced levels of the enzyme lead to inflammation, or exactly how body temperature plays a role in this process, despite observations that disease flares can be triggered by temperature-raising activities like strenuous exercise.
“The underlying disease mechanisms in MKD have been very difficult to elucidate, because newly identified patients are usually young children (and it’s very difficult to obtain any samples of tissues or cells other than small samples of blood), and also because until now there were no laboratory models that truly mimic the human disease,” senior author Michael J. Rogers, PhD, of the Garvan Institute said in a written comment.
Dr. Rogers and colleagues addressed this gap by creating the first murine models to carry the relevant mutant allele in MVK, the gene encoding mevalonate kinase. These mice had lower levels of the enzyme, which led to increased levels of mevalonic acid and defects in protein prenylation (the addition of hydrophobic moieties), the latter of which were significantly associated with inflammation.
“The discovery that shortage of geranylgeranyl diphosphate, the substrate necessary for prenylation of over 300 substrates including small GTPases, and not the elevated mevalonic acid levels, correlated with inflammation was an important finding that ultimately provided a pathomechanism that linked the mevalonate kinase deficiency to inflammasome activation,” said Raphaela T. Goldbach-Mansky, MD, chief of the translational autoinflammatory disease studies unit at the National Institute of Allergy and Infectious Diseases.
Dr. Goldbach-Mansky said the new mouse models can serve as “preclinical platforms” to test the efficacy and safety of possible treatments, such as supplementing geranylgeraniol, an intermediate product in the mevalonate pathway, or blocking NLRP3, the inflammasome in question.
While both of these interventions showed efficacy in mice, it is unclear whether the same therapies will work in people, as the models may not reflect all human disease characteristics.
“It remains unclear which human features are modeled in the mouse model,” Dr. Goldbach-Mansky said, noting that humans may exhibit unique inflammasomes and disease triggers.
Dr. Rogers aims to find out. After 8 years of work that culminated in the present publication, he and his colleagues are now exploring ways of circumventing the defective enzyme to restore normal metabolism. He expects “many more years of work” to understand exactly how MKD affects the immune system and other organs, and how these processes can be mitigated.
Still, he is optimistic.
“Of the many autoinflammatory diseases that are known so far, we believe that new treatments are truly within reach to overcome MKD,” Dr. Rogers said.
The study was supported by the Australian National Health and Medical Research Council, St. Vincent’s Clinic Foundation, the Allergy and Immunology Foundation of Australasia, and others. The investigators and Dr. Goldbach-Mansky declared no competing interests.
Increased core body temperature is a likely trigger of disease flares in the rare genetic autoinflammatory disorder mevalonate kinase deficiency (MKD), based on a study involving new mouse models.
The study also uncovered potential strategies for treating MKD, lead author Marcia A. Munoz, PhD, of the Garvan Institute of Medical Research and the University of New South Wales, Sydney, and colleagues reported in Journal of Clinical Investigation.
“MKD encompasses a severe manifestation – mevalonic aciduria, and a milder form – a periodic fever syndrome known as hyperimmunoglobulinemia D syndrome,” the investigators wrote.
They noted that severity inversely correlates with the amount of mevalonate kinase in the body. To date, however, it’s been unclear why reduced levels of the enzyme lead to inflammation, or exactly how body temperature plays a role in this process, despite observations that disease flares can be triggered by temperature-raising activities like strenuous exercise.
“The underlying disease mechanisms in MKD have been very difficult to elucidate, because newly identified patients are usually young children (and it’s very difficult to obtain any samples of tissues or cells other than small samples of blood), and also because until now there were no laboratory models that truly mimic the human disease,” senior author Michael J. Rogers, PhD, of the Garvan Institute said in a written comment.
Dr. Rogers and colleagues addressed this gap by creating the first murine models to carry the relevant mutant allele in MVK, the gene encoding mevalonate kinase. These mice had lower levels of the enzyme, which led to increased levels of mevalonic acid and defects in protein prenylation (the addition of hydrophobic moieties), the latter of which were significantly associated with inflammation.
“The discovery that shortage of geranylgeranyl diphosphate, the substrate necessary for prenylation of over 300 substrates including small GTPases, and not the elevated mevalonic acid levels, correlated with inflammation was an important finding that ultimately provided a pathomechanism that linked the mevalonate kinase deficiency to inflammasome activation,” said Raphaela T. Goldbach-Mansky, MD, chief of the translational autoinflammatory disease studies unit at the National Institute of Allergy and Infectious Diseases.
Dr. Goldbach-Mansky said the new mouse models can serve as “preclinical platforms” to test the efficacy and safety of possible treatments, such as supplementing geranylgeraniol, an intermediate product in the mevalonate pathway, or blocking NLRP3, the inflammasome in question.
While both of these interventions showed efficacy in mice, it is unclear whether the same therapies will work in people, as the models may not reflect all human disease characteristics.
“It remains unclear which human features are modeled in the mouse model,” Dr. Goldbach-Mansky said, noting that humans may exhibit unique inflammasomes and disease triggers.
Dr. Rogers aims to find out. After 8 years of work that culminated in the present publication, he and his colleagues are now exploring ways of circumventing the defective enzyme to restore normal metabolism. He expects “many more years of work” to understand exactly how MKD affects the immune system and other organs, and how these processes can be mitigated.
Still, he is optimistic.
“Of the many autoinflammatory diseases that are known so far, we believe that new treatments are truly within reach to overcome MKD,” Dr. Rogers said.
The study was supported by the Australian National Health and Medical Research Council, St. Vincent’s Clinic Foundation, the Allergy and Immunology Foundation of Australasia, and others. The investigators and Dr. Goldbach-Mansky declared no competing interests.
Increased core body temperature is a likely trigger of disease flares in the rare genetic autoinflammatory disorder mevalonate kinase deficiency (MKD), based on a study involving new mouse models.
The study also uncovered potential strategies for treating MKD, lead author Marcia A. Munoz, PhD, of the Garvan Institute of Medical Research and the University of New South Wales, Sydney, and colleagues reported in Journal of Clinical Investigation.
“MKD encompasses a severe manifestation – mevalonic aciduria, and a milder form – a periodic fever syndrome known as hyperimmunoglobulinemia D syndrome,” the investigators wrote.
They noted that severity inversely correlates with the amount of mevalonate kinase in the body. To date, however, it’s been unclear why reduced levels of the enzyme lead to inflammation, or exactly how body temperature plays a role in this process, despite observations that disease flares can be triggered by temperature-raising activities like strenuous exercise.
“The underlying disease mechanisms in MKD have been very difficult to elucidate, because newly identified patients are usually young children (and it’s very difficult to obtain any samples of tissues or cells other than small samples of blood), and also because until now there were no laboratory models that truly mimic the human disease,” senior author Michael J. Rogers, PhD, of the Garvan Institute said in a written comment.
Dr. Rogers and colleagues addressed this gap by creating the first murine models to carry the relevant mutant allele in MVK, the gene encoding mevalonate kinase. These mice had lower levels of the enzyme, which led to increased levels of mevalonic acid and defects in protein prenylation (the addition of hydrophobic moieties), the latter of which were significantly associated with inflammation.
“The discovery that shortage of geranylgeranyl diphosphate, the substrate necessary for prenylation of over 300 substrates including small GTPases, and not the elevated mevalonic acid levels, correlated with inflammation was an important finding that ultimately provided a pathomechanism that linked the mevalonate kinase deficiency to inflammasome activation,” said Raphaela T. Goldbach-Mansky, MD, chief of the translational autoinflammatory disease studies unit at the National Institute of Allergy and Infectious Diseases.
Dr. Goldbach-Mansky said the new mouse models can serve as “preclinical platforms” to test the efficacy and safety of possible treatments, such as supplementing geranylgeraniol, an intermediate product in the mevalonate pathway, or blocking NLRP3, the inflammasome in question.
While both of these interventions showed efficacy in mice, it is unclear whether the same therapies will work in people, as the models may not reflect all human disease characteristics.
“It remains unclear which human features are modeled in the mouse model,” Dr. Goldbach-Mansky said, noting that humans may exhibit unique inflammasomes and disease triggers.
Dr. Rogers aims to find out. After 8 years of work that culminated in the present publication, he and his colleagues are now exploring ways of circumventing the defective enzyme to restore normal metabolism. He expects “many more years of work” to understand exactly how MKD affects the immune system and other organs, and how these processes can be mitigated.
Still, he is optimistic.
“Of the many autoinflammatory diseases that are known so far, we believe that new treatments are truly within reach to overcome MKD,” Dr. Rogers said.
The study was supported by the Australian National Health and Medical Research Council, St. Vincent’s Clinic Foundation, the Allergy and Immunology Foundation of Australasia, and others. The investigators and Dr. Goldbach-Mansky declared no competing interests.
FROM THE JOURNAL OF CLINICAL INVESTIGATION
Early FMT shows promise for preventing recurrent C. difficile
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center (www.gastro.org/Cdiff).
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center (www.gastro.org/Cdiff).
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center (www.gastro.org/Cdiff).
FROM THE LANCET GASTROENTEROLOGY & HEPATOLOGY
Early FMT shows promise for preventing recurrent C. difficile
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.
Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.
The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.
“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”
The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.
“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”
The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.
Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).
One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.
“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
Encouraging findings, lingering concerns
Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.
“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”
Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.
John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.
“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”
Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.
“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.
Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.
While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.
“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.
This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.
FROM THE LANCET GASTROENTEROLOGY & HEPATOLOGY
New liver stiffness thresholds refine NASH risk stratification
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
FROM GUT
Night owls may have greater risks of T2D and CVD
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
FROM EXPERIMENTAL PHYSIOLOGY
Online yoga program improves physical function in OA
Although pain did not significantly improve in the yoga group, participants only completed about two-thirds of the recommended sessions, suggesting that more benefit may be possible with greater adherence, wrote lead author Kim L. Bennell, PhD, of the University of Melbourne, and colleagues in the Annals of Internal Medicine.
“To date, an online yoga program specifically for people with knee osteoarthritis has not been investigated,” the investigators said. “The need for such evidence-based packaged online exercise programs is highlighted in the 2020 U.S. National Public Health Agenda for Osteoarthritis.”
Methods and results
The trial involved 212 adults aged 45 years or older with symptomatic knee osteoarthritis. All patients had access to online educational materials about managing osteoarthritis.
Half of the participants were randomized into the 12-week online yoga program. This self-directed, unsupervised course consisted of 12 prerecorded 30-minute instructional yoga sessions, each with a unique sequence of poses to be completed three times in one week before moving on to the next class the following week. After 12 weeks, these participants could choose to continue doing yoga via the online program for 12 additional weeks, if desired.
The primary outcomes were knee pain and physical function, gauged by a 10-point numerical rating scale and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively. Adherence was defined as completion of at least 2 yoga sessions within the preceding week.
At the 12-week mark, the yoga group did not show any significant improvement in knee pain (–0.6; 95% confidence interval, –1.2 to 0.1), but they did achieve a mean 4-point reduction in WOMAC, suggesting significant improvement in knee function (–4.0; 95% CI, –6.8 to –1.3). Of note, however, this improvement was not enough to meet the threshold for minimal clinically important difference. At 24 weeks, the yoga group no longer showed significant improvement in knee function versus baseline.
“I don’t think a longer program would necessarily reduce knee pain, as benefits from a whole range of different types of exercise for knee osteoarthritis generally can show benefits within 8 weeks,” Dr. Bennell said in an interview.
Still, she noted that the average outcome in the trial may not represent what is possible if a patient commits to a regular yoga routine.
“I think it relates more to adherence [than duration], and I think benefits for knee pain would have been seen if a greater number of people had fully adhered to the program three times a week,” she said.
At 12 weeks, 68.8% of those in the yoga group were adherent, while just 28.4% were still adherent at week 24 after the optional extension period.
“As this was a self-directed program, adherence might be expected to be less than that of a supervised program,” Dr. Bennell noted.
Referring to unpublished data, Dr. Bennell said a sensitivity analysis showed that participants in the yoga group who completed yoga at least twice a week did show greater improvements in function and pain than those who did yoga less than twice per week.
“So it does suggest that adherence is important, as we might expect,” she said.
Another tool in the OA toolbox
Nick Trasolini, MD, of Wake Forest University School of Medicine, Winston-Salem, N.C., described the benefits in the trial as “modest” and noted that the improvement in function did not meet the threshold for minimal clinically important difference.
“Nevertheless,” he said in a written comment, “the [yoga] program was safe and associated with high participant satisfaction [mean satisfaction, 8 out of 10]. While this may not be the ‘silver bullet,’ it is another tool that we can offer to sufficiently motivated patients seeking non-operative solutions for knee osteoarthritis.”
Unfortunately, these tools remain “fraught with challenges,” Dr. Trasolini added.
“While multiple injection options are available (including corticosteroid, hyaluronic acid viscosupplementation, and biologic injections), the benefits of these injections can be short-lived,” he said. “This is frustrating to patients and physicians alike. Physical therapy is beneficial for knee osteoarthritis when deconditioning has led to decreased knee, hip, and core stability. However, physical therapy can be time consuming, painful, and cost prohibitive.”
In the present study, participants in the yoga group were somewhat willing (mean willingness, 5 out of 10) to pay for their 12-week yoga program. They reported that they would pay approximately $80 U.S. dollars for chance to do it all again.
The study was supported by grants from the National Health and Medical Research Council Program and the Centres of Research Excellence. The investigators disclosed additional relationships with Pfizer, Lilly, TLCBio, and others. Dr. Trasolini disclosed no relevant conflicts of interest.
Although pain did not significantly improve in the yoga group, participants only completed about two-thirds of the recommended sessions, suggesting that more benefit may be possible with greater adherence, wrote lead author Kim L. Bennell, PhD, of the University of Melbourne, and colleagues in the Annals of Internal Medicine.
“To date, an online yoga program specifically for people with knee osteoarthritis has not been investigated,” the investigators said. “The need for such evidence-based packaged online exercise programs is highlighted in the 2020 U.S. National Public Health Agenda for Osteoarthritis.”
Methods and results
The trial involved 212 adults aged 45 years or older with symptomatic knee osteoarthritis. All patients had access to online educational materials about managing osteoarthritis.
Half of the participants were randomized into the 12-week online yoga program. This self-directed, unsupervised course consisted of 12 prerecorded 30-minute instructional yoga sessions, each with a unique sequence of poses to be completed three times in one week before moving on to the next class the following week. After 12 weeks, these participants could choose to continue doing yoga via the online program for 12 additional weeks, if desired.
The primary outcomes were knee pain and physical function, gauged by a 10-point numerical rating scale and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively. Adherence was defined as completion of at least 2 yoga sessions within the preceding week.
At the 12-week mark, the yoga group did not show any significant improvement in knee pain (–0.6; 95% confidence interval, –1.2 to 0.1), but they did achieve a mean 4-point reduction in WOMAC, suggesting significant improvement in knee function (–4.0; 95% CI, –6.8 to –1.3). Of note, however, this improvement was not enough to meet the threshold for minimal clinically important difference. At 24 weeks, the yoga group no longer showed significant improvement in knee function versus baseline.
“I don’t think a longer program would necessarily reduce knee pain, as benefits from a whole range of different types of exercise for knee osteoarthritis generally can show benefits within 8 weeks,” Dr. Bennell said in an interview.
Still, she noted that the average outcome in the trial may not represent what is possible if a patient commits to a regular yoga routine.
“I think it relates more to adherence [than duration], and I think benefits for knee pain would have been seen if a greater number of people had fully adhered to the program three times a week,” she said.
At 12 weeks, 68.8% of those in the yoga group were adherent, while just 28.4% were still adherent at week 24 after the optional extension period.
“As this was a self-directed program, adherence might be expected to be less than that of a supervised program,” Dr. Bennell noted.
Referring to unpublished data, Dr. Bennell said a sensitivity analysis showed that participants in the yoga group who completed yoga at least twice a week did show greater improvements in function and pain than those who did yoga less than twice per week.
“So it does suggest that adherence is important, as we might expect,” she said.
Another tool in the OA toolbox
Nick Trasolini, MD, of Wake Forest University School of Medicine, Winston-Salem, N.C., described the benefits in the trial as “modest” and noted that the improvement in function did not meet the threshold for minimal clinically important difference.
“Nevertheless,” he said in a written comment, “the [yoga] program was safe and associated with high participant satisfaction [mean satisfaction, 8 out of 10]. While this may not be the ‘silver bullet,’ it is another tool that we can offer to sufficiently motivated patients seeking non-operative solutions for knee osteoarthritis.”
Unfortunately, these tools remain “fraught with challenges,” Dr. Trasolini added.
“While multiple injection options are available (including corticosteroid, hyaluronic acid viscosupplementation, and biologic injections), the benefits of these injections can be short-lived,” he said. “This is frustrating to patients and physicians alike. Physical therapy is beneficial for knee osteoarthritis when deconditioning has led to decreased knee, hip, and core stability. However, physical therapy can be time consuming, painful, and cost prohibitive.”
In the present study, participants in the yoga group were somewhat willing (mean willingness, 5 out of 10) to pay for their 12-week yoga program. They reported that they would pay approximately $80 U.S. dollars for chance to do it all again.
The study was supported by grants from the National Health and Medical Research Council Program and the Centres of Research Excellence. The investigators disclosed additional relationships with Pfizer, Lilly, TLCBio, and others. Dr. Trasolini disclosed no relevant conflicts of interest.
Although pain did not significantly improve in the yoga group, participants only completed about two-thirds of the recommended sessions, suggesting that more benefit may be possible with greater adherence, wrote lead author Kim L. Bennell, PhD, of the University of Melbourne, and colleagues in the Annals of Internal Medicine.
“To date, an online yoga program specifically for people with knee osteoarthritis has not been investigated,” the investigators said. “The need for such evidence-based packaged online exercise programs is highlighted in the 2020 U.S. National Public Health Agenda for Osteoarthritis.”
Methods and results
The trial involved 212 adults aged 45 years or older with symptomatic knee osteoarthritis. All patients had access to online educational materials about managing osteoarthritis.
Half of the participants were randomized into the 12-week online yoga program. This self-directed, unsupervised course consisted of 12 prerecorded 30-minute instructional yoga sessions, each with a unique sequence of poses to be completed three times in one week before moving on to the next class the following week. After 12 weeks, these participants could choose to continue doing yoga via the online program for 12 additional weeks, if desired.
The primary outcomes were knee pain and physical function, gauged by a 10-point numerical rating scale and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively. Adherence was defined as completion of at least 2 yoga sessions within the preceding week.
At the 12-week mark, the yoga group did not show any significant improvement in knee pain (–0.6; 95% confidence interval, –1.2 to 0.1), but they did achieve a mean 4-point reduction in WOMAC, suggesting significant improvement in knee function (–4.0; 95% CI, –6.8 to –1.3). Of note, however, this improvement was not enough to meet the threshold for minimal clinically important difference. At 24 weeks, the yoga group no longer showed significant improvement in knee function versus baseline.
“I don’t think a longer program would necessarily reduce knee pain, as benefits from a whole range of different types of exercise for knee osteoarthritis generally can show benefits within 8 weeks,” Dr. Bennell said in an interview.
Still, she noted that the average outcome in the trial may not represent what is possible if a patient commits to a regular yoga routine.
“I think it relates more to adherence [than duration], and I think benefits for knee pain would have been seen if a greater number of people had fully adhered to the program three times a week,” she said.
At 12 weeks, 68.8% of those in the yoga group were adherent, while just 28.4% were still adherent at week 24 after the optional extension period.
“As this was a self-directed program, adherence might be expected to be less than that of a supervised program,” Dr. Bennell noted.
Referring to unpublished data, Dr. Bennell said a sensitivity analysis showed that participants in the yoga group who completed yoga at least twice a week did show greater improvements in function and pain than those who did yoga less than twice per week.
“So it does suggest that adherence is important, as we might expect,” she said.
Another tool in the OA toolbox
Nick Trasolini, MD, of Wake Forest University School of Medicine, Winston-Salem, N.C., described the benefits in the trial as “modest” and noted that the improvement in function did not meet the threshold for minimal clinically important difference.
“Nevertheless,” he said in a written comment, “the [yoga] program was safe and associated with high participant satisfaction [mean satisfaction, 8 out of 10]. While this may not be the ‘silver bullet,’ it is another tool that we can offer to sufficiently motivated patients seeking non-operative solutions for knee osteoarthritis.”
Unfortunately, these tools remain “fraught with challenges,” Dr. Trasolini added.
“While multiple injection options are available (including corticosteroid, hyaluronic acid viscosupplementation, and biologic injections), the benefits of these injections can be short-lived,” he said. “This is frustrating to patients and physicians alike. Physical therapy is beneficial for knee osteoarthritis when deconditioning has led to decreased knee, hip, and core stability. However, physical therapy can be time consuming, painful, and cost prohibitive.”
In the present study, participants in the yoga group were somewhat willing (mean willingness, 5 out of 10) to pay for their 12-week yoga program. They reported that they would pay approximately $80 U.S. dollars for chance to do it all again.
The study was supported by grants from the National Health and Medical Research Council Program and the Centres of Research Excellence. The investigators disclosed additional relationships with Pfizer, Lilly, TLCBio, and others. Dr. Trasolini disclosed no relevant conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE