Conference Coverage

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

CHICAGO – A clinical decision-support tool designed to identify hospitalized patients who need thromboembolism prophylaxis and embedded in a hospital’s electronic health record led to significantly more appropriate prophylaxis, compared with usual care, and significantly cut the 30-day rate of thromboembolism in a randomized, multicenter trial with more than 10,000 patients.

“This is the first time that a clinical decision support tool not only changed [thromboprophylaxis prescribing] behavior but also affected hard outcomes. That’s remarkable,” lead investigator Alex C. Spyropoulos, MD, said in an interview.

Even so, outside experts expressed concerns about certain results and the trial design.

Mitchel L. Zoler/MDedge News

Use of the decision-support risk calculator for thromboembolism in the IMPROVE-DD VTE trial significantly boosted use of appropriate inpatient thromboprophylaxis starting at hospital admission by a relative 52%, and significantly increased outpatient thromboprophylaxis prescribed at discharge by a relative 93% in the study’s two primary endpoints, Dr. Spyropoulos reported at the American Heart Association scientific sessions.

This intervention led to a significant 29% relative reduction in the incidence of total thromboembolic events, both venous and arterial, during hospitalization and through 30 days post discharge.

The absolute thromboembolic event rates were 2.9% among 5,249 patients treated at either of two U.S. hospitals that used the EHR-based risk calculator and 4.0% in 5,450 patients seen at either of two other U.S. hospitals that served as controls and where usual care method identified patients who needed thromboprophylaxis, said Dr. Spyropoulos, professor and director of the anticoagulation and clinical thrombosis services for Northwell Health in New York. This included a 2.7% rate of venous thromboembolism and a 0.25% rate of arterial thromboembolism in the intervention patients, and a 3.3% rate of venous events and a 0.7% rate of arterial events in the controls.

Patients treated at the hospitals that used the EHR-embedded risk calculator also has a numerically lower rate of major bleeding events during hospitalization and 30-day postdischarge follow-up, a 0.15% rate compared with a 0.22% rate in the control patients, a difference that was not significant.
 

A ‘powerful message’

“It’s a powerful message to see an absolute 1.1% difference in the rate of thromboembolism and a trend to fewer major bleeds. I think this will change practice,” Dr. Spyropoulos added in the interview. “The next step is dissemination.”

But thromboprophylaxis experts cautioned that, while the results looked promising, the findings need more analysis and review, and the intervention may need further testing before it’s ready for widespread use.

For example, one unexpected result was an unexpected 2.1 percentage point increase in all-cause mortality linked with use of the decision-support tool. Total deaths from admission to 30 days after discharge occurred in 9.1% of the patients treated at the two hospitals that used the risk calculator and 7.0% among the control patients, a difference that Dr, Spyropoulos said was likely the result of unbalanced outcomes from COVID-19 infections that had no relevance to the tested intervention. The trial ran during December 2020–January 2022.
 

But wait – more detail and analysis needed

“I’d like to see more analysis of the data from this trial,” and “there is the issue of increased mortality,” commented Gregory Piazza, MD, director of vascular medicine at Brigham and Women’s Hospital in Boston, and a specialist in thromboembolism prevention and management. He also highlighted the need for greater detail on the arterial thromboembolic events tallied during the study.

With more details and analysis of these findings “we’ll learn more about the true impact” of this intervention, Dr. Piazza said in an interview.

Mitchel L. Zoler/MDedge News

“The increased mortality in the intervention group may have been due to differential treatment and decision-making and confounding and warrants further investigation,” commented Elaine M. Hylek, MD, a professor at Boston University and designated discussant for the report. Selection bias may have contributed to this possible confounding, Dr. Hylek noted.

Other limitations of the study cited by Dr. Hylek included its reliance on individual clinician decision-making to actually prescribe thromboprophylaxis, a lack of information on patient adherence to their thromboprophylaxis prescription, and an overall low rate of appropriate thromboprophylaxis prescribed to patients at discharge. The rates were 7.5% among the controls and 13.6% among patients in the intervention arm. For prescription at the time of hospitalization, the rates were 72.5% among control patients and 80.1% for patients seen at the two hospitals that used the decision-support tool.
 

The IMPROVE-DD VTE risk assessment tool

The clinical decision-support tool tested is called the IMPROVE-DD VTE risk assessment model, developed over several years by Dr. Spyropoulos and associates; they have also performed multiple validation studies. The model includes eight factors that score 1-3 points if positive that can add up to total scores of 0-14. A score of 0 or 1 is considered low risk, 2 or 3 intermediate risk, and 4 or more high risk. One of the scoring factors is the result of a D-dimer test, which explains the DD part of the name.

The eight factors and point assignments are prior venous thromboembolism: 3 points; known thrombophilia: 2 points; lower limb paralysis: 2 points; current cancer: 2 points; d-dimer level more than twofold the upper limit of normal: 2 points; immobilized for at least 7 days: 1 point; admitted to the ICU or coronary care unit: 1 point; and age greater than 60 years old: 1 point.

Development of the IMPROVE-DD VTE risk calculator received most of its funding from the U.S. Agency for Healthcare Research and Quality, and the risk tool will be available for hospitals and health systems to access at no charge through the agency’s website, Dr. Spyropoulos said. The researchers designed the calculator to operate in any EHR product.

IMPROVE-DD VTE “is a very valid, high-quality tool,” commented Dr. Piazza. “We’ve used some rather blunt tools in the past,” and especially praised inclusion of D-dimer results into the IMPROVE-DD VTE model.

“It’s nice to use a biomarker in addition to clinical factors,” he said. “A biomarker provides a more holistic picture; we can’t do genetic testing on every patient.”

Enrollment focused on higher-risk patients

The study ran at four academic, tertiary-care hospitals in the Northwell Health network in the New York region. It enrolled patients aged more than 60 years who were hospitalized for any of five diagnoses: heart failure; acute respiratory insufficiency, including chronic obstructive lung disease or asthma; acute infectious disease, including COVID-19; acute inflammatory disease, including rheumatic disease; or acute stroke. The study excluded patients with a history of atrial fibrillation, those who used an anticoagulant at home, or those who had received therapeutic anticoagulation within 24 hours of their hospital admission.

The anticoagulant prophylaxis that patients received depended on their calculated risk level – intermediate or high – and whether they were inpatients or being discharged. The anticoagulants that clinicians could prescribe included unfractionated heparin, enoxaparin, fondaparinux, rivaroxaban, and apixaban.

“We’ve been looking for a long time for a tool for medically ill patients that’s like the CHA2DS2-VASc score” for patients with atrial fibrillation. “These powerful data say we now have this, and the EHR provides a vehicle to easily implement it,” Dr. Spyropoulos said.

The IMPROVE-DD VTE study received partial funding from Janssen. Dr. Spyropoulos has been a consultant to Nayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; adviser to the ATLAS Group; and has received research support from Janssen. Dr. Piazza has received research funding from Bayer, BIG/EKOS, BMS, Janssen, and Portola. Dr. Hylek had been a consultant to Bayer and Ionis, and has received honoraria from Boehringer Ingelheim and Pfizer.

Noninvasive cosmetic treatments have been available for several years, but in the clinical experience of Jean Carruthers, MD, men have been slow to embrace them with the same gusto as women.

However, this could be changing as millennials – who tend to be more proactive about efforts to prevent skin aging – are getting older.

At a virtual course on laser and aesthetic skin therapy, Dr. Carruthers referred to the results of an online survey of 600 men aged 30-65 years conducted by Jared Jagdeo, MD, and colleagues in 2016, to gauge attitudes toward age-related changes of their facial features and their preferences for prioritizing treatment. The top five barriers to treatment cited by the respondents were: “I don’t think I need it yet” (47%); “concerned about safety/side effects” (46%); “concerned about injecting a foreign substance into my body” (45%); “cost” (42%), and “concerned my face won’t look natural” (41%).

“Since then, millennials took over as the largest portion of our workforce in North America,” said Dr. Carruthers who, with her husband, Alastair Carruthers, MD, pioneered the cosmetic use of onabotulinumtoxinA (Botox). “Millennials are interested in how they look and how to keep their aesthetic the best it can possibly be,” she said, so there may be “a generational aspect to this.”

Another factor that may affect the uptake of cosmetic procedures among men is the number of hours they spend gazing at their own image on a computer screen. Since the beginning of the COVID-19 pandemic, men have spent an increasing number of hours on video-conferencing calls via Zoom and other platforms, causing them to rethink how they view their appearance, Dr. Carruthers added. “Zoom dysmorphia” is the term that describes the phenomenon that developed during the pandemic where more patients expressed a desire to make changes to their appearance, including nose jobs and smoothing out forehead wrinkles.

“When we’re on a Zoom call, we’re spending 40% of our time looking at ourselves,” said Dr. Carruthers, clinical professor of ophthalmology and visual sciences at the University of British Columbia in Vancouver. “This would hint that the looking glass is not as powerful as the computer screen to motivate men” to pursue aesthetic treatments.

According to data from the American Society of Plastic Surgeons, the top 5 cosmetic surgical procedures performed in men in 2020 were nose shaping, eyelid surgery, cheek implants, liposuction, and ear surgery. The top 5 minimally-invasive procedures in men were botulinum toxin type A, followed by laser skin resurfacing, laser hair removal, soft tissue fillers, and microdermabrasion.

Why might men consider an injectable instead of surgery? Dr. Carruthers asked. “According to the 2016 survey by Dr. Jagdeo and colleagues, it’s to appear more youthful and to appear good for their age.”

From a clinical standpoint, success comes from understanding the subtle differences between treating men and women, she added.

In a 2022 article about optimizing skin tightening in aesthetics in men, Christian A. Albornoz, MD, and colleagues noted that in contrast to women, men “tend to have higher levels of collagen density and greater skin thickness, but these begin to decrease earlier on. They can also more frequently have severe photodamage”.

In another article published in 2018, Terrence Keaney, MD, and colleagues reviewed the objective data available on male aging and aesthetics. They stated that a “communication gap exists for men, as evidenced by the lack of information available online or by word of mouth about injectable treatments” and concluded that “educating men about available aesthetic treatments and about the safety and side effects associated with each treatment, as well as addressing concerns about their treatment results looking natural, are key considerations.”

That sentiment resonates with Dr. Carruthers. Part of the reason why men have not sought cosmetic treatments along with their female partners and friends seeking cosmetic treatments “is that they haven’t had anything in their cup,” she said. “Maybe this is something we need to think about, to try and help men come in and enjoy the positive benefits of aesthetic, noninvasive cosmetic treatments.”

The course was sponsored by Harvard Medical School, Massachusetts General Hospital, and Wellman Center for Photomedicine.

Dr. Carruthers disclosed that she is a consultant and researcher for Alastin, Appiell, Allergan Aesthetics, Avari Medical, Bonti, Evolus, Fount Bio, Jeune Aesthetics, Merz, and Revance Biopharma.

Noninvasive cosmetic treatments have been available for several years, but in the clinical experience of Jean Carruthers, MD, men have been slow to embrace them with the same gusto as women.

However, this could be changing as millennials – who tend to be more proactive about efforts to prevent skin aging – are getting older.

At a virtual course on laser and aesthetic skin therapy, Dr. Carruthers referred to the results of an online survey of 600 men aged 30-65 years conducted by Jared Jagdeo, MD, and colleagues in 2016, to gauge attitudes toward age-related changes of their facial features and their preferences for prioritizing treatment. The top five barriers to treatment cited by the respondents were: “I don’t think I need it yet” (47%); “concerned about safety/side effects” (46%); “concerned about injecting a foreign substance into my body” (45%); “cost” (42%), and “concerned my face won’t look natural” (41%).

“Since then, millennials took over as the largest portion of our workforce in North America,” said Dr. Carruthers who, with her husband, Alastair Carruthers, MD, pioneered the cosmetic use of onabotulinumtoxinA (Botox). “Millennials are interested in how they look and how to keep their aesthetic the best it can possibly be,” she said, so there may be “a generational aspect to this.”

Another factor that may affect the uptake of cosmetic procedures among men is the number of hours they spend gazing at their own image on a computer screen. Since the beginning of the COVID-19 pandemic, men have spent an increasing number of hours on video-conferencing calls via Zoom and other platforms, causing them to rethink how they view their appearance, Dr. Carruthers added. “Zoom dysmorphia” is the term that describes the phenomenon that developed during the pandemic where more patients expressed a desire to make changes to their appearance, including nose jobs and smoothing out forehead wrinkles.

“When we’re on a Zoom call, we’re spending 40% of our time looking at ourselves,” said Dr. Carruthers, clinical professor of ophthalmology and visual sciences at the University of British Columbia in Vancouver. “This would hint that the looking glass is not as powerful as the computer screen to motivate men” to pursue aesthetic treatments.

According to data from the American Society of Plastic Surgeons, the top 5 cosmetic surgical procedures performed in men in 2020 were nose shaping, eyelid surgery, cheek implants, liposuction, and ear surgery. The top 5 minimally-invasive procedures in men were botulinum toxin type A, followed by laser skin resurfacing, laser hair removal, soft tissue fillers, and microdermabrasion.

Why might men consider an injectable instead of surgery? Dr. Carruthers asked. “According to the 2016 survey by Dr. Jagdeo and colleagues, it’s to appear more youthful and to appear good for their age.”

From a clinical standpoint, success comes from understanding the subtle differences between treating men and women, she added.

In a 2022 article about optimizing skin tightening in aesthetics in men, Christian A. Albornoz, MD, and colleagues noted that in contrast to women, men “tend to have higher levels of collagen density and greater skin thickness, but these begin to decrease earlier on. They can also more frequently have severe photodamage”.

In another article published in 2018, Terrence Keaney, MD, and colleagues reviewed the objective data available on male aging and aesthetics. They stated that a “communication gap exists for men, as evidenced by the lack of information available online or by word of mouth about injectable treatments” and concluded that “educating men about available aesthetic treatments and about the safety and side effects associated with each treatment, as well as addressing concerns about their treatment results looking natural, are key considerations.”

That sentiment resonates with Dr. Carruthers. Part of the reason why men have not sought cosmetic treatments along with their female partners and friends seeking cosmetic treatments “is that they haven’t had anything in their cup,” she said. “Maybe this is something we need to think about, to try and help men come in and enjoy the positive benefits of aesthetic, noninvasive cosmetic treatments.”

The course was sponsored by Harvard Medical School, Massachusetts General Hospital, and Wellman Center for Photomedicine.

Dr. Carruthers disclosed that she is a consultant and researcher for Alastin, Appiell, Allergan Aesthetics, Avari Medical, Bonti, Evolus, Fount Bio, Jeune Aesthetics, Merz, and Revance Biopharma.

Noninvasive cosmetic treatments have been available for several years, but in the clinical experience of Jean Carruthers, MD, men have been slow to embrace them with the same gusto as women.

However, this could be changing as millennials – who tend to be more proactive about efforts to prevent skin aging – are getting older.

At a virtual course on laser and aesthetic skin therapy, Dr. Carruthers referred to the results of an online survey of 600 men aged 30-65 years conducted by Jared Jagdeo, MD, and colleagues in 2016, to gauge attitudes toward age-related changes of their facial features and their preferences for prioritizing treatment. The top five barriers to treatment cited by the respondents were: “I don’t think I need it yet” (47%); “concerned about safety/side effects” (46%); “concerned about injecting a foreign substance into my body” (45%); “cost” (42%), and “concerned my face won’t look natural” (41%).

“Since then, millennials took over as the largest portion of our workforce in North America,” said Dr. Carruthers who, with her husband, Alastair Carruthers, MD, pioneered the cosmetic use of onabotulinumtoxinA (Botox). “Millennials are interested in how they look and how to keep their aesthetic the best it can possibly be,” she said, so there may be “a generational aspect to this.”

Another factor that may affect the uptake of cosmetic procedures among men is the number of hours they spend gazing at their own image on a computer screen. Since the beginning of the COVID-19 pandemic, men have spent an increasing number of hours on video-conferencing calls via Zoom and other platforms, causing them to rethink how they view their appearance, Dr. Carruthers added. “Zoom dysmorphia” is the term that describes the phenomenon that developed during the pandemic where more patients expressed a desire to make changes to their appearance, including nose jobs and smoothing out forehead wrinkles.

“When we’re on a Zoom call, we’re spending 40% of our time looking at ourselves,” said Dr. Carruthers, clinical professor of ophthalmology and visual sciences at the University of British Columbia in Vancouver. “This would hint that the looking glass is not as powerful as the computer screen to motivate men” to pursue aesthetic treatments.

According to data from the American Society of Plastic Surgeons, the top 5 cosmetic surgical procedures performed in men in 2020 were nose shaping, eyelid surgery, cheek implants, liposuction, and ear surgery. The top 5 minimally-invasive procedures in men were botulinum toxin type A, followed by laser skin resurfacing, laser hair removal, soft tissue fillers, and microdermabrasion.

Why might men consider an injectable instead of surgery? Dr. Carruthers asked. “According to the 2016 survey by Dr. Jagdeo and colleagues, it’s to appear more youthful and to appear good for their age.”

From a clinical standpoint, success comes from understanding the subtle differences between treating men and women, she added.

In a 2022 article about optimizing skin tightening in aesthetics in men, Christian A. Albornoz, MD, and colleagues noted that in contrast to women, men “tend to have higher levels of collagen density and greater skin thickness, but these begin to decrease earlier on. They can also more frequently have severe photodamage”.

In another article published in 2018, Terrence Keaney, MD, and colleagues reviewed the objective data available on male aging and aesthetics. They stated that a “communication gap exists for men, as evidenced by the lack of information available online or by word of mouth about injectable treatments” and concluded that “educating men about available aesthetic treatments and about the safety and side effects associated with each treatment, as well as addressing concerns about their treatment results looking natural, are key considerations.”

That sentiment resonates with Dr. Carruthers. Part of the reason why men have not sought cosmetic treatments along with their female partners and friends seeking cosmetic treatments “is that they haven’t had anything in their cup,” she said. “Maybe this is something we need to think about, to try and help men come in and enjoy the positive benefits of aesthetic, noninvasive cosmetic treatments.”

The course was sponsored by Harvard Medical School, Massachusetts General Hospital, and Wellman Center for Photomedicine.

Dr. Carruthers disclosed that she is a consultant and researcher for Alastin, Appiell, Allergan Aesthetics, Avari Medical, Bonti, Evolus, Fount Bio, Jeune Aesthetics, Merz, and Revance Biopharma.

Vaccination campaigns in more than 80 nations have successfully reduced the prevalence of hepatitis B virus (HBV) surface antigen. That’s the good news.
 

Less good is the news that no countries are on track to meet the goals for HBV eradication by 2030 or 2050, and only 11 countries are on track to achieve all absolute or relative targets for hepatitis C virus (HCV) elimination, reported Sarah Blach, MHS, associate director of the Center for Disease Analysis Foundation, based in Lafayette, Colo.

“As countries progress toward eliminating hepatitis B and C, we really need to do more to expand political will and financing of national elimination programs. It’s great to see that it’s happening in some of these countries, but we really need that to expand,” she said at the annual meeting of the American Association for the Study of Liver Diseases.

Ms. Blach presented data from the foundation’s Polaris Observatory, an initiative that provides epidemiological data, modeling tools, training, and decision analytics to support eliminating HBV and HCV globally by 2030.

The investigators used mathematical disease burden models for HBV and HCV to assess worldwide trends toward viral elimination. They also evaluated HBV and HCV elimination policies as reported by authorities in various countries.

They forecast the year in which each country or territory would meet each of the World Health Organization’s four elimination targets from 110 HCV models and 166 HBV models. The targets are 90% diagnosed, 80% of the eligible population treated, 65% reduction in mortality, and 80% incidence reduction for HCV and either 95% incidence reduction or prevalence of 0.1% or less in children aged 5 years and younger for HBV.

Investigators summarized the results across countries by disease area and time period of elimination; that is, elimination before 2030, between 2031 and 2050, or after 2050.
 

Results for HCV and HBV targets

The 11 nations on track to achieve all absolute or relative (programmatic) targets for HCV by 2030 are Australia, Canada, Denmark, Egypt, Finland, France, Georgia, Japan, Norway, Spain, and the United Kingdom.

An additional 24 countries are on track to meet their goals for HCV between 2031 and 2050.

But the rest, including the United States, much of sub-Saharan Africa, China, and South Asia, are not on track to meet their goals for HCV by 2050.

No countries are on track to achieve the absolute or relative (programmatic) targets for elimination of HBV, Ms. Blach said.

However, 83 countries or territories, including the United States, are on track for achieving the HBV surface antigen prevalence target of less than 0.1% in children aged 5 years and younger by 2030.

Ms. Blach and colleagues also looked at results of quantitative policy surveys submitted by 61 countries. The respondents were asked to report on linkage to care, awareness and screening, monitoring and evaluation, ability to expand capacity, harm-reduction programs, financing of national programs, and political will to achieve targets.

The investigators scored countries on a scale of 1-10, with 10 being the highest score, in each category. For HCV, 25 countries (42%) had high scores, defined as 9 or 10, for political will, and 33 countries (54%) had high scores for national funding. For HBV, 17 countries (30%) received the high scores for political will, and 30 (51%) received the high scores for financing the national program.
 

The big picture

Most countries have not expanded HBV or HCV treatment beyond specialists, and HBV policies appear to lag behind policies directed toward HCV elimination, Ms. Blach noted.

“We do need to expand screening and treatment for hepatitis B moving forward,” she said.

The United States and the rest of the world need to do better, especially regarding HBV elimination, but the United States does appear to be making progress, said Richard Sterling, MD, MSc, from Virginia Commonwealth University, Richmond, who comoderated the session where Ms. Blach reported the data.

“My impression is that we’re doing a pretty good job with [HBV] vaccinations in the United States,” Dr. Sterling, who was not involved in the study, said in an interview.

One way to make progress, he said, may be to expand eligibility for HBV vaccines beyond the current upper age limit of 59 years.

Implementing simpler dosing regimens – the currently available vaccine is split into three doses – could improve vaccine compliance and lower costs, Dr. Sterling added.

During the session, Brian Conway, MD, medical director of the Vancouver Infectious Disease Centre, said it seems hard to use a composite set of data to determine a yes/no answer about whether a country is on track to reach targets.

“When you take my country of Canada, we have absolutely no national program, no hope of a national program, very little funding, and yet we make the cut. So how do you balance all these different variables to arrive at a yes/no answer and is there a way of putting a bit more subtlety into it?” Dr. Conway asked Ms. Blach.

Ms. Blach replied that the data are fluid, and countries can move closer or farther from reaching targets over time as conditions change.

Some countries seem to be improving efforts and “just need a bit more” work, Ms. Blach said.

“But we also saw some countries who we thought were going to be a shoo-in, and as time progressed the number of treatments just dropped in shocking ways. The reality is that a lot of countries are struggling to treat patients,” she said.

Canada “has a really great health system. It’s not a fragmented health system, and so even if you don’t have some of that push for elimination from the government level, having access to treatment, having access to those services, means that at least patients can come in and get what they need,” Ms. Blach said.

The study data are available for free on the Center for Disease Analysis Foundation’s Polaris website.

The study was funded by grants from the John C. Martin Foundation, ZeShan Foundation, EndHep2030, Gilead Sciences, and AbbVie. Ms. Blach is employed by the Center for Disease Analysis Foundation, which receives research grants from Gilead and AbbVie. Dr. Sterling and Dr. Conway reported no relevant disclosures.

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

Vaccination campaigns in more than 80 nations have successfully reduced the prevalence of hepatitis B virus (HBV) surface antigen. That’s the good news.
 

Less good is the news that no countries are on track to meet the goals for HBV eradication by 2030 or 2050, and only 11 countries are on track to achieve all absolute or relative targets for hepatitis C virus (HCV) elimination, reported Sarah Blach, MHS, associate director of the Center for Disease Analysis Foundation, based in Lafayette, Colo.

“As countries progress toward eliminating hepatitis B and C, we really need to do more to expand political will and financing of national elimination programs. It’s great to see that it’s happening in some of these countries, but we really need that to expand,” she said at the annual meeting of the American Association for the Study of Liver Diseases.

Ms. Blach presented data from the foundation’s Polaris Observatory, an initiative that provides epidemiological data, modeling tools, training, and decision analytics to support eliminating HBV and HCV globally by 2030.

The investigators used mathematical disease burden models for HBV and HCV to assess worldwide trends toward viral elimination. They also evaluated HBV and HCV elimination policies as reported by authorities in various countries.

They forecast the year in which each country or territory would meet each of the World Health Organization’s four elimination targets from 110 HCV models and 166 HBV models. The targets are 90% diagnosed, 80% of the eligible population treated, 65% reduction in mortality, and 80% incidence reduction for HCV and either 95% incidence reduction or prevalence of 0.1% or less in children aged 5 years and younger for HBV.

Investigators summarized the results across countries by disease area and time period of elimination; that is, elimination before 2030, between 2031 and 2050, or after 2050.
 

Results for HCV and HBV targets

The 11 nations on track to achieve all absolute or relative (programmatic) targets for HCV by 2030 are Australia, Canada, Denmark, Egypt, Finland, France, Georgia, Japan, Norway, Spain, and the United Kingdom.

An additional 24 countries are on track to meet their goals for HCV between 2031 and 2050.

But the rest, including the United States, much of sub-Saharan Africa, China, and South Asia, are not on track to meet their goals for HCV by 2050.

No countries are on track to achieve the absolute or relative (programmatic) targets for elimination of HBV, Ms. Blach said.

However, 83 countries or territories, including the United States, are on track for achieving the HBV surface antigen prevalence target of less than 0.1% in children aged 5 years and younger by 2030.

Ms. Blach and colleagues also looked at results of quantitative policy surveys submitted by 61 countries. The respondents were asked to report on linkage to care, awareness and screening, monitoring and evaluation, ability to expand capacity, harm-reduction programs, financing of national programs, and political will to achieve targets.

The investigators scored countries on a scale of 1-10, with 10 being the highest score, in each category. For HCV, 25 countries (42%) had high scores, defined as 9 or 10, for political will, and 33 countries (54%) had high scores for national funding. For HBV, 17 countries (30%) received the high scores for political will, and 30 (51%) received the high scores for financing the national program.
 

The big picture

Most countries have not expanded HBV or HCV treatment beyond specialists, and HBV policies appear to lag behind policies directed toward HCV elimination, Ms. Blach noted.

“We do need to expand screening and treatment for hepatitis B moving forward,” she said.

The United States and the rest of the world need to do better, especially regarding HBV elimination, but the United States does appear to be making progress, said Richard Sterling, MD, MSc, from Virginia Commonwealth University, Richmond, who comoderated the session where Ms. Blach reported the data.

“My impression is that we’re doing a pretty good job with [HBV] vaccinations in the United States,” Dr. Sterling, who was not involved in the study, said in an interview.

One way to make progress, he said, may be to expand eligibility for HBV vaccines beyond the current upper age limit of 59 years.

Implementing simpler dosing regimens – the currently available vaccine is split into three doses – could improve vaccine compliance and lower costs, Dr. Sterling added.

During the session, Brian Conway, MD, medical director of the Vancouver Infectious Disease Centre, said it seems hard to use a composite set of data to determine a yes/no answer about whether a country is on track to reach targets.

“When you take my country of Canada, we have absolutely no national program, no hope of a national program, very little funding, and yet we make the cut. So how do you balance all these different variables to arrive at a yes/no answer and is there a way of putting a bit more subtlety into it?” Dr. Conway asked Ms. Blach.

Ms. Blach replied that the data are fluid, and countries can move closer or farther from reaching targets over time as conditions change.

Some countries seem to be improving efforts and “just need a bit more” work, Ms. Blach said.

“But we also saw some countries who we thought were going to be a shoo-in, and as time progressed the number of treatments just dropped in shocking ways. The reality is that a lot of countries are struggling to treat patients,” she said.

Canada “has a really great health system. It’s not a fragmented health system, and so even if you don’t have some of that push for elimination from the government level, having access to treatment, having access to those services, means that at least patients can come in and get what they need,” Ms. Blach said.

The study data are available for free on the Center for Disease Analysis Foundation’s Polaris website.

The study was funded by grants from the John C. Martin Foundation, ZeShan Foundation, EndHep2030, Gilead Sciences, and AbbVie. Ms. Blach is employed by the Center for Disease Analysis Foundation, which receives research grants from Gilead and AbbVie. Dr. Sterling and Dr. Conway reported no relevant disclosures.

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

Vaccination campaigns in more than 80 nations have successfully reduced the prevalence of hepatitis B virus (HBV) surface antigen. That’s the good news.
 

Less good is the news that no countries are on track to meet the goals for HBV eradication by 2030 or 2050, and only 11 countries are on track to achieve all absolute or relative targets for hepatitis C virus (HCV) elimination, reported Sarah Blach, MHS, associate director of the Center for Disease Analysis Foundation, based in Lafayette, Colo.

“As countries progress toward eliminating hepatitis B and C, we really need to do more to expand political will and financing of national elimination programs. It’s great to see that it’s happening in some of these countries, but we really need that to expand,” she said at the annual meeting of the American Association for the Study of Liver Diseases.

Ms. Blach presented data from the foundation’s Polaris Observatory, an initiative that provides epidemiological data, modeling tools, training, and decision analytics to support eliminating HBV and HCV globally by 2030.

The investigators used mathematical disease burden models for HBV and HCV to assess worldwide trends toward viral elimination. They also evaluated HBV and HCV elimination policies as reported by authorities in various countries.

They forecast the year in which each country or territory would meet each of the World Health Organization’s four elimination targets from 110 HCV models and 166 HBV models. The targets are 90% diagnosed, 80% of the eligible population treated, 65% reduction in mortality, and 80% incidence reduction for HCV and either 95% incidence reduction or prevalence of 0.1% or less in children aged 5 years and younger for HBV.

Investigators summarized the results across countries by disease area and time period of elimination; that is, elimination before 2030, between 2031 and 2050, or after 2050.
 

Results for HCV and HBV targets

The 11 nations on track to achieve all absolute or relative (programmatic) targets for HCV by 2030 are Australia, Canada, Denmark, Egypt, Finland, France, Georgia, Japan, Norway, Spain, and the United Kingdom.

An additional 24 countries are on track to meet their goals for HCV between 2031 and 2050.

But the rest, including the United States, much of sub-Saharan Africa, China, and South Asia, are not on track to meet their goals for HCV by 2050.

No countries are on track to achieve the absolute or relative (programmatic) targets for elimination of HBV, Ms. Blach said.

However, 83 countries or territories, including the United States, are on track for achieving the HBV surface antigen prevalence target of less than 0.1% in children aged 5 years and younger by 2030.

Ms. Blach and colleagues also looked at results of quantitative policy surveys submitted by 61 countries. The respondents were asked to report on linkage to care, awareness and screening, monitoring and evaluation, ability to expand capacity, harm-reduction programs, financing of national programs, and political will to achieve targets.

The investigators scored countries on a scale of 1-10, with 10 being the highest score, in each category. For HCV, 25 countries (42%) had high scores, defined as 9 or 10, for political will, and 33 countries (54%) had high scores for national funding. For HBV, 17 countries (30%) received the high scores for political will, and 30 (51%) received the high scores for financing the national program.
 

The big picture

Most countries have not expanded HBV or HCV treatment beyond specialists, and HBV policies appear to lag behind policies directed toward HCV elimination, Ms. Blach noted.

“We do need to expand screening and treatment for hepatitis B moving forward,” she said.

The United States and the rest of the world need to do better, especially regarding HBV elimination, but the United States does appear to be making progress, said Richard Sterling, MD, MSc, from Virginia Commonwealth University, Richmond, who comoderated the session where Ms. Blach reported the data.

“My impression is that we’re doing a pretty good job with [HBV] vaccinations in the United States,” Dr. Sterling, who was not involved in the study, said in an interview.

One way to make progress, he said, may be to expand eligibility for HBV vaccines beyond the current upper age limit of 59 years.

Implementing simpler dosing regimens – the currently available vaccine is split into three doses – could improve vaccine compliance and lower costs, Dr. Sterling added.

During the session, Brian Conway, MD, medical director of the Vancouver Infectious Disease Centre, said it seems hard to use a composite set of data to determine a yes/no answer about whether a country is on track to reach targets.

“When you take my country of Canada, we have absolutely no national program, no hope of a national program, very little funding, and yet we make the cut. So how do you balance all these different variables to arrive at a yes/no answer and is there a way of putting a bit more subtlety into it?” Dr. Conway asked Ms. Blach.

Ms. Blach replied that the data are fluid, and countries can move closer or farther from reaching targets over time as conditions change.

Some countries seem to be improving efforts and “just need a bit more” work, Ms. Blach said.

“But we also saw some countries who we thought were going to be a shoo-in, and as time progressed the number of treatments just dropped in shocking ways. The reality is that a lot of countries are struggling to treat patients,” she said.

Canada “has a really great health system. It’s not a fragmented health system, and so even if you don’t have some of that push for elimination from the government level, having access to treatment, having access to those services, means that at least patients can come in and get what they need,” Ms. Blach said.

The study data are available for free on the Center for Disease Analysis Foundation’s Polaris website.

The study was funded by grants from the John C. Martin Foundation, ZeShan Foundation, EndHep2030, Gilead Sciences, and AbbVie. Ms. Blach is employed by the Center for Disease Analysis Foundation, which receives research grants from Gilead and AbbVie. Dr. Sterling and Dr. Conway reported no relevant disclosures.

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

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

CHICAGO – None of six commercial dietary supplements widely promoted and taken for lowering LDL cholesterol did the job any better than placebo in a randomized trial of adults without cardiovascular disease but at increased cardiovascular risk.

In contrast, those who took the low dose of a high-potency statin in the eight-arm comparative study showed a significant 38% drop in LDL cholesterol levels over 28 days, a performance that blew away the six supplements containing fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice.

The supplements showed little or no effect on any measured lipid biomarkers, which also included total cholesterol and triglycerides, or C-reactive protein (CRP), which reflects systemic inflammation.

The findings undercut the widespread heart-health marketing claims for such supplements and could potentially restore faith in statins for the many patients looking for alternatives, researchers say.

“We all see patients that have their medication lists littered with dietary supplements,” observed Luke J. Laffin, MD, of the Cleveland Clinic Foundation. And it’s more than just heart patients who use them.

Almost $50 billion is spent on dietary supplements annually in the United States, and recent data suggest that more than three-fourths of the population use them, 18% of those based on specious heart-health claims, Dr. Laffin said in a Nov. 6 presentation at the American Heart Association scientific sessions.

The findings of the Supplements, Placebo, or Rosuvastatin Study (SPORT) and how they are framed for the public “are important for public health,” he said.

“As cardiologists, primary care doctors, and others, we really should use these results to have evidence-based discussions with patients” regarding the value of even low-dose statins and the supplements’ “lack of benefit,” said Dr. Laffin, lead author on the SPORT publication, which was published the same day in the Journal of the American College of Cardiology.

Patients assigned to low-dose rosuvastatin showed a mean 24.4% drop in total cholesterol levels over 28 days, the study’s primary endpoint. That differed from the placebo group and those for each supplement at P < .001.

They also averaged a 19.2% decrease in serum triglycerides, P < .05 for all group comparisons. None of the six supplements was significantly different from placebo for change in levels of either total cholesterol or triglycerides.

Nor were there significant differences in adverse events across the groups; there were no adverse changes in liver or kidney function tests or glucose levels; and there were no signs of musculoskeletal symptoms, the published report notes.
 

How to message the results

The SPORT trial is valuable for “addressing the void of data on supplements and cardiovascular health,” Chiadi E. Ndumele, MD, PhD, Johns Hopkins University, Baltimore, said as the invited discussant following Dr. Laffin’s presentation.

But they also send a reassuring message about statins, he noted. In a recent study of statin-nonadherent patients, 80% “were worried about statin side effects as the primary reason for not taking their statin, and 72% preferred using natural supplements instead of taking their prescription therapy,” Dr. Ndumele said. “The reason for this is clearly mistrust, misinformation, and a lack of evidence.”

The next step, he proposed, should be to get the study’s positive message about statins to the public, and especially patients “who are hesitant about statin use.” The current study “underscores the fact that using a low dose of a high-potency statin is associated with a very, very low risk of side effects.”

At a media briefing on SPORT, Amit Khera, MD, agreed the randomized trial provides some needed evidence that can be discussed with patients. “If someone’s coming to see me for cholesterol, we can say definitively now, at least there is data that these [supplements] don’t help your cholesterol and statins do.” Dr. Khera directs the preventive cardiology program at University of Texas Southwestern Medical Center, Dallas.

“I think for those who are there very specifically to lower their cholesterol, hopefully this will resonate,” he said.

“I personally didn’t see a lot of harms in using these supplements. But I also didn’t see any benefits,” Dr. Khera told this news organization.

“Now, if you’re taking them for other reasons, so be it. But if you need to lower your cholesterol for cardiovascular health reasons,” he said, “you need to know that they are minimally to not effective at all.”

But such supplements still “are not without harm,” Dr. Laffin proposed at the press conference. For example, they have potential for drug-drug interactions, “not only with cardiovascular medicines, but those taken for other reasons,” he said. “There are 90,000 supplements on the market in the United States today, and there are all kinds of potential safety issues associated with them.”

In patient discussions, Dr. Laffin said, “I do not think it’s good enough to say, you can waste your money [on supplements] as long as you’re taking your statin. These can actually be harmful in certain situations.”

SPORT, described as a single-center study, randomly assigned 199 participants from “throughout the Cleveland Clinic Health System in northeast Ohio” to one of the eight treatment groups. The investigators were blinded to treatment assignments, Dr. Laffin reported.
 

High adherence

Entry criteria included age 40 to 75 years with no history of cardiovascular disease, LDL-cholesterol from 70 to 189 mg/dL, and a 5%-20% 10-year risk of atherosclerotic cardiovascular disease by the pooled cohort equations. The predominantly White cohort averaged 64.4 years in age and 59% were women.

They were assigned to receive rosuvastatin 5 mg daily, placebo, or daily doses of supplements, with 25 patients per group, except the fish-oil group, which comprised 24 patients.

The daily supplement dosages were 2,400 mg for fish oil (Nature Made); 2,400 mg for cinnamon (NutriFlair), 5,000 mcg allicin for the garlic (Garlique), 4,500 mg for turmeric curcumin (BioSchwartz), 1,600 mg plant sterols (CholestOff Plus, Nature Made), and 2,400 mg red yeast rice (Arazo Nutrition).

Adherence to the assigned regimens was high, Dr. Laffin said, given that only four participants took less than 70% of their assigned doses.

Levels of LDL cholesterol in the statin group fell by 37.9% in 28 days, and by 35.2% relative to the placebo group (P < .001 for both differences), whereas any changes in LDL cholesterol among patients taking the most supplements were not significantly different from the placebo group. Of note, LDL cholesterol levels rose 7.8% (P = .01) compared with placebo among the group assigned to the garlic supplement.

Rosuvastatin had no apparent effect on HDL cholesterol levels, nor did most of the supplements; but such levels in patients taking the plant sterol supplement decreased by 7.1% (P = .02) compared to placebo and by 4% (P = .01) compared to the statin group.

None of the noncontrol groups, including those assigned to rosuvastatin, showed significant changes in high-sensitivity CRP levels compared with the placebo group. The lack of rosuvastatin effect on the inflammatory biomarker, the researchers speculated, is probably explained by the statins’ low dose as well as the limited size of the trial population.

There were two serious adverse events, including one deep venous thrombosis in the placebo group and a liver adenocarcinoma in a patient assigned to fish oil who “had not yet taken any of the study drug at the time of the serious adverse event,” the published report notes.
It remains open whether any of the assigned regimens could show different results over the long term, Dr. Laffin said. The SPORT trial’s 28-day duration, he said, “may not have fully captured the impact of supplements on lipid and inflammatory biomarkers.”

Nor is it known whether the supplements can potentially affect clinical outcomes. But “you could make an argument that it would be unethical” to randomize similar patients to a placebo-controlled, cardiovascular outcomes trial comparing the same six supplements and a statin.

Dr. Laffin has disclosed consulting or serving on a steering committee for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and Crispr Therapeutics; receiving research funding from AstraZeneca; and having ownership interest in LucidAct Health and Gordy Health. Dr. Ndumele and Dr. Khera have reported no relevant financial relationships.

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

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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