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Study evaluates OTC treatments for molluscum contagiosum
“It’s important for clinicians who see children with molluscum to be aware of the many products marketed to patients and to be able to provide objective information about them,” senior author Elaine Siegfried, MD, said in an interview following the annual meeting of the Society for Pediatric Dermatology, where the abstract was presented during a poster session.
In the text of their abstract, Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and coauthors Isaac Hoft, of Open Mind Holistics in Ft. Collins, Colo., and Samantha K. Ong, BA, a student at SLU, noted that MC primarily infects children, with an annual incidence of 8%. “Although the disease is self-limited, associated symptoms, contagion and an average 1-year duration prompt concern and frequent medical visits,” they wrote.
The optimal treatment for MC has not been defined and there is currently no approved medication approved for the condition, although three products are in development: VP-102 (cantharidin) by Verrica Pharmaceuticals; SB206, a topical antiviral by Novan; and 10%-15% KOH formulation by the Gurina Foundation.
But many OTC products have been marketed to treat the condition. To identify the OTC products and to assess accompanying information related to safety, efficacy, and cost, the researchers performed an internet search using the terms “molluscum” plus “treatment,” “treatment at home,” “relief,” and “medication.” Eight products were identified for analysis: Conzerol (Elroselabs), Molleave (Innovative Med), Mollenol (Jeva Laboratories), MolluscumBLAST (Revitalize Life Organics), Molluscum Away Patches (Molluscum Away), Naturasil (Nature’s Innovation), Terrasil (Advanced Skincare % Topical Solutions), and Zymaderm (Naturopathix). Package sizes ranged from 0.78 to 1.5 ounces, and prices ranged from about $19 to almost $55.
Dr. Siegfried and colleagues found that all products provided instructions on application and use but most package labels did not include sufficient information about their plant-based ingredients or appropriate dosing. Six of the eight products contained Thuja occidentalis (Arbor vitae), a coniferous cedar whose essential oil has been used in homeopathic products for its anti-inflammatory and antiviral properties. Lemon extract, tea tree oil, and other botanicals were present in no more than three products each. Only two of the products provided information about the number of lesions that could be treated per package.
“The lack of national oversight as well as robust methods for high-level data analysis make safety and efficacy unclear for a Thuja extract marketed to treat MC,” the researchers wrote. “Numerous adverse drug events and positive intradermal skin tests related to Thuja have been reported.”
Dr. Siegfried added that many OTC products offer a money-back guarantee, “so when seeing a patient who failed to respond to one of these products, encourage them, at least, to request a refund, but to also submit a comment about lack of efficacy, in order to provide more balanced Internet information.”
Dr. Siegfried disclosed that she has served as an investigator and consultant for Verrica Pharmaceuticals, and as a consultant and Data Safety Monitoring board member for Novan, two of the companies currently developing drugs to treat molluscum. Her coauthors had no conflicts of interest to disclose.
“It’s important for clinicians who see children with molluscum to be aware of the many products marketed to patients and to be able to provide objective information about them,” senior author Elaine Siegfried, MD, said in an interview following the annual meeting of the Society for Pediatric Dermatology, where the abstract was presented during a poster session.
In the text of their abstract, Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and coauthors Isaac Hoft, of Open Mind Holistics in Ft. Collins, Colo., and Samantha K. Ong, BA, a student at SLU, noted that MC primarily infects children, with an annual incidence of 8%. “Although the disease is self-limited, associated symptoms, contagion and an average 1-year duration prompt concern and frequent medical visits,” they wrote.
The optimal treatment for MC has not been defined and there is currently no approved medication approved for the condition, although three products are in development: VP-102 (cantharidin) by Verrica Pharmaceuticals; SB206, a topical antiviral by Novan; and 10%-15% KOH formulation by the Gurina Foundation.
But many OTC products have been marketed to treat the condition. To identify the OTC products and to assess accompanying information related to safety, efficacy, and cost, the researchers performed an internet search using the terms “molluscum” plus “treatment,” “treatment at home,” “relief,” and “medication.” Eight products were identified for analysis: Conzerol (Elroselabs), Molleave (Innovative Med), Mollenol (Jeva Laboratories), MolluscumBLAST (Revitalize Life Organics), Molluscum Away Patches (Molluscum Away), Naturasil (Nature’s Innovation), Terrasil (Advanced Skincare % Topical Solutions), and Zymaderm (Naturopathix). Package sizes ranged from 0.78 to 1.5 ounces, and prices ranged from about $19 to almost $55.
Dr. Siegfried and colleagues found that all products provided instructions on application and use but most package labels did not include sufficient information about their plant-based ingredients or appropriate dosing. Six of the eight products contained Thuja occidentalis (Arbor vitae), a coniferous cedar whose essential oil has been used in homeopathic products for its anti-inflammatory and antiviral properties. Lemon extract, tea tree oil, and other botanicals were present in no more than three products each. Only two of the products provided information about the number of lesions that could be treated per package.
“The lack of national oversight as well as robust methods for high-level data analysis make safety and efficacy unclear for a Thuja extract marketed to treat MC,” the researchers wrote. “Numerous adverse drug events and positive intradermal skin tests related to Thuja have been reported.”
Dr. Siegfried added that many OTC products offer a money-back guarantee, “so when seeing a patient who failed to respond to one of these products, encourage them, at least, to request a refund, but to also submit a comment about lack of efficacy, in order to provide more balanced Internet information.”
Dr. Siegfried disclosed that she has served as an investigator and consultant for Verrica Pharmaceuticals, and as a consultant and Data Safety Monitoring board member for Novan, two of the companies currently developing drugs to treat molluscum. Her coauthors had no conflicts of interest to disclose.
“It’s important for clinicians who see children with molluscum to be aware of the many products marketed to patients and to be able to provide objective information about them,” senior author Elaine Siegfried, MD, said in an interview following the annual meeting of the Society for Pediatric Dermatology, where the abstract was presented during a poster session.
In the text of their abstract, Dr. Siegfried, professor of pediatrics and dermatology at Saint Louis University, and coauthors Isaac Hoft, of Open Mind Holistics in Ft. Collins, Colo., and Samantha K. Ong, BA, a student at SLU, noted that MC primarily infects children, with an annual incidence of 8%. “Although the disease is self-limited, associated symptoms, contagion and an average 1-year duration prompt concern and frequent medical visits,” they wrote.
The optimal treatment for MC has not been defined and there is currently no approved medication approved for the condition, although three products are in development: VP-102 (cantharidin) by Verrica Pharmaceuticals; SB206, a topical antiviral by Novan; and 10%-15% KOH formulation by the Gurina Foundation.
But many OTC products have been marketed to treat the condition. To identify the OTC products and to assess accompanying information related to safety, efficacy, and cost, the researchers performed an internet search using the terms “molluscum” plus “treatment,” “treatment at home,” “relief,” and “medication.” Eight products were identified for analysis: Conzerol (Elroselabs), Molleave (Innovative Med), Mollenol (Jeva Laboratories), MolluscumBLAST (Revitalize Life Organics), Molluscum Away Patches (Molluscum Away), Naturasil (Nature’s Innovation), Terrasil (Advanced Skincare % Topical Solutions), and Zymaderm (Naturopathix). Package sizes ranged from 0.78 to 1.5 ounces, and prices ranged from about $19 to almost $55.
Dr. Siegfried and colleagues found that all products provided instructions on application and use but most package labels did not include sufficient information about their plant-based ingredients or appropriate dosing. Six of the eight products contained Thuja occidentalis (Arbor vitae), a coniferous cedar whose essential oil has been used in homeopathic products for its anti-inflammatory and antiviral properties. Lemon extract, tea tree oil, and other botanicals were present in no more than three products each. Only two of the products provided information about the number of lesions that could be treated per package.
“The lack of national oversight as well as robust methods for high-level data analysis make safety and efficacy unclear for a Thuja extract marketed to treat MC,” the researchers wrote. “Numerous adverse drug events and positive intradermal skin tests related to Thuja have been reported.”
Dr. Siegfried added that many OTC products offer a money-back guarantee, “so when seeing a patient who failed to respond to one of these products, encourage them, at least, to request a refund, but to also submit a comment about lack of efficacy, in order to provide more balanced Internet information.”
Dr. Siegfried disclosed that she has served as an investigator and consultant for Verrica Pharmaceuticals, and as a consultant and Data Safety Monitoring board member for Novan, two of the companies currently developing drugs to treat molluscum. Her coauthors had no conflicts of interest to disclose.
FROM SPD 2021
GUIDE-HF: CardioMEMS-guided meds fall short in mild to moderate heart failure
Medical therapy for heart failure guided by an implanted pulmonary artery pressure (PAP) sensor didn’t improve survival or risk for HF events like hospitalization over a year in a major randomized trial that entered a broad range of patients with mild to moderate disease.
But medical therapy adjustments based on PAP readings from the miniature CardioMEMS (Abbott) implant might well have surpassed conventional HF management for outcomes had the world not been turned upside down by SARS-CoV-2 and the pandemic lockdowns, assert researchers from the GUIDE-HF trial.
Something about the crisis, they concluded – although not without some pushback – led to better outcomes in the standard-care control group, apparently muddling any potential differences from those on PAP-guided management.
Working with regulators, the team conducted a “pre–COVID-19 impact analysis” that compared outcomes before the March 2020 national COVID-19 emergency declaration that forced much of the United States with shelter in place.
By that time, all of the trial’s patients had been followed for at least 3 months, and about three-fourths of its endpoints had already been counted, JoAnn Lindenfeld, MD, Vanderbilt University Medical Center, Nashville, Tenn., said at a media briefing prior to unveiling GUIDE-HF at the all-virtual European Society of Cardiology Congress 2021.
The pre–COVID-19 analysis, approved several months before the end of the trial – while the data were still blinded – had been “suggested by both regulatory agencies and professional societies in Europe and in the United States,” Dr. Lindenfeld said.
It pointed to a possible benefit for the CardioMEMS-guided strategy, a barely significant 19% drop in risk (P = .049) for the primary endpoint of death, HF hospitalization, or urgent HF hospital visit. The effect was driven by a 24% decline in HF events (P = .014), with no significant contribution from mortality.
“The benefits of hemodynamic monitoring and management in reducing heart failure hospitalizations extended to patients with less severe heart failure”; that is, those in New York Heart Association class 2 and any in NYHA class 3 with “elevated natriuretic peptides but no previous hospitalization,” said Dr. Lindenfeld, who is also lead author on the GUIDE-HF report published in the Lancet.
Such benefits would suggest that CardioMEMS-guided management can improve outcomes in an HF population much broader than the device’s current indication.
But as it happens, the trial’s prospectively defined 12-month primary outcomes were less impressive. A 12% decline in risk for the composite endpoint among patients managed by CardioMEMS failed to reach significance compared with standard management (P = .16).
“Several factors could explain the considerable loss of benefit of hemodynamic-guided management during the COVID-19 pandemic,” the Lancet report explained. They include “improved patient compliance with medical and dietary regimens, reduced respiratory infections, altered health-care provider behavior, changes in disease progression due to COVID-19, or other as yet unknown effects of a major pandemic.”
Expanded population
Importantly, GUIDE-HF had entered 1,000 patients in NYHA class 2-4 and either an HF hospitalization in the previous year or elevated natriuretic peptide levels. About 44% of the entrants in NYHA class 3 did not have a 1-year history of HF hospitalization.
That’s a more heterogeneous and potentially lower-risk cohort than patients in the randomized CHAMPION study of 11 years ago, which led to the implant’s approval on both sides of the Atlantic.
In that trial, CardioMEMS-guided management was followed by 30% drop in risk for HF hospitalization over 6 months (P < .001). But CHAMPION was limited to patients in NYHA class 3 with a history of HF hospitalization, the device’s current indication in both the United States and Europe.
The GUIDE-HF findings “reinforce that patients with class 3 heart failure and prior heart failure hospitalization are those in whom there is the clearest benefit, based on the prior CHAMPION trial. These are the patients where this monitoring strategy may be best targeted,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, said in an interview.
Although GUIDE-HF didn’t show a significant benefit for NYHA class 2 patients with elevated biomarkers, who aren’t covered by the device’s current labeling, that group showed “some suggestions of potential benefit,” noted Dr. Fonarow, who isn’t a coauthor on the Lancet report. So, “there may be select patients with class 2 heart failure where monitoring could be considered on a case-by-case basis.”
In an interview, Larry A. Allen, MD, MHS, said that, “while the technology is pretty amazing, the real question is whether it tells us something that we didn’t already know that leads to improved care. Unfortunately, as tested here, it doesn’t, or at least not enough to make a big difference.”
The pre–COVID-19 impact analysis “should be interpreted with caution, and not as the primary finding,” Dr. Allen, from the University of Colorado at Denver, Aurora, who is not a GUIDE-HF coauthor, said in an interview.
One might hypothesize, he said, “that, in the setting of limited in-person visits with loss of physical examination, perhaps CardioMEMS would be more – not less – helpful during the pandemic. And yet the opposite was seen.”
The pandemic has “markedly altered all kinds of aspects of patient care and trial conduct, but that doesn’t make the data derived during that period uninformative,” Dr. Allen said. “And as we are increasingly reminded, the future will be a new normal, not a prepandemic normal.”
A third group
The GUIDE-HF trial includes, in addition to the 1,000 randomized patients, a single-group observational cohort of 2,600 patients, whose outcomes will be reported at another time, noted the published report.
But in the randomized comparison, conducted at 118 centers in North America, all patients were implanted with the CardioMEMS device and blinded as to their assigned strategy. Enrollment took place between March 2018 and Dec. 20, 2019.
Of the 1,000 successfully implanted patients, 497 were assigned to the pressure-guided strategy, in which “titration of diuretics was recommended if pulmonary artery pressure provided evidence of excess intravascular volume, and titration of vasodilators was recommended if elevated vascular resistance was evident,” the report stated.
The remaining 503 patients assigned to standard care served as control subjects, for whom “investigators were aware of treatment assignment but did not have access to PAP data.”
The hazard ratio for the primary endpoint in the pressure-guided group, compared with the control group, was 0.88 (95% confidence interval, 0.74-1.05; P = .16) over a median follow-up of 11.7 months.
But in the sensitivity analysis comparing outcomes before and after the COVID-19 lockdowns, using established methodology, the report stated, the primary-endpoint HR was 0.81 (95% CI, 0.66-1.00; P = .049).
The difference is owed to improved outcomes in the control group under pandemic conditions, the researchers concluded. Patients assigned to conventional management –whatever that meant during shelter-in-place – experienced 21% fewer primary-endpoint events than their own rate before the pandemic. After the COVID-19 emergency was declared, there was no significant difference in event rates between the two randomization groups.
In the primary 12-month analysis, the HR for HF events in the guided-therapy was not significant reduced, at 0.85 (95% CI, 0.70-1.03; P = .096). But in the pre-COVID-19 analysis, that risk fell significantly with CardioMEMS-guided management, for an HR of 0.76 (95% CI, 0.61-0.95; P = .014).
An editorial accompanying the GUIDE-HF publication (Lancet. 2021 Aug 27. doi: 10.1016/S0140-6736[21]01914-0) asserts that the trial “did not enroll an ideal group of patients for showing the efficacy of pulmonary artery pressure monitoring, since many had baseline pressures in the target range with little possibility of short-term gain.”
Also, wrote John G. F. Cleland, MD, PhD, University of Glasgow, and Pierpaolo Pellicori, MD, Imperial College London, “follow-up was too short, and interventions did not substantially change pulmonary artery pressure.”
They continue: “Monitoring alone cannot improve outcome, but consequent actions might. The GUIDE-HF results are encouraging but inconclusive, and should inform further research, possibly a large, simple, open-label trial to investigate a system of care rather than a single technology.”
GUIDE-HF was funded by Abbott. Dr. Lindenfeld disclosed receiving research grants from AstraZeneca, Sensible Medical, and Volumetrix; and consulting for Abbott, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards, Impulse Dynamics, and VWave. Dr. Fonarow reported consulting for Abbott and that his institution has participated in the GUIDE-HF trial; he has elsewhere disclosed consulting for Amgen, AstraZeneca, CHF Solutions Lifesciences, Janssen, Medtronic, and Novartis. Dr. Allen had elsewhere reported consulting for Abbott, Amgen, Boston Scientific, and Novartis. Dr. Cleland disclosed receiving personal fees from Abbott for serving on an advisory board for the MitraClip device, unrelated to the CardioMEMS device. Dr. Pellicori reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
Medical therapy for heart failure guided by an implanted pulmonary artery pressure (PAP) sensor didn’t improve survival or risk for HF events like hospitalization over a year in a major randomized trial that entered a broad range of patients with mild to moderate disease.
But medical therapy adjustments based on PAP readings from the miniature CardioMEMS (Abbott) implant might well have surpassed conventional HF management for outcomes had the world not been turned upside down by SARS-CoV-2 and the pandemic lockdowns, assert researchers from the GUIDE-HF trial.
Something about the crisis, they concluded – although not without some pushback – led to better outcomes in the standard-care control group, apparently muddling any potential differences from those on PAP-guided management.
Working with regulators, the team conducted a “pre–COVID-19 impact analysis” that compared outcomes before the March 2020 national COVID-19 emergency declaration that forced much of the United States with shelter in place.
By that time, all of the trial’s patients had been followed for at least 3 months, and about three-fourths of its endpoints had already been counted, JoAnn Lindenfeld, MD, Vanderbilt University Medical Center, Nashville, Tenn., said at a media briefing prior to unveiling GUIDE-HF at the all-virtual European Society of Cardiology Congress 2021.
The pre–COVID-19 analysis, approved several months before the end of the trial – while the data were still blinded – had been “suggested by both regulatory agencies and professional societies in Europe and in the United States,” Dr. Lindenfeld said.
It pointed to a possible benefit for the CardioMEMS-guided strategy, a barely significant 19% drop in risk (P = .049) for the primary endpoint of death, HF hospitalization, or urgent HF hospital visit. The effect was driven by a 24% decline in HF events (P = .014), with no significant contribution from mortality.
“The benefits of hemodynamic monitoring and management in reducing heart failure hospitalizations extended to patients with less severe heart failure”; that is, those in New York Heart Association class 2 and any in NYHA class 3 with “elevated natriuretic peptides but no previous hospitalization,” said Dr. Lindenfeld, who is also lead author on the GUIDE-HF report published in the Lancet.
Such benefits would suggest that CardioMEMS-guided management can improve outcomes in an HF population much broader than the device’s current indication.
But as it happens, the trial’s prospectively defined 12-month primary outcomes were less impressive. A 12% decline in risk for the composite endpoint among patients managed by CardioMEMS failed to reach significance compared with standard management (P = .16).
“Several factors could explain the considerable loss of benefit of hemodynamic-guided management during the COVID-19 pandemic,” the Lancet report explained. They include “improved patient compliance with medical and dietary regimens, reduced respiratory infections, altered health-care provider behavior, changes in disease progression due to COVID-19, or other as yet unknown effects of a major pandemic.”
Expanded population
Importantly, GUIDE-HF had entered 1,000 patients in NYHA class 2-4 and either an HF hospitalization in the previous year or elevated natriuretic peptide levels. About 44% of the entrants in NYHA class 3 did not have a 1-year history of HF hospitalization.
That’s a more heterogeneous and potentially lower-risk cohort than patients in the randomized CHAMPION study of 11 years ago, which led to the implant’s approval on both sides of the Atlantic.
In that trial, CardioMEMS-guided management was followed by 30% drop in risk for HF hospitalization over 6 months (P < .001). But CHAMPION was limited to patients in NYHA class 3 with a history of HF hospitalization, the device’s current indication in both the United States and Europe.
The GUIDE-HF findings “reinforce that patients with class 3 heart failure and prior heart failure hospitalization are those in whom there is the clearest benefit, based on the prior CHAMPION trial. These are the patients where this monitoring strategy may be best targeted,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, said in an interview.
Although GUIDE-HF didn’t show a significant benefit for NYHA class 2 patients with elevated biomarkers, who aren’t covered by the device’s current labeling, that group showed “some suggestions of potential benefit,” noted Dr. Fonarow, who isn’t a coauthor on the Lancet report. So, “there may be select patients with class 2 heart failure where monitoring could be considered on a case-by-case basis.”
In an interview, Larry A. Allen, MD, MHS, said that, “while the technology is pretty amazing, the real question is whether it tells us something that we didn’t already know that leads to improved care. Unfortunately, as tested here, it doesn’t, or at least not enough to make a big difference.”
The pre–COVID-19 impact analysis “should be interpreted with caution, and not as the primary finding,” Dr. Allen, from the University of Colorado at Denver, Aurora, who is not a GUIDE-HF coauthor, said in an interview.
One might hypothesize, he said, “that, in the setting of limited in-person visits with loss of physical examination, perhaps CardioMEMS would be more – not less – helpful during the pandemic. And yet the opposite was seen.”
The pandemic has “markedly altered all kinds of aspects of patient care and trial conduct, but that doesn’t make the data derived during that period uninformative,” Dr. Allen said. “And as we are increasingly reminded, the future will be a new normal, not a prepandemic normal.”
A third group
The GUIDE-HF trial includes, in addition to the 1,000 randomized patients, a single-group observational cohort of 2,600 patients, whose outcomes will be reported at another time, noted the published report.
But in the randomized comparison, conducted at 118 centers in North America, all patients were implanted with the CardioMEMS device and blinded as to their assigned strategy. Enrollment took place between March 2018 and Dec. 20, 2019.
Of the 1,000 successfully implanted patients, 497 were assigned to the pressure-guided strategy, in which “titration of diuretics was recommended if pulmonary artery pressure provided evidence of excess intravascular volume, and titration of vasodilators was recommended if elevated vascular resistance was evident,” the report stated.
The remaining 503 patients assigned to standard care served as control subjects, for whom “investigators were aware of treatment assignment but did not have access to PAP data.”
The hazard ratio for the primary endpoint in the pressure-guided group, compared with the control group, was 0.88 (95% confidence interval, 0.74-1.05; P = .16) over a median follow-up of 11.7 months.
But in the sensitivity analysis comparing outcomes before and after the COVID-19 lockdowns, using established methodology, the report stated, the primary-endpoint HR was 0.81 (95% CI, 0.66-1.00; P = .049).
The difference is owed to improved outcomes in the control group under pandemic conditions, the researchers concluded. Patients assigned to conventional management –whatever that meant during shelter-in-place – experienced 21% fewer primary-endpoint events than their own rate before the pandemic. After the COVID-19 emergency was declared, there was no significant difference in event rates between the two randomization groups.
In the primary 12-month analysis, the HR for HF events in the guided-therapy was not significant reduced, at 0.85 (95% CI, 0.70-1.03; P = .096). But in the pre-COVID-19 analysis, that risk fell significantly with CardioMEMS-guided management, for an HR of 0.76 (95% CI, 0.61-0.95; P = .014).
An editorial accompanying the GUIDE-HF publication (Lancet. 2021 Aug 27. doi: 10.1016/S0140-6736[21]01914-0) asserts that the trial “did not enroll an ideal group of patients for showing the efficacy of pulmonary artery pressure monitoring, since many had baseline pressures in the target range with little possibility of short-term gain.”
Also, wrote John G. F. Cleland, MD, PhD, University of Glasgow, and Pierpaolo Pellicori, MD, Imperial College London, “follow-up was too short, and interventions did not substantially change pulmonary artery pressure.”
They continue: “Monitoring alone cannot improve outcome, but consequent actions might. The GUIDE-HF results are encouraging but inconclusive, and should inform further research, possibly a large, simple, open-label trial to investigate a system of care rather than a single technology.”
GUIDE-HF was funded by Abbott. Dr. Lindenfeld disclosed receiving research grants from AstraZeneca, Sensible Medical, and Volumetrix; and consulting for Abbott, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards, Impulse Dynamics, and VWave. Dr. Fonarow reported consulting for Abbott and that his institution has participated in the GUIDE-HF trial; he has elsewhere disclosed consulting for Amgen, AstraZeneca, CHF Solutions Lifesciences, Janssen, Medtronic, and Novartis. Dr. Allen had elsewhere reported consulting for Abbott, Amgen, Boston Scientific, and Novartis. Dr. Cleland disclosed receiving personal fees from Abbott for serving on an advisory board for the MitraClip device, unrelated to the CardioMEMS device. Dr. Pellicori reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
Medical therapy for heart failure guided by an implanted pulmonary artery pressure (PAP) sensor didn’t improve survival or risk for HF events like hospitalization over a year in a major randomized trial that entered a broad range of patients with mild to moderate disease.
But medical therapy adjustments based on PAP readings from the miniature CardioMEMS (Abbott) implant might well have surpassed conventional HF management for outcomes had the world not been turned upside down by SARS-CoV-2 and the pandemic lockdowns, assert researchers from the GUIDE-HF trial.
Something about the crisis, they concluded – although not without some pushback – led to better outcomes in the standard-care control group, apparently muddling any potential differences from those on PAP-guided management.
Working with regulators, the team conducted a “pre–COVID-19 impact analysis” that compared outcomes before the March 2020 national COVID-19 emergency declaration that forced much of the United States with shelter in place.
By that time, all of the trial’s patients had been followed for at least 3 months, and about three-fourths of its endpoints had already been counted, JoAnn Lindenfeld, MD, Vanderbilt University Medical Center, Nashville, Tenn., said at a media briefing prior to unveiling GUIDE-HF at the all-virtual European Society of Cardiology Congress 2021.
The pre–COVID-19 analysis, approved several months before the end of the trial – while the data were still blinded – had been “suggested by both regulatory agencies and professional societies in Europe and in the United States,” Dr. Lindenfeld said.
It pointed to a possible benefit for the CardioMEMS-guided strategy, a barely significant 19% drop in risk (P = .049) for the primary endpoint of death, HF hospitalization, or urgent HF hospital visit. The effect was driven by a 24% decline in HF events (P = .014), with no significant contribution from mortality.
“The benefits of hemodynamic monitoring and management in reducing heart failure hospitalizations extended to patients with less severe heart failure”; that is, those in New York Heart Association class 2 and any in NYHA class 3 with “elevated natriuretic peptides but no previous hospitalization,” said Dr. Lindenfeld, who is also lead author on the GUIDE-HF report published in the Lancet.
Such benefits would suggest that CardioMEMS-guided management can improve outcomes in an HF population much broader than the device’s current indication.
But as it happens, the trial’s prospectively defined 12-month primary outcomes were less impressive. A 12% decline in risk for the composite endpoint among patients managed by CardioMEMS failed to reach significance compared with standard management (P = .16).
“Several factors could explain the considerable loss of benefit of hemodynamic-guided management during the COVID-19 pandemic,” the Lancet report explained. They include “improved patient compliance with medical and dietary regimens, reduced respiratory infections, altered health-care provider behavior, changes in disease progression due to COVID-19, or other as yet unknown effects of a major pandemic.”
Expanded population
Importantly, GUIDE-HF had entered 1,000 patients in NYHA class 2-4 and either an HF hospitalization in the previous year or elevated natriuretic peptide levels. About 44% of the entrants in NYHA class 3 did not have a 1-year history of HF hospitalization.
That’s a more heterogeneous and potentially lower-risk cohort than patients in the randomized CHAMPION study of 11 years ago, which led to the implant’s approval on both sides of the Atlantic.
In that trial, CardioMEMS-guided management was followed by 30% drop in risk for HF hospitalization over 6 months (P < .001). But CHAMPION was limited to patients in NYHA class 3 with a history of HF hospitalization, the device’s current indication in both the United States and Europe.
The GUIDE-HF findings “reinforce that patients with class 3 heart failure and prior heart failure hospitalization are those in whom there is the clearest benefit, based on the prior CHAMPION trial. These are the patients where this monitoring strategy may be best targeted,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, said in an interview.
Although GUIDE-HF didn’t show a significant benefit for NYHA class 2 patients with elevated biomarkers, who aren’t covered by the device’s current labeling, that group showed “some suggestions of potential benefit,” noted Dr. Fonarow, who isn’t a coauthor on the Lancet report. So, “there may be select patients with class 2 heart failure where monitoring could be considered on a case-by-case basis.”
In an interview, Larry A. Allen, MD, MHS, said that, “while the technology is pretty amazing, the real question is whether it tells us something that we didn’t already know that leads to improved care. Unfortunately, as tested here, it doesn’t, or at least not enough to make a big difference.”
The pre–COVID-19 impact analysis “should be interpreted with caution, and not as the primary finding,” Dr. Allen, from the University of Colorado at Denver, Aurora, who is not a GUIDE-HF coauthor, said in an interview.
One might hypothesize, he said, “that, in the setting of limited in-person visits with loss of physical examination, perhaps CardioMEMS would be more – not less – helpful during the pandemic. And yet the opposite was seen.”
The pandemic has “markedly altered all kinds of aspects of patient care and trial conduct, but that doesn’t make the data derived during that period uninformative,” Dr. Allen said. “And as we are increasingly reminded, the future will be a new normal, not a prepandemic normal.”
A third group
The GUIDE-HF trial includes, in addition to the 1,000 randomized patients, a single-group observational cohort of 2,600 patients, whose outcomes will be reported at another time, noted the published report.
But in the randomized comparison, conducted at 118 centers in North America, all patients were implanted with the CardioMEMS device and blinded as to their assigned strategy. Enrollment took place between March 2018 and Dec. 20, 2019.
Of the 1,000 successfully implanted patients, 497 were assigned to the pressure-guided strategy, in which “titration of diuretics was recommended if pulmonary artery pressure provided evidence of excess intravascular volume, and titration of vasodilators was recommended if elevated vascular resistance was evident,” the report stated.
The remaining 503 patients assigned to standard care served as control subjects, for whom “investigators were aware of treatment assignment but did not have access to PAP data.”
The hazard ratio for the primary endpoint in the pressure-guided group, compared with the control group, was 0.88 (95% confidence interval, 0.74-1.05; P = .16) over a median follow-up of 11.7 months.
But in the sensitivity analysis comparing outcomes before and after the COVID-19 lockdowns, using established methodology, the report stated, the primary-endpoint HR was 0.81 (95% CI, 0.66-1.00; P = .049).
The difference is owed to improved outcomes in the control group under pandemic conditions, the researchers concluded. Patients assigned to conventional management –whatever that meant during shelter-in-place – experienced 21% fewer primary-endpoint events than their own rate before the pandemic. After the COVID-19 emergency was declared, there was no significant difference in event rates between the two randomization groups.
In the primary 12-month analysis, the HR for HF events in the guided-therapy was not significant reduced, at 0.85 (95% CI, 0.70-1.03; P = .096). But in the pre-COVID-19 analysis, that risk fell significantly with CardioMEMS-guided management, for an HR of 0.76 (95% CI, 0.61-0.95; P = .014).
An editorial accompanying the GUIDE-HF publication (Lancet. 2021 Aug 27. doi: 10.1016/S0140-6736[21]01914-0) asserts that the trial “did not enroll an ideal group of patients for showing the efficacy of pulmonary artery pressure monitoring, since many had baseline pressures in the target range with little possibility of short-term gain.”
Also, wrote John G. F. Cleland, MD, PhD, University of Glasgow, and Pierpaolo Pellicori, MD, Imperial College London, “follow-up was too short, and interventions did not substantially change pulmonary artery pressure.”
They continue: “Monitoring alone cannot improve outcome, but consequent actions might. The GUIDE-HF results are encouraging but inconclusive, and should inform further research, possibly a large, simple, open-label trial to investigate a system of care rather than a single technology.”
GUIDE-HF was funded by Abbott. Dr. Lindenfeld disclosed receiving research grants from AstraZeneca, Sensible Medical, and Volumetrix; and consulting for Abbott, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards, Impulse Dynamics, and VWave. Dr. Fonarow reported consulting for Abbott and that his institution has participated in the GUIDE-HF trial; he has elsewhere disclosed consulting for Amgen, AstraZeneca, CHF Solutions Lifesciences, Janssen, Medtronic, and Novartis. Dr. Allen had elsewhere reported consulting for Abbott, Amgen, Boston Scientific, and Novartis. Dr. Cleland disclosed receiving personal fees from Abbott for serving on an advisory board for the MitraClip device, unrelated to the CardioMEMS device. Dr. Pellicori reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
Aerobic exercise can reduce AFib frequency, severity: ACTIVE-AF
Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.
Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.
The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.
This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.
The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”
Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.
The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.
“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.
This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.
ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
Aim for 3.5 hours a week
A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.
And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.
ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.
The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.
Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.
The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.
“We certainly cautioned against far exceeding this level,” he added.
Patients in the usual care group received exercise advice but no active intervention.
All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.
The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.
At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).
This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.
Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.
“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.
Cost was not a barrier since the sessions with an exercise physiologist were free.
Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.
Most patients liked the variety of physical activity options.
The researchers plan to determine any gender differences in ACTIVE-AF.
Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.
The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.
Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.
The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.
This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.
The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”
Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.
The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.
“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.
This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.
ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
Aim for 3.5 hours a week
A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.
And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.
ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.
The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.
Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.
The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.
“We certainly cautioned against far exceeding this level,” he added.
Patients in the usual care group received exercise advice but no active intervention.
All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.
The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.
At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).
This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.
Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.
“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.
Cost was not a barrier since the sessions with an exercise physiologist were free.
Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.
Most patients liked the variety of physical activity options.
The researchers plan to determine any gender differences in ACTIVE-AF.
Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.
The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with atrial fibrillation (AFib) gained significant benefits from a 6-month program of supervised and unsupervised moderate exercise versus usual care, new randomized trial results show.
Among 120 AFib patients in the ACTIVE-AF trial, those randomized to the exercise arm had significantly less frequent AFib recurrence and less severe symptoms over a 1-year period, said Adrian Elliott, PhD, who will present this late-breaking research at the European Society of Cardiology (ESC) Congress 2021.
The trial “demonstrates that some patients can control their arrhythmia through physical activity, without the need for complex interventions such as ablation or medications to keep their heart in normal rhythm,” Dr. Elliott, from the University of Adelaide, Australia, said in a statement from the ESC.
This is “the largest randomized controlled trial investigating the value of an exercise prescription in patients with symptomatic paroxysmal or persistent [AFib],” he told this news organization in an email.
The findings “really provide the evidence needed that recommending aerobic exercise in patients with symptomatic AFib can lower the severity of symptoms and prevent the recurrence of AFib for many patients,” he said. Aerobic exercise should be incorporated into patient treatment, he added, “alongside the use of medications, as guided by a cardiologist, and management of obesity, hypertension, and sleep apnea.”
Mina K. Chung, MD, lead author of a Scientific Statement from the American Heart Association on Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation, as previously reported, agrees.
The “findings support the AHA Scientific Statement that we should encourage our patients with AFib to include regular moderate exercise to help prevent AFib, reduce AFib burden, and improve AFib-related symptoms and quality of life,” Dr. Chung, a cardiologist at the Cleveland Clinic, summarized in an email.
“Our recommendation is to encourage AFib patients to aim for at least the AHA physical activity guidelines for the general population, which advise 150 minutes each week of moderate-intensity exercise,” Dr. Chung said.
This is a “reasonable” goal, but “some might argue that a slightly higher target of physical activity duration may be considered,” Dr. Elliott commented.
ACTIVE-AF, he noted, suggests that “as a general guide, patients [with AFib] should strive to build up to 3.5 hours per week of aerobic exercise and incorporate some higher intensity activities to improve cardiorespiratory fitness.”
Aim for 3.5 hours a week
A previous observational study showed that patients who improved their cardiorespiratory fitness over a 5-year period were significantly less likely to have AFib recurrences.
And in a randomized trial of 51 patients, 12 weeks of aerobic interval training reduced the time spent in AFib compared to usual care, during a 4-week follow-up.
ACTIVE-AF aimed to investigate the value of exercise in AFib in a larger, longer, randomized trial.
The researchers enrolled 120 patients with an average age of 65 years, of whom 43% were women.
Patients in the treatment group received individualized guided exercise from an exercise physiologist in the cardiology clinic once a week for 3 months, then every second week for the following 3 months along with a physical activity plan to follow at home for the other days – aiming to build up to 3.5 hours of physical activity a week.
The supervised sessions, Dr. Elliott explained, were typically higher intensity to raise cardiorespiratory fitness, while the home-based exercise was a moderate intensity aerobic activity of the patient’s choice, such as walking, indoor cycling, or swimming.
“We certainly cautioned against far exceeding this level,” he added.
Patients in the usual care group received exercise advice but no active intervention.
All patients received usual medical care from their cardiologist, who was blinded to the study group allocation.
The co-primary outcomes were AFib symptom severity score and the percentage of patients with recurrent AFib at 12 months, defined as having an AFib episode that lasted longer than 30 seconds or undergoing ablation or requiring ongoing anti-arrhythmic drug therapy.
At 12 months, the percentage of patients with AFib recurrence was significantly lower in the exercise group than in the control group (60% vs. 80%; hazard ratio, 0.50; 95% confidence interval, 0.33-0.78; P = .002).
This means that more patients in the exercise group had a normal heart rhythm without needing an invasive intervention (ablation) or continued use of drugs, Dr. Elliott stressed.
Patients in the exercise group also had significantly less severe symptoms – palpitations, shortness of breath, and fatigue – than patients in the control group.
“On average, patients were achieving close to 180 minutes [of physical activity] per week by 6 months of the intervention and attended 18 supervised sessions in the clinic,” Dr. Elliott said.
Cost was not a barrier since the sessions with an exercise physiologist were free.
Lack of time was the most common reason for missing the physical activity targets, especially for patients with work and family commitments.
Most patients liked the variety of physical activity options.
The researchers plan to determine any gender differences in ACTIVE-AF.
Further research is needed, Dr. Elliott added, to determine which type of exercise is best, whether exercise plus weight loss is synergistic, and whether exercise leads to better long-term freedom from arrhythmia, reduced hospitalization, and improved survival.
The study was partially supported by the National Heart Foundation of Australia through a postdoctoral fellowship to Dr. Elliott. The researchers and Dr. Chung have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
EMPEROR-Preserved: Empagliflozin scores HFpEF breakthrough
Updated August 30, 2021
The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).
Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.
“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.
The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.
Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
Practice will change ‘quickly’
“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.
Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.
About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.
“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.
Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.
EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.
The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.
Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.
More women enrolled than ever before
EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.
One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.
The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).
The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.
Pooling EMPEROR-Preserved with EMPEROR-Reduced
The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.
“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.
This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.
“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.
Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.
“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.
EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.
Updated August 30, 2021
The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).
Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.
“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.
The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.
Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
Practice will change ‘quickly’
“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.
Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.
About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.
“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.
Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.
EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.
The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.
Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.
More women enrolled than ever before
EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.
One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.
The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).
The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.
Pooling EMPEROR-Preserved with EMPEROR-Reduced
The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.
“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.
This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.
“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.
Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.
“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.
EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.
Updated August 30, 2021
The SGLT2 inhibitor empagliflozin achieved in EMPEROR-Preserved what no other agent could previously do: unequivocally cut the incidence of cardiovascular death or hospitalization in patients with heart failure and preserved ejection fraction (HFpEF).
Treatment with empagliflozin (Jardiance) led to a significant 21% relative reduction in the rate of cardiovascular death or hospitalization for heart failure (HHF), compared with placebo, among 5,988 randomized patients with HFpEF during a median 26 months of follow-up, proving that patients with HFpEF finally have a treatment that gives them clinically meaningful benefit, and paving the way to an abrupt change in management of these patients, experts said.
“This is the first trial to show unequivocal benefits of any drug on major heart failure outcomes in patients with HFpEF,” Stefan D. Anker, MD, PhD, declared at the virtual annual congress of the European Society of Cardiology.
The 21% relative reduction, which reflected a cut in the absolute rate of the trial’s primary composite endpoint of 3.3% compared with placebo, was driven mainly by a significant 27% relative reduction in the incidence of HHF (P < .001). Empagliflozin treatment, on top of standard therapy for patients with HFpEF, also resulted in a nonsignificant 9% relative risk reduction in the incidence of cardiovascular death, but it had no discernible impact on the rate of death from any cause, said Dr. Anker, professor of cardiology at Charité Medical University in Berlin.
Concurrently with his talk at the meeting, the results were published online in the New England Journal of Medicine.
Practice will change ‘quickly’
“This will definitely change our practice, and quite quickly,” said Carlos Aguiar, MD, chair of the Advanced Heart Failure and Heart Transplantation Unit at Hospital Santa Cruz in Carnaxide, Portugal, who was not involved in the study.
Transition to routine use of empagliflozin in patients with HFpEF should be swift because it has already become a mainstay of treatment for patients with heart failure with reduced ejection fraction (HFrEF) based on evidence for empagliflozin in EMPEROR-Reduced. A second sodium-glucose cotransporter 2 (SGLT2 ) inhibitor, dapagliflozin (Farxiga), is also an option for treating HFrEF based on results in the DAPA-HF trial, and the DELIVER trial, still in progress, is testing dapagliflozin as a HFpEF treatment in about 6,000 patients, with results expected in 2022.
About half of the patients in EMPEROR-Preserved had diabetes, and the treatment effects on HFpEF were similar regardless of patients’ diabetes status. Empagliflozin, like other members of the SGLT2 inhibitor class, boosts urinary excretion of glucose and received initial regulatory approval as an agent for glycemic control in patients with type 2 diabetes. Empagliflozin also has U.S.-approved marketing indications for treating patients with HFrEF whether or not they also have diabetes, and for reducing cardiovascular death in patients with type 2 diabetes and cardiovascular disease.
“We already use this drug class in cardiovascular medicine and to treat patients with type 2 diabetes, and we have been eager to find a treatment for patients with HFpEF. This is something that will be really significant,” said Dr. Aguiar.
Heart failure clinicians have “become familiar prescribing” SGLT2 inhibitors following approval of HFrEF indications for some of these agents, noted Mary Norine Walsh, MD, a heart failure specialist with Ascension Medical Group in Indianapolis. The new results “are good news because there have been so few options” for patients with HFpEF, she said in an interview.
EMPEROR-Preserved “is the first phase 3 clinical trial that exclusively enrolled patients with heart failure and an ejection fraction of more than 40% to meet its primary outcome,” and the results “represent a major win against a medical condition that had previously proven formidable,” Mark H. Drazner, MD, said in an editorial that accompanied the published results.
The trial’s findings “should contribute to a change in clinical practice given the paucity of therapeutic options available for patients with HFpEF,” wrote Dr. Drazner, a heart failure specialist who is professor and clinical chief of cardiology at UT Southwestern Medical Center in Dallas.
Theresa A, McDonagh, MD, MBChB, who chaired the panel that just released revised guidelines from the European Society of Cardiology for managing patients with heart failure, predicted that empagliflozin treatment for patients with HFpEF will soon show up in guidelines. It will likely receive a “should be considered” ranking despite being a single study because of the impressive size of the treatment effect and lack of well-supported alternative treatments, she commented as a discussant of the trial during its presentation at the congress. If the DELIVER trial with dapagliflozin shows a similar effect, the recommendation would likely become even stronger, added Dr. McDonagh, a heart failure specialist and professor of cardiology at King’s College, London.
More women enrolled than ever before
EMPEROR-Preserved enrolled adults with chronic HFpEF in New York Heart Association functional class II-IV and a left ventricular ejection fraction greater than 40% starting in 2017 at more than 600 sites in more than 20 countries worldwide including the United States. As background therapy, more than 80% of patients received treatment with either an ACE inhibitor or angiotensin receptor blocker (in some instances in the form of sacubitril/valsartan), more than 80% were on a beta-blocker, and about a third were taking a mineralocorticoid receptor antagonist, making them “very well treated HFpEF patients,” Dr. Anker said.
One of the most notable features of enrollment was that 45% of participants were women, giving this trial the highest inclusion of women compared with all prior studies in patients with HFpEF or with HFrEF, said Dr. Walsh. “HFpEF is very prevalent in woman,” she noted, and having this high participation rate of women in the study increases its relevance to these patients. “It’s important to be able to tell women that patients like you were in the study so we can more easily apply the lessons from the trial to you. That can’t be stressed enough,” she said.
The primary outcome occurred in 415 (13.8%) of the 2,997 patients in the empagliflozin group and in 511 (17.1%) of 2,991 patients who received placebo (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P < .001).
The study showed a safety profile consistent with prior experience with empagliflozin, Dr. Anker added.
Pooling EMPEROR-Preserved with EMPEROR-Reduced
The investigators who ran EMPEROR-Preserved designed the trial to closely parallel the EMPEROR-Reduced trial in patients with HFrEF, and they included a prespecified analysis (EMPEROR-Pooled) that combined the more than 9,700 patients in the two studies. This showed a consistent and robust benefit from empagliflozin for reducing HHF across a wide spectrum of patients with heart failure, ranging from patients with left ventricular ejection fractions of less than 25% to patients with ejection fractions as high as 64%. However, the analysis also showed that patients with ejection fractions of 65% or greater received no discernible benefit from empagliflozin, Milton Packer, MD, reported in a separate talk at the congress.
“The findings demonstrate the benefits of empagliflozin across a broad range of patients with heart failure who have ejection fractions of less than 60%-65%,” said Dr. Packer, a researcher at Baylor University Medical Center in Dallas.
This apparent attenuation of an effect at higher ejection fractions “has been observed in other HFpEF trials, most recently in the PARAGON-HF trial” of sacubitril/valsartan (Entresto), he noted. Additional analyses led by Dr. Packer showed that in patients with ejection fractions below 65% the HHF benefit from empagliflozin consistently surpassed the benefit seen with sacubitril/valsartan in PARAGON-HF. But he recommended using both drugs in patients with HFpEF and an ejection fraction up to about 60%.
“If I had a patient with HFpEF I would use both drugs as well as beta-blockers and mineralocorticoid receptor antagonists,” he said during a press briefing.
Another finding from analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials together was that patients with reduced ejection fractions showed a significant 49% relative reduction in the incidence of serious renal outcomes, but this effect was completely blunted in EMPEROR-Preserved.
“Ejection fraction influences the effects of empagliflozin on major renal outcomes,” concluded Dr. Packer in a report on this analysis published simultaneously with the main EMPEROR-Preserved findings (N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMc2112411). “These data from the EMPEROR trials are unique. We have no comparable data” from any of the other reported studies of SGLT2 inhibitors,” he said.
EMPEROR-Preserved was sponsored by Boehringer Ingelheim and by Eli Lilly, the two companies that jointly market empagliflozin (Jardiance). Dr. Anker has received personal fees from Boehringer Ingelheim and from several other companies, and he has received grants and personal fees from Abbott Vascular and Vifor. Dr. Packer has received consulting fees from Boehringer Ingelheim and from numerous other companies. Dr. McDonagh has has recent financial relationships with AstraZeneca, Cprpus, Novartis, Pfizer, and Vifor. Dr. Aguiar and Dr. Walsh had no disclosures.
FROM ESC CONGRESS 2021
Neurodegenerative nature of schizophrenia makes case for LAIs
Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.
“The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.
That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
Reconceptualizing the illness
Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.
The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.
Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.
Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.
In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.
“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”
Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”
During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.
Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.
“The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.
That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
Reconceptualizing the illness
Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.
The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.
Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.
Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.
In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.
“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”
Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”
During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.
Schizophrenia is a complex disease caused by dysfunction in specific brain regions or circuits. In fact, schizophrenia is not a single disease but several hundred different diseases, according to Henry A. Nasrallah, MD, who spoke on the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
The underlying causes of schizophrenia can be either genetic or environmental, but all involve changes in brain development in the fetus or newborn. Psychosis can occur in a range of disorders, including epilepsy, Parkinson’s disease, cerebral tumors, and narcolepsy, to name just a few. Although it starts out as a neurodevelopmental disorder, schizophrenia becomes neurodegenerative after onset, with each new psychotic episode leading to further damage, said Dr. Nasrallah, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati. Further damage leaves patients with greater and greater disability over time, said Dr. Nasrallah at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
The course of illness in some ways resembles the cascading disability associated with strokes. Schizophrenia relapses lead to subcortical atrophy, ventricular enlargement, and further loss of white matter. The accumulating damage is a result of microglia activation, which leads to neuroinflammation and oxidative stress. Mitochondria may also produce insufficient amounts of the antioxidant glutathione.
“The main reason for relapse in schizophrenia is poor adherence to antipsychotic medications, due to anosognosia, memory impairment, avolition, and substance use. It is absolutely necessary to realize that, while oral antipsychotics are effective in the hospital due to enforced compliance by the nursing staff, patients should be switched to long-acting injectable antipsychotics (LAIs) upon discharge from the first episode, which astonishingly is rarely done by 99% of clinicians,” said Dr. Nasrallah in an interview.
That frequent failure leads to further neurodegeneration and increasing disability, which in turn can lead to high rates of homelessness, suicide, and as well as incarceration, because many state hospitals that used to provide medical care for relapsing individuals have been closed down. All of these consequences place great financial and emotional burdens on families and loved ones.
Reconceptualizing the illness
Dr. Nasrallah also advocated that schizophrenia should be classified as a neurologic disorder instead of a psychiatric disorder. He said that the neuropsychiatric mechanisms behind these related diseases support that classification, and neurologic disorders receive much more insurance coverage.
The neuroinflammatory mechanisms underlying schizophrenia suggest that therapies such as omega-3 fatty acids could provide benefit during the prodromal stages of illness. Antioxidants like N-acetyl cysteine could potentially be useful during psychotic episodes, since it boosts levels of glutathione to reduce damaging free radicals. Other approaches could prevent microglia activation, which appears to initiate neurodegeneration.
Another consequence of psychosis is programmed cell death, or apoptosis, in response to reduced levels of neurotropic agents. That could potentially be countered using agents to prevent apoptosis.
Dr. Nasrallah believes clinicians should not use first-generation antipsychotics such as haloperidol, because research has shown that those drugs, while effective, also destroy neurons. Second-generation antipsychotics (SGAs) are safer and avoid that neurotoxicity, and they also have a neuroprotective effect. The SGAs may owe their improved efficacy and safety to the fact that they don’t bind as strongly to dopamine receptors, and they are stronger 5-hydroxytryptamine2A antagonists, according to Dr. Nasrallah. A meta-analysis of 18 studies showed that patients on SGAs maintained gray matter volume, and may even achieve increases in the hippocampus and the prefrontal cortex.
In the Q&A session after the presentation, Dr. Nasrallah was asked whether treatment should be kept up for the rest of the patient’s life, or whether medication should be tapered – and perhaps stopped. He likened treatment of schizophrenia to diabetes or high blood pressure.
“It’s an illness. A lot of medical disorders require lifetime treatment, and there is no difference between psychiatry and the rest of medicine,” he said. “You have to continue the medication at the dose that worked in the acute episode, hopefully the lowest possible dose.”
Dr. Nasrallah did concede that it can be challenging to get patients to accept permanent treatment, and he shared his own strategy to achieve that outcome. “I don’t tell the patient, ‘You’re going to take this the rest of your life.’ It depresses them. So I say, ‘Let’s keep this on board for a year, and I’ll see you regularly, and I’ll monitor you, and we’ll see how it goes, and then we will make another decision at the end of the year.’ ”
During that year, Dr. Nasrallah educates the patient and develops a rapport. “I will show them a lot of data and information about the illness and the hazards of stopping [treatment]. And by the end of the year, most of my patients say: ‘Yeah, I agree. Let’s continue the good thing and let’s not fix something that’s not broken.’ ”
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has also served on a speaker’s bureau for most of those companies, in addition to that of Noven.
REPORTING FROM FOCUS ON NEUROPSYCHIATRY 2021
Nonmotor symptoms common in Parkinson’s
The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.
The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.
The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.
Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.
Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.
Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.
Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.
This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.
As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.
Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.
The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.
The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.
In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.
Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.
Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.
When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.
Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.
“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.
The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.
The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.
The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.
Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.
Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.
Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.
Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.
This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.
As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.
Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.
The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.
The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.
In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.
Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.
Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.
When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.
Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.
“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.
The hallmark of Parkinson’s disease is the accompanying motor symptoms, but the condition can bring other challenges. Among those are nonmotor symptoms, including depression, dementia, and even psychosis.
The culprit is Lewy bodies, which are also responsible for Lewy body dementia. “What we call Lewy body dementia and Parkinson’s disease are caused by the same pathological process – the formation of Lewy bodies in the brain,” Leslie Citrome, MD, MPH, said in an interview. Dr. Citrome discussed some of the psychiatric comorbidities associated with Parkinson’s disease at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In fact, the association goes both ways. “Many people with Parkinson’s disease develop a dementia. Many people with Lewy body dementia develop motor symptoms that look just like Parkinson’s disease,” said Dr. Citrome, professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, and president of the American Society for Clinical Psychopharmacology.
The motor symptoms of Parkinson’s disease are generally attributable to loss of striatal dopaminergic neurons, while nonmotor symptoms can be traced to loss of neurons in nondopaminergic regions. Nonmotor symptoms – often including sleep disorders, depression, cognitive changes, and psychosis – may occur before motor symptoms. Other problems may include autonomic dysfunction, such as constipation, sexual dysfunction, sweating, or urinary retention.
Patients might not be aware that nonmotor symptoms can occur with Parkinson’s disease and may not even consider mentioning mood changes or hallucinations to their neurologist. Family members may also be unaware.
Sleep problems are common in Parkinson’s disease, including rapid eye-movement sleep behavior disorders, vivid dreams, restless legs syndrome, insomnia, and daytime somnolence. Dopamine agonists may also cause unintended sleep.
Depression is extremely common, affecting up to 90% of Parkinson’s disease patients, and this may be related to dopaminergic losses. Antidepressant medications can worsen Parkinson’s disease symptoms: Tricyclic antidepressants increase risk of adverse events from anticholinergic drugs. Selective serotonin reuptake inhibitors (SSRIs) can exacerbate tremor and may increase risk of serotonin syndrome when combined with MAO‐B inhibitors.
Dr. Citrome was not aware of any antidepressant drugs that have been tested specifically in Parkinson’s disease patients, though “I’d be surprised if there wasn’t,” he said during the Q&A session. “There’s no one perfect antidepressant for people with depression associated with Parkinson’s disease. I would make sure to select one that they would tolerate and be willing to take and that doesn’t interfere with their treatment of their movement disorder, and (I would make sure) that there’s no drug-drug interaction,” he said.
This can include reduced working memory, learning, and planning, and generally does not manifest until at least 1 year after motor symptoms have begun. Rivastigmine is Food and Drug Administration–approved for treatment of cognitive impairment in Parkinson’s disease.
As many as 60% of Parkinson’s disease patients suffer from psychosis at some point, often visual hallucinations or delusions, which can include beliefs of spousal infidelity.
Many clinicians prescribe quetiapine off label, but there are not compelling data to support that it reduces intensity and frequency of hallucinations and delusions, according to Dr. Citrome. However, it is relatively easy to prescribe, requiring no preauthorizations, it is inexpensive, and it may improve sleep.
The FDA approved pimavanserin in 2016 for hallucinations and delusions in Parkinson’s disease, and it doesn’t worsen motor symptoms, Dr. Citrome said. That’s because pimavanserin is a highly selective antagonist of the 5-HT2A receptor, with no effect on dopaminergic, histaminergic, adrenergic, or muscarinic receptors.
The drug improves positive symptoms beginning at days 29 and 43, compared with placebo. An analysis by Dr. Citrome’s group found a number needed to treat (NNT) of 7 to gain a benefit over placebo if the metric is a ≥ 30% reduction in baseline symptom score. The drug had an NNT of 9 to achieve a ≥ 50% reduction, and an NNT of 5 to achieve a score of much improved or very much improved on the Clinical Global Impression–Improvement (CGI-I) scale. In general, an NNT less than 10 suggests that a drug is clinically useful.
In contrast, the number needed to harm (NNH) represents the number of patients who would need to receive a therapy to add one adverse event, compared with placebo. A number greater than 10 indicates that the therapy may be tolerable.
Using various measures, the NNH was well over 10 for pimavanserin. With respect to somnolence, the NNH over placebo was 138, and for a weight gain of 7% or more, the NNH was 594.
Overall, the study found that 4 patients would need to be treated to achieve a benefit over placebo with respect to a ≥ 3–point improvement in the Scale of Positive Symptoms–Parkinson’s Disease (SAPS-PD), while 21 would need to receive the drug to lead to one additional discontinuation because of an adverse event, compared to placebo.
When researchers compared pimavanserin to off-label use of quetiapine, olanzapine, and clozapine, they found a Cohen’s d value of 0.50, which was better than quetiapine and olanzapine, but lower than for clozapine. However, there is no requirement of blood monitoring, and clozapine can potentially worsen motor symptoms.
Dr. Citrome’s presentation should be a reminder to neurologists that psychiatric disorders are an important patient concern, said Henry A. Nasrallah, MD, professor of psychiatry, neurology, and neuroscience at the University of Cincinnati, who moderated the session.
“I think this serves as a model to recognize that many neurological disorders actually present with numerous psychiatric disorders,” Dr. Nasrallah said during the meeting, presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
Dr. Citrome has consulted for AbbVie, Acadia, Alkermes, Allergan, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer-Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular, Janssen, Karuna, Lundbeck, Lyndra, MedAvante-ProPhase, Merck, Neurocrine, Noven, Otsuka, Ovid, Relmada, Sage, Sunovion, and Teva. He has been a speaker for most of those companies, and he holds stock in Bristol Myers Squibb, Eli Lilly, J&J, Merck, and Pfizer.
Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Indivior, Intra-Cellular, Janssen, Neurocrine, Otsuka, Sunovion, and Teva. He has served on a speakers bureau for most of those companies, in addition to that of Noven.
FROM FOCUS ON NEUROPSYCHIATRY 2021
Study informs about risks of discontinuing meds in JIA
Flares are modest in preliminary data.
Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.
The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.
In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.
The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
Median time to flare: 219 days
Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).
In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.
Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.
Systemic JIA recapture rate at 6 months: 76%
At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.
About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.
The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.
Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.
“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”
JIA recurrence risk is unclear
In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.
“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.
“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.
Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.
For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.
“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.
Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.
Flares are modest in preliminary data.
Flares are modest in preliminary data.
Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.
The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.
In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.
The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
Median time to flare: 219 days
Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).
In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.
Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.
Systemic JIA recapture rate at 6 months: 76%
At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.
About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.
The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.
Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.
“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”
JIA recurrence risk is unclear
In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.
“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.
“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.
Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.
For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.
“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.
Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.
Many but not all children with juvenile idiopathic arthritis (JIA) can regain remission after stopping and then restarting treatment, according to preliminary data from the ongoing Recapture-JIA study that were presented in a symposium sponsored by the Rheumatology Research Foundation.
The aim of this study is to evaluate the risks of discontinuing treatment after a period when JIA has been well controlled. Such data are of increasing interest to parents now that many children with JIA are achieving sustained periods of remission, according to Sarah Ringold, MD, a pediatric rheumatologist and associate professor of pediatrics at Seattle Children’s Hospital.
In follow-up so far, “recapture rates range from 50% to 76%” depending on type of JIA, reported Dr. Ringold, who said that patients with systemic JIA have so far been the most likely to achieve a good response when treatment is restarted.
The study is being conducted through the Childhood Arthritis and Rheumatology Research Alliance, which has 71 participating centers and has accrued data on more than 10,000 children with rheumatic diseases. For the study, the researchers identified 384 children with JIA who were already enrolled in the CARRA registry and had discontinued medications and then subsequently restarted them, and they also enrolled a prospective cohort of patients new to the registry who presented with flare after discontinuing their medication. Dr. Ringold reported on 64 of the patients in the prospective cohort.
Median time to flare: 219 days
Of findings so far, disease recurrence after discontinuation has been generally characterized by flares “of moderate activity” several months to more than a year after treatment discontinuation, according to Dr. Ringold, who emphasized repeatedly that these data are preliminary. The median time to a flare after treatment discontinuation was approximately 7 months (219 days).
In the combined cohorts, the median age at onset of JIA was 4 years. The median age at time of discontinuation was 9 years. More than half (55%) were taking a conventional disease-modifying antirheumatic drug (DMARD) and 35% were taking a tumor necrosis factor inhibitor at the time that their therapy was discontinued.
Most JIA types are represented. The most common form is rheumatoid factor–negative oligoarticular JIA. The main outcome looked the rate of clinically inactive disease at 6 months in children who had discontinued therapy after a period of remission. They defined clinically inactive disease as a Physician’s Global Assessment of less than 1 and an active joint count of 0.
Systemic JIA recapture rate at 6 months: 76%
At the time of disease flare after treatment discontinuation across both the retrospective and prospective cohorts, the median clinical Juvenile Arthritis Disease Activity Score based on 10 joints (cJADAS10; score range of 0-30) was 3.5. The recapture rate to clinically inactive disease at 6 months was 76% in those with systemic JIA and 50% in those with rheumatoid factor–positive polyarticular JIA. Other subtypes fell within this range. Rates of inactive disease at 6 months according to cJADAS10 score were lower, ranging from 26% with enthesitis-related arthritis/juvenile psoriatic arthritis to 57% with systemic JIA.
About 40% of those who restarted on therapy after a flare took the same medication again. About one-third of patients were restarted on glucocorticoids, mostly involving injections to inflamed joints, and data are not yet in about whether these were restarted alone or with other drugs, according to Dr. Ringold.
The final analysis of this study will explore clinical and laboratory variables associated with disease recapture. In the prospective cohort, which did not reach its planned enrollment of 150 children because the COVID pandemic, a broad array of these variables was evaluated at baseline.
Numerous studies have already looked at predictors of sustained remission after stopping medications of JIA, according to Dr. Ringold, but she said that there is relatively little information about outcomes in children who stop medications, flare, and are retreated. Other experts agree.
“We know little about how successfully DMARDs can be discontinued and used again after a disease flare,” reported Jens Klotsche, MD, a researcher at the German Rheumatism Research Center, which is part of the Leibniz Institute in Berlin. Dr. Klotsche, who is an author of a recent study that found etanercept effective for retreatment when children with JIA had discontinued therapy, agreed that “data from large cohort studies are necessary to support the treatment decisions by clinicians, parents, and patients.”
JIA recurrence risk is unclear
In a systematic review published 2 years ago, rates of flare following discontinuation of treatment for JIA were relatively high, but there were some limitations to this analysis, according to the lead author, Olha Halyabar, MD, a pediatric rheumatologist at Boston Children’s Hospital.
“The data in our systematic review showed that overall quality of evidence was low, with large variations and sometimes very different conclusions,” Dr. Halyabar said in an interview. She believes that the data generated by the CARRA analysis will be valuable, particularly in evaluating outcomes across subtypes.
“Even though, at this point, [previously published] reports indicate overall high rates of recurrence (>50% for some JIA subtypes), there are some encouraging studies from early treat-to-target strategies,” she said, adding that large datasets like those from CARRA offer an opportunity to gather data likely to be clinically useful.
Dr. Ringold cautioned that there are some limitations to the CARRA analysis, including some missing data from the retrospective cohort. She also pointed out that patients have been assessed at routine clinical visits rather than at standardized intervals, introducing a potential for bias.
For parents concerned about the costs, inconvenience, and side effects from sustained JIA treatment once remission is achieved, data from CARRA will allow clinicians to provide evidence-based counseling on balancing the risks of discontinuing therapy, including the likelihood of regaining remission when disease returns, against the goals of stopping treatment.
“Parents are having more conversations about when to stop medications,” Dr. Ringold said. She indicated that these data should be helpful for providing guidance.
Dr. Ringold, Dr. Klotsche, and Dr. Halyabar reported having no potential conflicts of interest.
FROM RHEUMATOLOGY RESEARCH FOUNDATION SUMMER SERIES
Eyes on ESC ‘21: Hope for EMPEROR-Preserved, guidelines remade
There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.
Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.
There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.
The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
The virtues of virtual
That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.
“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”
But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.
“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.
“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.
New and updated guidelines
Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).
Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.
“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”
A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?
As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
Spotlight on EMPEROR-Preserved
The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.
That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.
And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.
Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.
“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.
“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”
For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.
There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”
Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
Other offerings, Friday, Aug. 27
Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.
The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.
In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.
The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.
The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.
Saturday, Aug. 28
The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.
The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.
The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.
Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.
Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.
Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.
Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.
Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.
After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.
The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace.
Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
Sunday, Aug. 29
The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.
Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.
Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.
The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.
The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.
On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.
As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.
Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.
Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.
The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.
COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.
The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.
Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
Monday, Aug. 30
The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.
Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.
Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.
The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.
Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.
They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.
Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.
Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.
The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.
The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
Program structure and format
A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.
Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.
Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.
The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.
Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.
A version of this article first appeared on Medscape.com.
There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.
Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.
There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.
The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
The virtues of virtual
That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.
“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”
But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.
“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.
“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.
New and updated guidelines
Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).
Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.
“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”
A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?
As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
Spotlight on EMPEROR-Preserved
The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.
That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.
And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.
Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.
“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.
“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”
For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.
There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”
Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
Other offerings, Friday, Aug. 27
Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.
The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.
In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.
The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.
The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.
Saturday, Aug. 28
The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.
The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.
The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.
Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.
Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.
Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.
Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.
Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.
After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.
The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace.
Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
Sunday, Aug. 29
The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.
Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.
Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.
The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.
The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.
On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.
As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.
Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.
Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.
The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.
COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.
The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.
Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
Monday, Aug. 30
The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.
Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.
Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.
The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.
Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.
They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.
Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.
Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.
The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.
The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
Program structure and format
A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.
Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.
Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.
The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.
Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.
A version of this article first appeared on Medscape.com.
There will be so much more to the annual congress of the European Society of Cardiology, which begins Aug. 27 with an all-virtual format, than detailed primary results of EMPEROR-Preserved, a trial that could mark a turning point for heart failure (HF) medical therapy.
Also among the featured Hot Line and Late-Breaking Science sessions are – along with many other studies – explorations of arrhythmia management (ablation or guided by loop recorder); secondary prevention, including by vaccination; oral anticoagulation, notably after transcatheter valve procedures; and colchicine or thrombosis prophylaxis in hospitalized patients with COVID-19.
There will even be a head-to-head comparison of two long-familiar left atrial appendage (LAA) occluders, and a population-based, randomized trial of sodium restriction through wide-scale use of a potassium-based salt substitute.
The congress will also introduce four guideline documents at sessions throughout the Congress, one on each day. They cover new and modified recommendations for heart failure; pacing, including cardiac resynchronization therapy (CRT); cardiovascular (CV) disease prevention; and, with cosponsorship from the European Association for Cardio-Thoracic Surgery, valvular heart disease.
The virtues of virtual
That next year’s Congress is slated for Aug. 27-30 in Barcelona should be welcome news for anyone whose “what if” curiosity about all-virtual conferences has already been satisfied. But with experience comes wisdom, as the medical societies have learned that online scientific meetings have some winning qualities that may be worth keeping, as least for a while.
“I think there is no doubt that the digital format will continue, for several reasons. One is that this pandemic is not over,” ESC Congress program committee chair Stephan Windecker, MD, Bern (Switzerland) University Hospital, , told this news organization. “As long as it is not over, the digital format is here to stay.”
But it also appears that people who haven’t been able to attend the congress in person are keen to log in and engage online, Dr. Windecker said. The 2020 all-virtual conference drew a much younger pool of registrants, on average, than did the live conferences before the pandemic.
“I think that’s an indication of people that may be in training, in early stages of their career, or they don’t have the support from departments or from their practice, or other financial means.” But they are able to participate via computer, tablet, or smartphone, he said.
“Another advantage is that the recorded content can be replayed at the convenience of whoever wants to consume it at a later point in time,” he added. “Those are just some examples why the digital format is likely to stay,” on its own or in a new age of hybrid meetings.
New and updated guidelines
Leading off the guideline series is the document on diagnosis and treatment of acute and chronic HF, which leveraged the past few busy years of HF clinical trials to arrive at a number of new recommendations and strengthened level-of-evidence ratings. It covers both drug and device therapy of HF with reduced ejection fraction (HFrEF) and acute decompensated HF, and tweaks and further enshrines the concept of HF with mildly reduced ejection fraction (HFmrEF).
Several updated recommendations for both long-used and novel medications, notably the sodium-glucose cotransporter 2 inhibitors, will be included because of the recently appreciated evidence-based impact in HFrEF, Dr. Windecker noted.
“I think it will be particularly interesting to look for the SGLT2 inhibitors as not a completely new class of drugs, but certainly one where there has been a lot of new evidence, to look at how those drugs will be integrated in the overall care pathway.”
A top-line preview of the new HF guideline limited to drug therapy, presented at July’s Heart Failure Association of the European Society of Cardiology (ESC-HFA), provided a simple answer to a common question in the new, bountiful age of HFrEF medications: Which meds, initiated in what order?
As it happens, the new recommendation for first-line HFrEF drug therapy is not a silver bullet, but a shotgun – prompt initiation of at least four meds, one from each of four drug classes: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2 inhibitors. Each class, as described in the document, is to be started as soon as safely feasible, in a sequence deemed appropriate for each individual patient.
Spotlight on EMPEROR-Preserved
The world already knows that the trial, which tested the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) on top of standard therapy, “met” its primary endpoint in almost 6,000 patients with HF with preserved ejection fraction (HFpEF), who included some with HFmrEF by more contemporary definitions.
That means patients in EMPEROR-Preserved assigned to take empagliflozin showed significantly fewer events that made up the study’s primary endpoint, a composite of CV death or HF hospitalization. It appears to be the first clearly significant overall medical therapy benefit for a clinical primary endpoint in a major randomized HFpEF drug trial.
And that, pending fuller presentation of trial results at the Congress on Aug. 27, could be a huge deal for the half of HF patients with left ventricular ejection fractions (LVEF) higher than the HFrEF range.
Those early top-line results weren’t a decisive bombshell for a field now filled with hope for a practice-changing empagliflozin outcome in EMPEROR-Preserved, which isn’t a certainty. They were more like the “boom” of a mortar launching a rocket of fireworks that may explode into a chrysanthemum or green comet or, sometimes, turn out to be no more than a dud. The promise of the early cursory results critically depends on further details.
“Provided there is a compelling benefit, this is what everyone has been waiting for in this condition for decades,” Mikhail N. Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said.
“Already knowing that the trial met the primary endpoint is obviously very intriguing and encouraging,” he added. “But there are things we don’t know, such as: What is the magnitude of benefit? And whether that benefit, whatever the magnitude, is driven by reductions in both heart failure hospitalizations and cardiovascular death, or only one of the two.”
For example: “If we see an impressive benefit for reduction of hospitalizations, but not a significant reduction in death, that would still be a huge advance. That’s because, to date, we don’t have any drug for HFpEF that has convincingly demonstrated a compelling reduction in heart failure hospitalization or improvement in symptoms, function, or quality of life,” observed Dr. Kosiborod, who wasn’t part of EMPEROR-Preserved.
There have been “suggestions” from HFrEF trials that empagliflozin and dapagliflozin (Farxiga, AstraZeneca) “have very comparable effects on at least the endpoint of cardiovascular death or hospitalization for heart failure,” he said. “So, my expectation would be that whatever is observed in EMPEROR-Preserved is likely a class effect, as well.”
Following EMPEROR-Preserved on the agenda is EMPEROR-Pooled, a patient-level combined analysis of the EMPEROR series of trials that spans the range of HF, regardless of ejection fraction or diabetes status, primarily exploring the effects of empagliflozin on renal function.
Other offerings, Friday, Aug. 27
Scheduled immediately after EMPEROR-Preserved is a presentation on the SMART-MI trial, which should clarify whether management guided by continuous ambulatory monitoring is effective in patients considered at especially high arrhythmic risk. Entry called for recent myocardial infarction and an LVEF of 36%-50% with evidence of cardiac autonomic dysfunction.
The trial randomly assigned 400 such patients to be or not be implanted with a Reveal LINQ (Medtronic) loop recorder and followed them for up to 18 months, primarily for detection of potentially serious arrhythmic events. Endpoints that involved mortality, hospitalization or other clinical events were secondary.
In a time slot preceding both SMART-MI and EMPEROR-Preserved, the GUIDE-HF trial is following a projected 3,600 patients with HF implanted with a CardioMEMS HF System (Abbott) pulmonary artery (PA) pressure sensor to explore the its value for guiding management.
The trial’s three cohorts, followed for at least 12 months, include randomized sensor-monitored and control groups of patients with New York Heart Association class 2-4 symptoms, as well as a third observational set of patients in NYHA class 3. That’s the indication for which the CardioMEMS monitor gained approval in the United States in 2014 based on the 2011 CHAMPION trial, and which fared just as well in the 2017 CHAMPION Post-Approval Study.
The Friday Hot Lines also include Dal-GenE, which has entered about 6,000 patients with recent MI to test the once-abandoned cholesterol ester transfer protein (CETP) inhibitor dalcetrapib (DalCor) for any secondary-prevention benefits when used selectively. The trial’s hook: All its patients are confirmed to have the AA genotype of the rs1967309 variant in the ADCY9 gene, which has been associated with a pronounced clinical response to CETP inhibition.
Saturday, Aug. 28
The direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in patients with nonvalvular atrial fibrillation (AFib). But whether DOACs are similarly preferable in the growing world population of people who have undergone transcatheter aortic valve replacement (TAVR or TAVI), an issue explored with variable results in the ATLANTIS and GALILEO trials, is far from settled.
The ENVISAGE-TAVI AF trial explored the question for the factor X inhibitor edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) in 1,400 patients with AFib and a transfemoral TAVR in the previous 5 days, who were randomly assigned to the DOAC or standard management along with discretionary antiplatelet therapy. They’ve been followed for up to 3 years for a composite endpoint of clinical events – including death, MI, and stroke – and for major bleeding.
The day will also feature MASTER DAPT, a comparison of two dual-antiplatelet therapy (DAPT) regimens in an estimated 4,300 patients considered to be high-risk for bleeding who had received the sirolimus-eluting Ultimaster (Terumo) coronary stent, which has a bioresorbable polymer coating.
Investigators have randomly assigned patients to receive either very-short-duration DAPT, for about a month after stenting, followed by a P2Y12 inhibitor alone for up to a year after the procedure; or a more conventional regimen of a P2Y12 inhibitor for 6-12 months with aspirin maintained for a total of 12 months.
Later that day, investigators from the FIGARO-DKD trial will present their results based on 7,437 patients with type 2 diabetes and chronic kidney disease (CKD), a much fuller version than the top-line findings announced by sponsor Bayer 3 months ago.
Those top-line results suggested that patients assigned to receive the nonsteroidal nonselective mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia) on top of standard care benefited with a drop in risk for the primary endpoint of CV death or nonfatal CV events.
Finerenone was recently approved in the United States for treating patients with both type 2 diabetes and CKD based on the published FIDELIO-DKD trial, which had seen less CKD progression and fewer CV events in such patients who took the novel MRA.
Although similar in design to FIGARO-DKD, FIDELIO-DKD had entered fewer patients with early-stage diabetic kidney disease (DKD). That led researchers to pool the two trials’ populations to create a cohort that spans the spectrum of DKD severity. An analysis of the pooled cohort, dubbed FIDELITY, is on the schedule after FIGARO-DKD.
After FIDELITY is the prospective APAF-CRT trial that is following a projected 1,830 patients with permanent, symptomatic AFib and a recent hospitalization for AFib or HF and who were not good candidates for standard ablation. They were assigned to receive either atrioventricular junctional ablation followed by CRT, with or without a defibrillation, on top of optimal meds – a so-called “ablate-and-pace” strategy – or an implantable cardioverter defibrillator with rate-control drug therapy.
The new analysis represents the trial’s second phase in which mortality was followed for 4 years as the primary endpoint, in contrast to the previously reported initial phase that followed the first 102 patients for 2 years for the composite primary endpoint of death, worsening HF, and HF hospitalization. The first phase had halted enrollment before reaching its planned target of 280 patients after an interim analysis showed a significant benefit for ablate and pace.
Next up: DECAAF 2, a randomized assessment of whether catheter ablation for AFib guided by delayed gadolinium enhancement on MRI, a proxy for scar tissue, can be more effective than standard AFib ablation by pulmonary vein isolation alone. An estimated 900 patients with persistent AFib who had never before undergone ablation for the arrhythmia were randomly assigned to one strategy or the other and followed for AFib recurrence over 18 months.
Sunday, Aug. 29
The TOMAHAWK trial aimed to clarify the optimal timing of invasive coronary angiography for resuscitated patients with non–ST-segment elevation out-of-hospital cardiac arrest, a broad population in a setting for which there is little randomized-trial guidance. Investigators randomly assigned 558 such patients to undergo immediate invasive angiography or to direct intensive care unit admission for initial standard care with discretionary delayed angiography. Patients were followed for all-cause mortality, with other clinical events and neurologic outcomes as secondary endpoints.
Next on the schedule, the RIPCORD-2 trial randomly assigned 1,100 patients with stable known or suspected coronary artery disease (CAD) to undergo conventional angiography alone or with added direct pressure-wire measurement of fractional flow reserve to guide management decisions. Primary outcomes include health care costs and patient-reported quality of life at 1 year.
Slated for later that day, the Asymptomatic Carotid Surgery Trial-2 (ACST-2) has entered an estimated 3600 patients with a substantial carotid artery narrowing not associated with symptoms but for which either carotid endarterectomy (CEA) or carotid artery stenting (CAS) was considered anatomically feasible. There also must have been “substantial uncertainty” regarding the optimal procedure choice.
The trial, conducted in 40 countries primarily in Europe and North America and launched in 2008, randomly assigned the patients to undergo either CEA or CAS, in both cases with appropriate medical therapy, and followed them for periprocedural events and up to 10 years for strokes and stroke-related events.
The LOOP study, which is to directly follow ACST-2, has explored whether screening for AFib using the Medtronic Reveal LINQ monitor in older patients with non-AFib stroke risk factors – with oral anticoagulation prescribed for those who test positive – can lower their risk for stroke or systemic embolism. It randomly assigned 6,000 such patients to care guided by the loop recorder or to standard care.
On a somewhat larger scale, the Salt Substitute and Stroke Study (SSaSS) randomly assigned a total of 20,996 people in about 600 villages across northern China and Tibet to sodium-restriction intervention and control groups by village. All participants had a history of stroke or were aged at least 60 years with uncontrolled hypertension.
As described by the trial’s online portal, participants in villages assigned to the intervention group were given a supply of a low-sodium, potassium-supplementing salt substitute to replace their own salt supplies, along with education on the health benefits of sodium restriction. Participants in control villages continued their normal diets and, at the trial’s beginning, received “advice to reduce their salt intake.” All were required to own a telephone.
Clinical events, including strokes and hospitalizations throughout a 5-year follow-up, were tracked by phone calls made to all participants every 6 months and were documented at follow-up home visits.
Sunday is also to feature a Late-Breaking Trials session with a focus on COVID-19, which leads off with COLCOVID, a test of colchicine in patients hospitalized for suspected SARS-CoV-2 infection and in acute respiratory distress.
The 1,279 participants in Argentina were randomly assigned to receive or not receive the potent anti-inflammatory agent on top of antivirals and other standard management and followed for death or new need for mechanical ventilation. A successful outcome would contrast with the RECOVERY trial, which terminated a colchicine group of patients hospitalized with COVID-19 because of a lack of efficacy earlier this year.
COLCOVID is to be followed by the MICHELLE trial of rivaroxaban (Xarelto, Bayer/Janssen) prophylaxis, compared with no preventive oral anticoagulant, in 320 patients who, when hospitalized with COVID-19, had been on parenteral anticoagulants because of an elevated risk for venous thromboembolism. The trial, conducted in Brazil, called for postdischarge rivaroxaban at a once-daily dosage of 10 mg for about 1 month.
The session also includes a presentation called “Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial,” the primary outcomes of which will be reported on the first day of the Congress.
Following is a presentation on the PREPARE-IT study of icosapent ethyl (Vascepa, Amarin), given at high dosages intended to be anti-inflammatory, compared with placebo, in an estimated 4,000 adults. The trial has two groups: A prevention group of adults living and circulating in the community; and a treatment group of patients aged at least 40 years with confirmed symptomatic SARS-CoV-2 infection for whom the need for hospitalization isn’t clear.
Monday, Aug. 30
The final day of the Congress features a trial called Influenza Vaccination after Myocardial Infarction (IAMI), which has tested the secondary preventive effect of influenza vaccination by randomly assigning 2,571 patients to receive a standard vaccine or a saline placebo injection on one occasion.
Entry to the international trial called for a diagnosis of MI with or without ST-segment elevation, or stable CAD and age at least 75 years with other risk factors. The patients were followed for death, MI, stent thrombosis, and a slew of secondary endpoints over 12 months.
Monday offerings continue later in a time block leading off with the STEP trial, which has randomly assigned an estimated 8,000 patients at 40 centers in China who are 60 to 80 years of age with a systolic blood pressure of 140 to <190 mm Hg to be on standard guideline-based therapy or an intensive drug-management strategy.
The systolic BP goals are 130 to <150 mm Hg for standard care and 110 to <130 mm Hg for the intensive regimen. The composite primary endpoint includes death and clinical events related to acute coronary syndromes, HF, revascularization, and stroke.
Following on heels of STEP, the Amulet IDE trial – the first major randomized comparison of two transcatheter LAA closure devices – entered 1,878 patients with nonvalvular AFib who were considered high-risk for bleeding and stroke or systemic embolism.
They were randomly assigned in the noninferiority trial to receive either the AMPLATZER Amulet (Abbott Medical Devices) or the WATCHMAN (Boston Scientific) closure devices and were followed for safety and efficacy for up to 5 years.
Both LAA closure devices, intended to make patients with AFib less reliant on oral anticoagulation, are now available on both sides of the Atlantic – as well as many other countries – after the Amulet’s United States market approval on Aug. 16, based largely on the Amulet IDE trial.
Rounding out the final Hot Line set is one of the latest efforts to show the efficacy and safety of a very short DAPT period after coronary stenting in patients with acute coronary syndromes, the STOPDAPT-2 ACS trial.
The study assigned 3,008 patients in Japan to receive aspirin and clopidogrel for either 1 month or 1 year after implantation with an everolimus-eluting cobalt-chromium stent and followed them for up to 5 years for a composite of MI, CV death, stent thrombosis, stroke, and bleeding.
The trial follows the published STOPDAPT-2 trial that showed superiority for the 1-month DAPT regimen in a predominantly stable-CAD population treated with the same kind of stent.
Program structure and format
A total of 15 online channels are to be available in the morning, European time, their schedules running in parallel. Presentations often are prerecorded, but also include live sessions at 8:00 a.m. Central time and 12 p.m. CET (2:00 a.m. and 6:00 a.m. Eastern time) to liven up the channel offerings, Dr. Windecker observed, and to make them more immediate and potentially interactive.
Many of the parallel channels are devoted throughout the Congress to particular silos of cardiology; for example, arrhythmias and device therapy is on channel 3; CAD and acute care is on 5; HF is on 6; and preventive cardiology is on 9.
Other channels swing across different topics from day to day, such as channel 1, which covers COVID-19 topics on the first and third day of the meeting, “advances in science” on day 2, and “digital health, public health, health economics” on day 4.
The focus each day, starting at 2:00 p.m. CET (8:00 a.m. ET) and continuing into the evening in Europe, shifts over to the Prime Time live program, which features the Hot Line and guideline presentations and many of the live abstract presentations.
Dr. Kosiborod, not a researcher with the EMPEROR trials, is chair of the Dapagliflozin in Preserved Ejection Fraction Heart Failure ( PRESERVED-HF ) trial, which is scheduled for presentation at the September 2021 Heart Failure Society of American meeting.
A version of this article first appeared on Medscape.com.
Psoriatic arthritis health care costs continue to rise over time
Annual health care costs for patients with psoriatic arthritis rose over recent 5-year periods across all categories of resource use to a significantly greater extent than among patients with psoriasis only or those without any psoriatic disease diagnoses, according to commercial insurance claims data.
Using an IBM MarketScan Commercial Database, researchers examined claims data for 208,434 patients with psoriasis, 47,274 with PsA, and 255,708 controls who had neither psoriasis nor PsA. Controls were matched for age and sex. Those with RA, ankylosing spondylitis, Crohn’s disease, or ulcerative colitis were excluded.
The investigators examined data for 2009-2020, following patients for 5 years within that period. They looked at hospitalizations, outpatient and pharmacy services, lab services, and office visits, Steven Peterson, director of market access for rheumatology at Janssen Pharmaceuticals, said in his presentation of the data at the Pan American League of Associations for Rheumatology 2021 annual meeting, held recently as a virtual event.
The research was also published online May 2, 2021, in Clinical Rheumatology.
Big differences between the groups were seen in the first year, when the average health care costs for the PsA group were $28,322, about half of which was outpatient drug costs. That compared with $12,039 for the psoriasis group and $6,672 for the control group.
The differences tended to widen over time. By the fifth year, average costs for the PsA group were $34,290, nearly 60% of which were drug costs. That compared with $12,877 for the psoriasis group and $8,569 for the control group. In each year examined, outpatient drug costs accounted for less than half of the expenses for the psoriasis group and about a quarter for the control group.
Researchers found that the PsA group needed 28.7 prescriptions per person per year, compared with 17.0 and 12.7 in the psoriasis and control groups, respectively, Mr. Peterson said. He also noted that patients with PsA and psoriasis tended to have higher rates of hypertension, depression, and anxiety.
“The cost and resource utilization disparity between these patient groups demonstrates the high remaining unmet medical need for patients with psoriasis and psoriatic arthritis,” Mr. Peterson said during the virtual proceedings.
Do findings reflect treatment advances?
Elaine Husni, MD, MPH, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic, where she studies health outcomes in PsA, said the findings are helpful in pointing to a trend across a large sample. But she added it’s important to remember that the increasing costs could reflect recent advances in PsA treatment, which include costly biologic drugs.
“There’s a ton more treatments for psoriasis and psoriatic arthritis than there were even just 5 years ago,” she said in an interview. She was not involved in the research.
Dr. Husni would like to see a more detailed look at the costs, from the categories of expenses to the patients who are incurring the highest costs.
“Is it just a couple of percent of really sick patients that are driving the psoriatic arthritis group?” she wondered.
She also pointed out that PsA is going to be more expensive by its very nature. PsA tends to develop 3-10 years after psoriasis, adding to the costs for someone who already has psoriasis and at a time when they are older and likely have higher health care costs because of comorbidities that develop with age.
Dr. Husni said she does think about treatment costs, in that a less expensive first-line drug might be more appropriate than going straight to a more expensive biologic, especially because they also tend to be safer. She said it’s not just a simple question of curbing costs.
“Is there a way that we can personalize medicine?” she asked. “Is there a way that we can be more accurate about which people may need the more expensive drugs, and which patients may need the less expensive drugs? Are we getting better at monitoring so we can avoid high-cost events?”
Mr. Peterson is an employee of Janssen Pharmaceuticals. Dr. Husni reported serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, UCB, Novartis, Lilly, and Pfizer.
* Update, 9/28/21: The headline and parts of this story were updated to better reflect the study on which it reports.
A version of this article first appeared on Medscape.com.
Annual health care costs for patients with psoriatic arthritis rose over recent 5-year periods across all categories of resource use to a significantly greater extent than among patients with psoriasis only or those without any psoriatic disease diagnoses, according to commercial insurance claims data.
Using an IBM MarketScan Commercial Database, researchers examined claims data for 208,434 patients with psoriasis, 47,274 with PsA, and 255,708 controls who had neither psoriasis nor PsA. Controls were matched for age and sex. Those with RA, ankylosing spondylitis, Crohn’s disease, or ulcerative colitis were excluded.
The investigators examined data for 2009-2020, following patients for 5 years within that period. They looked at hospitalizations, outpatient and pharmacy services, lab services, and office visits, Steven Peterson, director of market access for rheumatology at Janssen Pharmaceuticals, said in his presentation of the data at the Pan American League of Associations for Rheumatology 2021 annual meeting, held recently as a virtual event.
The research was also published online May 2, 2021, in Clinical Rheumatology.
Big differences between the groups were seen in the first year, when the average health care costs for the PsA group were $28,322, about half of which was outpatient drug costs. That compared with $12,039 for the psoriasis group and $6,672 for the control group.
The differences tended to widen over time. By the fifth year, average costs for the PsA group were $34,290, nearly 60% of which were drug costs. That compared with $12,877 for the psoriasis group and $8,569 for the control group. In each year examined, outpatient drug costs accounted for less than half of the expenses for the psoriasis group and about a quarter for the control group.
Researchers found that the PsA group needed 28.7 prescriptions per person per year, compared with 17.0 and 12.7 in the psoriasis and control groups, respectively, Mr. Peterson said. He also noted that patients with PsA and psoriasis tended to have higher rates of hypertension, depression, and anxiety.
“The cost and resource utilization disparity between these patient groups demonstrates the high remaining unmet medical need for patients with psoriasis and psoriatic arthritis,” Mr. Peterson said during the virtual proceedings.
Do findings reflect treatment advances?
Elaine Husni, MD, MPH, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic, where she studies health outcomes in PsA, said the findings are helpful in pointing to a trend across a large sample. But she added it’s important to remember that the increasing costs could reflect recent advances in PsA treatment, which include costly biologic drugs.
“There’s a ton more treatments for psoriasis and psoriatic arthritis than there were even just 5 years ago,” she said in an interview. She was not involved in the research.
Dr. Husni would like to see a more detailed look at the costs, from the categories of expenses to the patients who are incurring the highest costs.
“Is it just a couple of percent of really sick patients that are driving the psoriatic arthritis group?” she wondered.
She also pointed out that PsA is going to be more expensive by its very nature. PsA tends to develop 3-10 years after psoriasis, adding to the costs for someone who already has psoriasis and at a time when they are older and likely have higher health care costs because of comorbidities that develop with age.
Dr. Husni said she does think about treatment costs, in that a less expensive first-line drug might be more appropriate than going straight to a more expensive biologic, especially because they also tend to be safer. She said it’s not just a simple question of curbing costs.
“Is there a way that we can personalize medicine?” she asked. “Is there a way that we can be more accurate about which people may need the more expensive drugs, and which patients may need the less expensive drugs? Are we getting better at monitoring so we can avoid high-cost events?”
Mr. Peterson is an employee of Janssen Pharmaceuticals. Dr. Husni reported serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, UCB, Novartis, Lilly, and Pfizer.
* Update, 9/28/21: The headline and parts of this story were updated to better reflect the study on which it reports.
A version of this article first appeared on Medscape.com.
Annual health care costs for patients with psoriatic arthritis rose over recent 5-year periods across all categories of resource use to a significantly greater extent than among patients with psoriasis only or those without any psoriatic disease diagnoses, according to commercial insurance claims data.
Using an IBM MarketScan Commercial Database, researchers examined claims data for 208,434 patients with psoriasis, 47,274 with PsA, and 255,708 controls who had neither psoriasis nor PsA. Controls were matched for age and sex. Those with RA, ankylosing spondylitis, Crohn’s disease, or ulcerative colitis were excluded.
The investigators examined data for 2009-2020, following patients for 5 years within that period. They looked at hospitalizations, outpatient and pharmacy services, lab services, and office visits, Steven Peterson, director of market access for rheumatology at Janssen Pharmaceuticals, said in his presentation of the data at the Pan American League of Associations for Rheumatology 2021 annual meeting, held recently as a virtual event.
The research was also published online May 2, 2021, in Clinical Rheumatology.
Big differences between the groups were seen in the first year, when the average health care costs for the PsA group were $28,322, about half of which was outpatient drug costs. That compared with $12,039 for the psoriasis group and $6,672 for the control group.
The differences tended to widen over time. By the fifth year, average costs for the PsA group were $34,290, nearly 60% of which were drug costs. That compared with $12,877 for the psoriasis group and $8,569 for the control group. In each year examined, outpatient drug costs accounted for less than half of the expenses for the psoriasis group and about a quarter for the control group.
Researchers found that the PsA group needed 28.7 prescriptions per person per year, compared with 17.0 and 12.7 in the psoriasis and control groups, respectively, Mr. Peterson said. He also noted that patients with PsA and psoriasis tended to have higher rates of hypertension, depression, and anxiety.
“The cost and resource utilization disparity between these patient groups demonstrates the high remaining unmet medical need for patients with psoriasis and psoriatic arthritis,” Mr. Peterson said during the virtual proceedings.
Do findings reflect treatment advances?
Elaine Husni, MD, MPH, director of the Arthritis and Musculoskeletal Center at the Cleveland Clinic, where she studies health outcomes in PsA, said the findings are helpful in pointing to a trend across a large sample. But she added it’s important to remember that the increasing costs could reflect recent advances in PsA treatment, which include costly biologic drugs.
“There’s a ton more treatments for psoriasis and psoriatic arthritis than there were even just 5 years ago,” she said in an interview. She was not involved in the research.
Dr. Husni would like to see a more detailed look at the costs, from the categories of expenses to the patients who are incurring the highest costs.
“Is it just a couple of percent of really sick patients that are driving the psoriatic arthritis group?” she wondered.
She also pointed out that PsA is going to be more expensive by its very nature. PsA tends to develop 3-10 years after psoriasis, adding to the costs for someone who already has psoriasis and at a time when they are older and likely have higher health care costs because of comorbidities that develop with age.
Dr. Husni said she does think about treatment costs, in that a less expensive first-line drug might be more appropriate than going straight to a more expensive biologic, especially because they also tend to be safer. She said it’s not just a simple question of curbing costs.
“Is there a way that we can personalize medicine?” she asked. “Is there a way that we can be more accurate about which people may need the more expensive drugs, and which patients may need the less expensive drugs? Are we getting better at monitoring so we can avoid high-cost events?”
Mr. Peterson is an employee of Janssen Pharmaceuticals. Dr. Husni reported serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, UCB, Novartis, Lilly, and Pfizer.
* Update, 9/28/21: The headline and parts of this story were updated to better reflect the study on which it reports.
A version of this article first appeared on Medscape.com.
Explosive aggression may be neurologic
Aggression is an underappreciated mental health issue, and biological mechanisms might help explain more extreme forms like intermittent explosive disorder (IED), which is characterized by episodes of sudden impulses and inappropriate aggression, violence, or even verbal outbursts. IED can lead to road rage, domestic abuse, in addition to throwing objects and engaging in other destructive behaviors.
Despite those consequences, aggression hasn’t gained the same level of attention as other psychiatric conditions, according to Emil F. Coccaro, MD, who spoke about the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“People seem to think that aggressive behavior is bad behavior, and therefore people just need an attitude adjustment. So there’s this sort of stigma, and there are no advocacy groups for it. There are no poster children for it. But there’s a whole lot of biology and neuroscience behind it,” said Dr. Coccaro, in an interview. He is a professor and vice chair of research in psychiatry and behavioral health at Ohio State University, Columbus.
, who spoke at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
There is a general view that psychiatric conditions may lead to increased aggression, but there is little evidence of that. “As a general statement, having a psychological [illness] in and of itself does not really increase the risk of being aggressive. What does is being aggressive in general, and substance use disorder. And the thing with [people who have] substance use disorders is that they only get aggressive when they are aggressive to begin with,” said Dr. Coccaro, noting that the strongest case for the relationship surrounds alcohol abuse.
The DSM-5 criteria for IED include: verbal or physical aggression without destruction, at least twice per week, or three or more episodes of assault or physical destruction within a year. The behavior must be out of proportion to the provocation, cause distress or impairment, and not be accountable by other diagnoses. “If they’re blowing up twice a week, for a few months, and usually they’re doing it for a long time, then that’s different than just blowing up very occasionally. Healthy people, nonaggressive people, maybe they blow up once a year, or even less frequently than that,” Dr. Coccaro said.
Functional magnetic resonance imaging and other imaging studies consistently show differences associated with aggression.
“The IEDs really do distinguish themselves from the psychiatric controls. They also have other stuff going on with them; they have a hostile attribution. And they’re kind of irritable at baseline. They’re not walking around irritable all the time, but the people around them may be walking on eggshells,” Dr. Coccaro said.
The results from these sorts of studies aren’t fully conclusive and can’t be used for diagnosis, in part because of a lack of power. “It’s hard to do these MRI studies and lots and lots of subjects, because they’re kind of expensive,” Dr. Coccaro said. “We’re just not there yet.”
Other, less expensive imaging techniques like near-infrared spectroscopy may improve matters. “That might be something down the road that could lead to something (diagnostic). Right now, most imaging studies are being done to really understand mechanisms,” said Dr. Coccaro.
Those mechanistic studies suggest that the culprit for IED may be a combination of too much drive from subcortical structures like the amygdala and insufficient inhibitor function in the frontal part of the brain. The frontal cortex may suffer a loss of gray matter, according to Dr. Coccaro, and there may be insufficient connectivity, which could weaken signals coming from the frontal areas that might otherwise inhibit lower centers of the brain.
Treatment for IED could be aimed at improving that connectivity and signaling. Ketamine and other anesthetic agents like nitrous oxide may increase connectivity to nerve cells by increasing branching at synaptic dendrites.
Selective serotonin reuptake inhibitors have the potential to treat IED, but their utility is limited because they bind to the presynaptic transporter for serotonin, and more aggressive people have fewer of those transporters. “You only get so much bang for your buck,” Dr. Coccaro said.
Cognitive-behavioral therapy that focuses on anger management and relaxation shows promise. “CBT does help people deal with what’s coming at them. So it’s like, ‘oh, I’m getting angry, I better start doing those relaxation (techniques).’ It teaches them to rethink things.”
During the Q&A session following the presentation, Henry A. Nasrallah, MD, who moderated the session, pointed out that misattribution can occur, leading an affected individual to misread someone’s facial expression and react aggressively, which is a problem also seen in psychosis.
“There are studies showing [that if] you show them a series of faces with different affects, many times paranoid patients read a normal facial expression as threatening. So it may be that it’s the same thing with aggression,” said Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
In the midst of the ongoing COVID-19 pandemic, it’s also possible that mask-wearing could improve or worsen such misunderstandings. “There is expression in the eyes that you can see, but you miss a lot,” Dr. Coccaro said.
For now, the effects of masks remain largely unknown. But that will change. “Sooner or later we will have a bunch of papers coming out about how masks have changed a lot of behaviors,” Dr. Nasrallah said.
Dr. Coccaro has consulted for Avanir, Azevan, and Brackett. Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan Janssen, Otsuka, Indivior, IntraCellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim. Dr. Nasrallah has been on a speaker’s bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.
Aggression is an underappreciated mental health issue, and biological mechanisms might help explain more extreme forms like intermittent explosive disorder (IED), which is characterized by episodes of sudden impulses and inappropriate aggression, violence, or even verbal outbursts. IED can lead to road rage, domestic abuse, in addition to throwing objects and engaging in other destructive behaviors.
Despite those consequences, aggression hasn’t gained the same level of attention as other psychiatric conditions, according to Emil F. Coccaro, MD, who spoke about the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“People seem to think that aggressive behavior is bad behavior, and therefore people just need an attitude adjustment. So there’s this sort of stigma, and there are no advocacy groups for it. There are no poster children for it. But there’s a whole lot of biology and neuroscience behind it,” said Dr. Coccaro, in an interview. He is a professor and vice chair of research in psychiatry and behavioral health at Ohio State University, Columbus.
, who spoke at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
There is a general view that psychiatric conditions may lead to increased aggression, but there is little evidence of that. “As a general statement, having a psychological [illness] in and of itself does not really increase the risk of being aggressive. What does is being aggressive in general, and substance use disorder. And the thing with [people who have] substance use disorders is that they only get aggressive when they are aggressive to begin with,” said Dr. Coccaro, noting that the strongest case for the relationship surrounds alcohol abuse.
The DSM-5 criteria for IED include: verbal or physical aggression without destruction, at least twice per week, or three or more episodes of assault or physical destruction within a year. The behavior must be out of proportion to the provocation, cause distress or impairment, and not be accountable by other diagnoses. “If they’re blowing up twice a week, for a few months, and usually they’re doing it for a long time, then that’s different than just blowing up very occasionally. Healthy people, nonaggressive people, maybe they blow up once a year, or even less frequently than that,” Dr. Coccaro said.
Functional magnetic resonance imaging and other imaging studies consistently show differences associated with aggression.
“The IEDs really do distinguish themselves from the psychiatric controls. They also have other stuff going on with them; they have a hostile attribution. And they’re kind of irritable at baseline. They’re not walking around irritable all the time, but the people around them may be walking on eggshells,” Dr. Coccaro said.
The results from these sorts of studies aren’t fully conclusive and can’t be used for diagnosis, in part because of a lack of power. “It’s hard to do these MRI studies and lots and lots of subjects, because they’re kind of expensive,” Dr. Coccaro said. “We’re just not there yet.”
Other, less expensive imaging techniques like near-infrared spectroscopy may improve matters. “That might be something down the road that could lead to something (diagnostic). Right now, most imaging studies are being done to really understand mechanisms,” said Dr. Coccaro.
Those mechanistic studies suggest that the culprit for IED may be a combination of too much drive from subcortical structures like the amygdala and insufficient inhibitor function in the frontal part of the brain. The frontal cortex may suffer a loss of gray matter, according to Dr. Coccaro, and there may be insufficient connectivity, which could weaken signals coming from the frontal areas that might otherwise inhibit lower centers of the brain.
Treatment for IED could be aimed at improving that connectivity and signaling. Ketamine and other anesthetic agents like nitrous oxide may increase connectivity to nerve cells by increasing branching at synaptic dendrites.
Selective serotonin reuptake inhibitors have the potential to treat IED, but their utility is limited because they bind to the presynaptic transporter for serotonin, and more aggressive people have fewer of those transporters. “You only get so much bang for your buck,” Dr. Coccaro said.
Cognitive-behavioral therapy that focuses on anger management and relaxation shows promise. “CBT does help people deal with what’s coming at them. So it’s like, ‘oh, I’m getting angry, I better start doing those relaxation (techniques).’ It teaches them to rethink things.”
During the Q&A session following the presentation, Henry A. Nasrallah, MD, who moderated the session, pointed out that misattribution can occur, leading an affected individual to misread someone’s facial expression and react aggressively, which is a problem also seen in psychosis.
“There are studies showing [that if] you show them a series of faces with different affects, many times paranoid patients read a normal facial expression as threatening. So it may be that it’s the same thing with aggression,” said Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
In the midst of the ongoing COVID-19 pandemic, it’s also possible that mask-wearing could improve or worsen such misunderstandings. “There is expression in the eyes that you can see, but you miss a lot,” Dr. Coccaro said.
For now, the effects of masks remain largely unknown. But that will change. “Sooner or later we will have a bunch of papers coming out about how masks have changed a lot of behaviors,” Dr. Nasrallah said.
Dr. Coccaro has consulted for Avanir, Azevan, and Brackett. Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan Janssen, Otsuka, Indivior, IntraCellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim. Dr. Nasrallah has been on a speaker’s bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.
Aggression is an underappreciated mental health issue, and biological mechanisms might help explain more extreme forms like intermittent explosive disorder (IED), which is characterized by episodes of sudden impulses and inappropriate aggression, violence, or even verbal outbursts. IED can lead to road rage, domestic abuse, in addition to throwing objects and engaging in other destructive behaviors.
Despite those consequences, aggression hasn’t gained the same level of attention as other psychiatric conditions, according to Emil F. Coccaro, MD, who spoke about the topic at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“People seem to think that aggressive behavior is bad behavior, and therefore people just need an attitude adjustment. So there’s this sort of stigma, and there are no advocacy groups for it. There are no poster children for it. But there’s a whole lot of biology and neuroscience behind it,” said Dr. Coccaro, in an interview. He is a professor and vice chair of research in psychiatry and behavioral health at Ohio State University, Columbus.
, who spoke at the meeting presented by MedscapeLive. MedscapeLive and this news organization are owned by the same parent company.
There is a general view that psychiatric conditions may lead to increased aggression, but there is little evidence of that. “As a general statement, having a psychological [illness] in and of itself does not really increase the risk of being aggressive. What does is being aggressive in general, and substance use disorder. And the thing with [people who have] substance use disorders is that they only get aggressive when they are aggressive to begin with,” said Dr. Coccaro, noting that the strongest case for the relationship surrounds alcohol abuse.
The DSM-5 criteria for IED include: verbal or physical aggression without destruction, at least twice per week, or three or more episodes of assault or physical destruction within a year. The behavior must be out of proportion to the provocation, cause distress or impairment, and not be accountable by other diagnoses. “If they’re blowing up twice a week, for a few months, and usually they’re doing it for a long time, then that’s different than just blowing up very occasionally. Healthy people, nonaggressive people, maybe they blow up once a year, or even less frequently than that,” Dr. Coccaro said.
Functional magnetic resonance imaging and other imaging studies consistently show differences associated with aggression.
“The IEDs really do distinguish themselves from the psychiatric controls. They also have other stuff going on with them; they have a hostile attribution. And they’re kind of irritable at baseline. They’re not walking around irritable all the time, but the people around them may be walking on eggshells,” Dr. Coccaro said.
The results from these sorts of studies aren’t fully conclusive and can’t be used for diagnosis, in part because of a lack of power. “It’s hard to do these MRI studies and lots and lots of subjects, because they’re kind of expensive,” Dr. Coccaro said. “We’re just not there yet.”
Other, less expensive imaging techniques like near-infrared spectroscopy may improve matters. “That might be something down the road that could lead to something (diagnostic). Right now, most imaging studies are being done to really understand mechanisms,” said Dr. Coccaro.
Those mechanistic studies suggest that the culprit for IED may be a combination of too much drive from subcortical structures like the amygdala and insufficient inhibitor function in the frontal part of the brain. The frontal cortex may suffer a loss of gray matter, according to Dr. Coccaro, and there may be insufficient connectivity, which could weaken signals coming from the frontal areas that might otherwise inhibit lower centers of the brain.
Treatment for IED could be aimed at improving that connectivity and signaling. Ketamine and other anesthetic agents like nitrous oxide may increase connectivity to nerve cells by increasing branching at synaptic dendrites.
Selective serotonin reuptake inhibitors have the potential to treat IED, but their utility is limited because they bind to the presynaptic transporter for serotonin, and more aggressive people have fewer of those transporters. “You only get so much bang for your buck,” Dr. Coccaro said.
Cognitive-behavioral therapy that focuses on anger management and relaxation shows promise. “CBT does help people deal with what’s coming at them. So it’s like, ‘oh, I’m getting angry, I better start doing those relaxation (techniques).’ It teaches them to rethink things.”
During the Q&A session following the presentation, Henry A. Nasrallah, MD, who moderated the session, pointed out that misattribution can occur, leading an affected individual to misread someone’s facial expression and react aggressively, which is a problem also seen in psychosis.
“There are studies showing [that if] you show them a series of faces with different affects, many times paranoid patients read a normal facial expression as threatening. So it may be that it’s the same thing with aggression,” said Dr. Nasrallah, who is a professor of psychiatry, neurology, and neuroscience at the University of Cincinnati.
In the midst of the ongoing COVID-19 pandemic, it’s also possible that mask-wearing could improve or worsen such misunderstandings. “There is expression in the eyes that you can see, but you miss a lot,” Dr. Coccaro said.
For now, the effects of masks remain largely unknown. But that will change. “Sooner or later we will have a bunch of papers coming out about how masks have changed a lot of behaviors,” Dr. Nasrallah said.
Dr. Coccaro has consulted for Avanir, Azevan, and Brackett. Dr. Nasrallah has consulted for Acadia, Alkermes, Allergan Janssen, Otsuka, Indivior, IntraCellular, Neurocrine, Sunovion, Teva, and Boehringer-Ingelheim. Dr. Nasrallah has been on a speaker’s bureau for Acadia, Alkermes, Allergan, Janssen, Otsuka, Indivior, Intracellular, Neurocrine, Noven, Sunovion, and Teva.
REPORTING FROM FOCUS ON NEUROPSYCHIATRY 2021