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FIRE a win for physiology-guided MI complete revascularization in older patients
(MVD) in a large, randomized trial.
In the study with more than 1,400 patients, CR was guided by assessments of the functional effect of coronary lesions other than the MI culprit, a process that selects or excludes the lesions, regardless of angiographic profile, as targets for percutaneous coronary intervention (PCI).
Such physiology-guided CR led to a significant 27% drop in risk for a composite primary endpoint over 1 year in the trial, called FIRE (Functional Assessment in Elderly MI Patients with Multivessel Disease), compared with the culprit-only approach. The endpoint included death, MI, stroke, or ischemia-driven revascularization.
Risk for cardiovascular (CV) death or MI fell by 36% in the trial, and all-cause mortality declined 30%. The differences were significant, although the study wasn’t powered for those secondary endpoints. Safety outcomes were similar for the two revascularization approaches.
FIRE was noteworthy for entering only patients with ST-segment elevation or non–ST-segment elevation MI (STEMI or NSTEMI) who were age 75 years or older, a higher-risk age group poorly represented in earlier CR trials. Such patients in practice are usually managed with the culprit lesion–only approach because of a lack of good evidence supporting CR, observed Simone Biscaglia, MD, the study’s principal investigator.
“This is the first trial actually showing a benefit” from physiology-guided CR in older patients with acute MI that is similar to what the strategy can offer younger patients, said Dr. Biscaglia, from Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy.
Biscaglia made the comments at a media briefing on FIRE held during the annual congress of the European Society of Cardiology, where he presented the study. He is also lead author on its publication in the New England Journal of Medicine.
“This is a remarkable trial that adds substantially to prior studies that examined the topic of complete versus culprit-only revascularization,” Deepak L. Bhatt, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
It shows “quite clearly” that physiology-guided CR is superior to the culprit-only approach in patients with acute MI, said Dr. Bhatt, who is also director of Mount Sinai Heart at Mount Sinai Hospital and not connected to FIRE.
The primary findings applied to a range of different patient subgroups, including those older than 80. That’s important, he said, because “it is sometimes incorrectly assumed that patients who are older may not benefit from complete revascularization in this setting.”
And the trial’s finding of reduced risk for CV death or MI in the CR group “really should make the complete revascularization approach the standard of care in MI patients without contraindications,” Dr. Bhatt said. And certainly, “age per se should no longer be considered a contraindication.”
“First and foremost, the FIRE trial confirms the benefit of complete revascularization that has been observed in previous trials and provides additional evidence for this approach in older patients,” wrote the author of an editorial accompanying the published report.
The mortality reduction with CR at 1 years “is particularly notable” and underscores that CR should be considered in all patients with acute MI, “regardless of age,” wrote Shamir R. Mehta, MD, McMaster University, Hamilton, Ont., and Hamilton Health Sciences.
Dr. Mehta was principal investigator for the 2019 COMPLETE trial, which made the case for CR, guided by standard angiography, in patients with MVD and STEMI; their age averaged about 62 years.
FIRE definitely ought to sway practice toward greater use of physiology-guided CR regardless of age, observed Vijay Kunadian, MBBS, MD, invited discussant for the Biscaglia presentation. “My oldest patient is 98,” she said, “and it is beneficial without a doubt.”
But Dr. Kunadian, from Newcastle (England) University, said that the trial results can’t be generalized to all older patients. That’s because their outcomes after CR could vary depending on, for example, their different frailties or comorbidities, cognition, or CV history. “So, there is an absolute need to individualize care.”
FIRE enrolled patients 75 years or older with MVD, about 64% male, who had been admitted with acute STEMI or NSTEMI at 34 sites in Italy, Spain, and Poland. All underwent successful culprit-lesion PCI using, as “strongly” recommended, the same model of sirolimus-eluting stent.
Patients were randomly assigned to physiology-guided CR of nonculprit lesions, at the same session or at least during the same hospitalization, or to no further revascularization: 720 and 725 patients, respectively.
The hazard ratio for the composite primary outcome, CR versus culprit-only PCI was 0.73 (95% confidence interval, 0.57-0.93; P = .01). The benefit was driven by reductions in three individual components of the primary endpoint: death, MI, and revascularization, but not stroke.
The HR for CV death or MI was 0.64 (95% CI, 0.47-0.88) and for death from any cause was 0.70 (95% CI, 0.51-0.96).
There was no significant difference in the primary safety outcome, a composite of contrast-related acute kidney injury, stroke, or Bleeding Academic Research Consortium grade 3 to 5 bleeding at 1 year. The rates were 22.5% in those assigned to CR and 20.4% in the culprit-only group.
The functional effect of individual lesions was assessed by either of two methods, crossing them with a standard “pressure wire” or by angiographic derivation of their quantitative flow ratio.
The choice was “left to operator discretion,” Dr. Biscaglia said in an interview, “because we wanted to mirror clinical practice at the participating centers.” Still, the CR primary benefit was independent of the physiology-guidance method.
FIRE’s sponsor – the nonprofit Consorzio Futuro in Ricerca, Italy – received grant support from Sahajanand Medical Technologies, Medis Medical Imaging systems, Eukon, Siemens Healthineers, General Electric Healthcare, and Insight Lifetech. Dr. Biscaglia had no other disclosures. Dr. Mehta reported receiving grants from Abbott Vascular and personal fees from Amgen, Janssen, and Bristol Myers Squibb. Dr. Bhatt reported numerous disclosures with various companies and organizations. Dr. Kunadian had no disclosures.
A version of this article first appeared on Medscape.com.
(MVD) in a large, randomized trial.
In the study with more than 1,400 patients, CR was guided by assessments of the functional effect of coronary lesions other than the MI culprit, a process that selects or excludes the lesions, regardless of angiographic profile, as targets for percutaneous coronary intervention (PCI).
Such physiology-guided CR led to a significant 27% drop in risk for a composite primary endpoint over 1 year in the trial, called FIRE (Functional Assessment in Elderly MI Patients with Multivessel Disease), compared with the culprit-only approach. The endpoint included death, MI, stroke, or ischemia-driven revascularization.
Risk for cardiovascular (CV) death or MI fell by 36% in the trial, and all-cause mortality declined 30%. The differences were significant, although the study wasn’t powered for those secondary endpoints. Safety outcomes were similar for the two revascularization approaches.
FIRE was noteworthy for entering only patients with ST-segment elevation or non–ST-segment elevation MI (STEMI or NSTEMI) who were age 75 years or older, a higher-risk age group poorly represented in earlier CR trials. Such patients in practice are usually managed with the culprit lesion–only approach because of a lack of good evidence supporting CR, observed Simone Biscaglia, MD, the study’s principal investigator.
“This is the first trial actually showing a benefit” from physiology-guided CR in older patients with acute MI that is similar to what the strategy can offer younger patients, said Dr. Biscaglia, from Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy.
Biscaglia made the comments at a media briefing on FIRE held during the annual congress of the European Society of Cardiology, where he presented the study. He is also lead author on its publication in the New England Journal of Medicine.
“This is a remarkable trial that adds substantially to prior studies that examined the topic of complete versus culprit-only revascularization,” Deepak L. Bhatt, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
It shows “quite clearly” that physiology-guided CR is superior to the culprit-only approach in patients with acute MI, said Dr. Bhatt, who is also director of Mount Sinai Heart at Mount Sinai Hospital and not connected to FIRE.
The primary findings applied to a range of different patient subgroups, including those older than 80. That’s important, he said, because “it is sometimes incorrectly assumed that patients who are older may not benefit from complete revascularization in this setting.”
And the trial’s finding of reduced risk for CV death or MI in the CR group “really should make the complete revascularization approach the standard of care in MI patients without contraindications,” Dr. Bhatt said. And certainly, “age per se should no longer be considered a contraindication.”
“First and foremost, the FIRE trial confirms the benefit of complete revascularization that has been observed in previous trials and provides additional evidence for this approach in older patients,” wrote the author of an editorial accompanying the published report.
The mortality reduction with CR at 1 years “is particularly notable” and underscores that CR should be considered in all patients with acute MI, “regardless of age,” wrote Shamir R. Mehta, MD, McMaster University, Hamilton, Ont., and Hamilton Health Sciences.
Dr. Mehta was principal investigator for the 2019 COMPLETE trial, which made the case for CR, guided by standard angiography, in patients with MVD and STEMI; their age averaged about 62 years.
FIRE definitely ought to sway practice toward greater use of physiology-guided CR regardless of age, observed Vijay Kunadian, MBBS, MD, invited discussant for the Biscaglia presentation. “My oldest patient is 98,” she said, “and it is beneficial without a doubt.”
But Dr. Kunadian, from Newcastle (England) University, said that the trial results can’t be generalized to all older patients. That’s because their outcomes after CR could vary depending on, for example, their different frailties or comorbidities, cognition, or CV history. “So, there is an absolute need to individualize care.”
FIRE enrolled patients 75 years or older with MVD, about 64% male, who had been admitted with acute STEMI or NSTEMI at 34 sites in Italy, Spain, and Poland. All underwent successful culprit-lesion PCI using, as “strongly” recommended, the same model of sirolimus-eluting stent.
Patients were randomly assigned to physiology-guided CR of nonculprit lesions, at the same session or at least during the same hospitalization, or to no further revascularization: 720 and 725 patients, respectively.
The hazard ratio for the composite primary outcome, CR versus culprit-only PCI was 0.73 (95% confidence interval, 0.57-0.93; P = .01). The benefit was driven by reductions in three individual components of the primary endpoint: death, MI, and revascularization, but not stroke.
The HR for CV death or MI was 0.64 (95% CI, 0.47-0.88) and for death from any cause was 0.70 (95% CI, 0.51-0.96).
There was no significant difference in the primary safety outcome, a composite of contrast-related acute kidney injury, stroke, or Bleeding Academic Research Consortium grade 3 to 5 bleeding at 1 year. The rates were 22.5% in those assigned to CR and 20.4% in the culprit-only group.
The functional effect of individual lesions was assessed by either of two methods, crossing them with a standard “pressure wire” or by angiographic derivation of their quantitative flow ratio.
The choice was “left to operator discretion,” Dr. Biscaglia said in an interview, “because we wanted to mirror clinical practice at the participating centers.” Still, the CR primary benefit was independent of the physiology-guidance method.
FIRE’s sponsor – the nonprofit Consorzio Futuro in Ricerca, Italy – received grant support from Sahajanand Medical Technologies, Medis Medical Imaging systems, Eukon, Siemens Healthineers, General Electric Healthcare, and Insight Lifetech. Dr. Biscaglia had no other disclosures. Dr. Mehta reported receiving grants from Abbott Vascular and personal fees from Amgen, Janssen, and Bristol Myers Squibb. Dr. Bhatt reported numerous disclosures with various companies and organizations. Dr. Kunadian had no disclosures.
A version of this article first appeared on Medscape.com.
(MVD) in a large, randomized trial.
In the study with more than 1,400 patients, CR was guided by assessments of the functional effect of coronary lesions other than the MI culprit, a process that selects or excludes the lesions, regardless of angiographic profile, as targets for percutaneous coronary intervention (PCI).
Such physiology-guided CR led to a significant 27% drop in risk for a composite primary endpoint over 1 year in the trial, called FIRE (Functional Assessment in Elderly MI Patients with Multivessel Disease), compared with the culprit-only approach. The endpoint included death, MI, stroke, or ischemia-driven revascularization.
Risk for cardiovascular (CV) death or MI fell by 36% in the trial, and all-cause mortality declined 30%. The differences were significant, although the study wasn’t powered for those secondary endpoints. Safety outcomes were similar for the two revascularization approaches.
FIRE was noteworthy for entering only patients with ST-segment elevation or non–ST-segment elevation MI (STEMI or NSTEMI) who were age 75 years or older, a higher-risk age group poorly represented in earlier CR trials. Such patients in practice are usually managed with the culprit lesion–only approach because of a lack of good evidence supporting CR, observed Simone Biscaglia, MD, the study’s principal investigator.
“This is the first trial actually showing a benefit” from physiology-guided CR in older patients with acute MI that is similar to what the strategy can offer younger patients, said Dr. Biscaglia, from Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy.
Biscaglia made the comments at a media briefing on FIRE held during the annual congress of the European Society of Cardiology, where he presented the study. He is also lead author on its publication in the New England Journal of Medicine.
“This is a remarkable trial that adds substantially to prior studies that examined the topic of complete versus culprit-only revascularization,” Deepak L. Bhatt, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.
It shows “quite clearly” that physiology-guided CR is superior to the culprit-only approach in patients with acute MI, said Dr. Bhatt, who is also director of Mount Sinai Heart at Mount Sinai Hospital and not connected to FIRE.
The primary findings applied to a range of different patient subgroups, including those older than 80. That’s important, he said, because “it is sometimes incorrectly assumed that patients who are older may not benefit from complete revascularization in this setting.”
And the trial’s finding of reduced risk for CV death or MI in the CR group “really should make the complete revascularization approach the standard of care in MI patients without contraindications,” Dr. Bhatt said. And certainly, “age per se should no longer be considered a contraindication.”
“First and foremost, the FIRE trial confirms the benefit of complete revascularization that has been observed in previous trials and provides additional evidence for this approach in older patients,” wrote the author of an editorial accompanying the published report.
The mortality reduction with CR at 1 years “is particularly notable” and underscores that CR should be considered in all patients with acute MI, “regardless of age,” wrote Shamir R. Mehta, MD, McMaster University, Hamilton, Ont., and Hamilton Health Sciences.
Dr. Mehta was principal investigator for the 2019 COMPLETE trial, which made the case for CR, guided by standard angiography, in patients with MVD and STEMI; their age averaged about 62 years.
FIRE definitely ought to sway practice toward greater use of physiology-guided CR regardless of age, observed Vijay Kunadian, MBBS, MD, invited discussant for the Biscaglia presentation. “My oldest patient is 98,” she said, “and it is beneficial without a doubt.”
But Dr. Kunadian, from Newcastle (England) University, said that the trial results can’t be generalized to all older patients. That’s because their outcomes after CR could vary depending on, for example, their different frailties or comorbidities, cognition, or CV history. “So, there is an absolute need to individualize care.”
FIRE enrolled patients 75 years or older with MVD, about 64% male, who had been admitted with acute STEMI or NSTEMI at 34 sites in Italy, Spain, and Poland. All underwent successful culprit-lesion PCI using, as “strongly” recommended, the same model of sirolimus-eluting stent.
Patients were randomly assigned to physiology-guided CR of nonculprit lesions, at the same session or at least during the same hospitalization, or to no further revascularization: 720 and 725 patients, respectively.
The hazard ratio for the composite primary outcome, CR versus culprit-only PCI was 0.73 (95% confidence interval, 0.57-0.93; P = .01). The benefit was driven by reductions in three individual components of the primary endpoint: death, MI, and revascularization, but not stroke.
The HR for CV death or MI was 0.64 (95% CI, 0.47-0.88) and for death from any cause was 0.70 (95% CI, 0.51-0.96).
There was no significant difference in the primary safety outcome, a composite of contrast-related acute kidney injury, stroke, or Bleeding Academic Research Consortium grade 3 to 5 bleeding at 1 year. The rates were 22.5% in those assigned to CR and 20.4% in the culprit-only group.
The functional effect of individual lesions was assessed by either of two methods, crossing them with a standard “pressure wire” or by angiographic derivation of their quantitative flow ratio.
The choice was “left to operator discretion,” Dr. Biscaglia said in an interview, “because we wanted to mirror clinical practice at the participating centers.” Still, the CR primary benefit was independent of the physiology-guidance method.
FIRE’s sponsor – the nonprofit Consorzio Futuro in Ricerca, Italy – received grant support from Sahajanand Medical Technologies, Medis Medical Imaging systems, Eukon, Siemens Healthineers, General Electric Healthcare, and Insight Lifetech. Dr. Biscaglia had no other disclosures. Dr. Mehta reported receiving grants from Abbott Vascular and personal fees from Amgen, Janssen, and Bristol Myers Squibb. Dr. Bhatt reported numerous disclosures with various companies and organizations. Dr. Kunadian had no disclosures.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
ESC backs SGLT2 inhibitor plus GLP-1 in diabetes with high CVD risk
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AMSTERDAM – The era of guidelines that recommended treatment with either a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagonlike peptide-1 (GLP-1) receptor agonist in people with type 2 diabetes mellitus and established cardiovascular disease (CVD) ended with new recommendations from the European Society of Cardiology that call for starting both classes simultaneously.
said Darren K. McGuire, MD, at the annual congress of the European Society of Cardiology.
The society’s new guidelines for managing CVD in patients with diabetes, released on Aug. 25 and presented in several sessions at the Congress, also break with the past by calling for starting treatment with both an SGLT-2 inhibitor and a GLP-1 receptor agonist without regard to a person’s existing level of glucose control, including their current and target hemoglobin A1c levels, and regardless of background therapy, added Dr. McGuire, a cardiologist and professor at the UT Southwestern Medical Center in Dallas and a member of the ESC panel that wrote the new guidelines.
Instead, the new guidance calls for starting both drug classes promptly in people diagnosed with type 2 diabetes and established atherosclerotic CVD.
Both the previous ESC guidelines from 2019 as well as the current Standards of Care for 2023 document from the American Diabetes Association call for using one class or the other, but they hedge on combined treatment as discretionary.
Different mechanisms mean additive benefits
“With increasing numbers of patients with type 2 diabetes in trials for SGLT-2 inhibitors or GLP-1 receptor agonists who were also on the other drug class, we’ve done large, stratified analyses that suggest no treatment-effect modification” when people received agents from both drug classes, Dr. McGuire explained in an interview. “While we don’t understand the mechanisms of action of these drugs for CVD, we’ve become very confident that they use different mechanisms” that appear to have at least partially additive effects.
“Their benefits for CVD risk reduction are completely independent of their glucose effects. They are cardiology drugs,” Dr. McGuire added.
The new ESC guidelines highlight two other clinical settings where people with type 2 diabetes should receive an SGLT-2 inhibitor regardless of their existing level of glucose control and any other medical treatment: people with heart failure and people with chronic kidney disease (CKD) based on a depressed estimated glomerular filtration rate and an elevated urine albumin-to-creatinine ratio.
Nephropathy was considered by the ESC’s guideline panel to confer risk that is similar to that of established atherosclerotic CVD, Dr. McGuire said.
The guidelines also, for the first time for ESC recommendations, made treatment with finerenone (Kerendia, Bayer) a class 1 level A recommendation for people with type 2 diabetes and CKD.
SCORE2-Diabetes risk estimator
Another major change in the new ESC guideline revision is introduction of a CVD risk calculator intended to estimate the risk among people with type 2 diabetes but without established CVD, heart failure, or CKD.
Called the SCORE2-Diabetes risk estimator, it calculates a person’s 10-year risk for CVD and includes adjustment based on the European region where a person lives; it also tallies different risk levels for women and for men.
The researchers who developed the SCORE2-Diabetes calculator used data from nearly 230,000 people to devise the tool and then validated it with data from an additional 217,000 Europeans with type 2 diabetes.
Key features of the calculator include its use of routinely collected clinical values, such as age, sex, systolic blood pressure, smoking status, serum cholesterol levels, age at diabetes diagnosis, hemoglobin A1c level, and estimated glomerular filtration rate.
“For the first time we have a clear score to categorize risk” in people with type 2 diabetes and identify who needs more aggressive treatment to prevent CVD development,” said Emanuele Di Angelantonio, MD, PhD, deputy director of the cardiovascular epidemiology unit at the University of Cambridge (England).
The guidelines say that people who have a low (< 5%) or moderate (5%-9%) 10-year risk for CVD are possible candidates for metformin treatment. Those with high (10%-19%) or very high (≥ 20%) risk are possible candidates for treatment with metformin and/or an SGLT-2 inhibitor and/or a GLP-1 receptor agonist, said Dr. Di Angelantonio during his talk at the congress on the new risk score.
“The risk score is a good addition” because it estimates future CVD risk better and more systematically than usual practice, which generally relies on no systematic tool, said Naveed Sattar, PhD, professor of metabolic medicine at the University of Glasgow (Scotland) and also a member of the guideline-writing panel.
The new risk score “is a reasonable way” to identify people without CVD but at elevated risk who might benefit from treatment with a relatively expensive drug, such as an SGLT-2 inhibitor, Dr. Sattar said in an interview. “It doesn’t rely on any fancy biomarkers or imaging, and it takes about 30 seconds to calculate. It’s not perfect, but it gets the job done,” and it will increase the number of people with type 2 diabetes who will receive an SGLT-2 inhibitor, he predicted.
Dr. McGuire has been a consultant to Altimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Intercept, Lexion, Lilly, Merck, New Amsterdam, and Pfizer. Dr. Di Angelantonio had no disclosures. Dr. Sattar has been a consultant to Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics.
A version of this article appeared on Medscape.com.
AT ESC CONGRESS 2023
Acoramidis shows encouraging results in ATTR cardiomyopathy
AMSTERDAM –
The drug, acoramidis (BridgeBio Pharma), showed a significant reduction, compared with placebo, in the primary endpoint, a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and 6-minute walking distance, in the ATTRibute-CM trial.
The combination of all-cause mortality/cardiovascular hospitalization was also significantly reduced.
The trial was presented at the annual congress of the European Society of Cardiology by Julian Gillmore, MD, head of the University College London Centre for Amyloidosis.
“ATTRibute-CM was a robustly positive trial, showing benefits across the board for acoramidis, and suggest the tantalizing possibility of genuine clinical improvements,” Dr. Gillmore concluded.
ATTR-CM is a debilitating and progressive condition that increases mortality and reduces quality of life. Although this form of cardiomyopathy was considered to be very rare not long ago, improvements in imaging techniques and treatment developments have resulted in an upsurge in diagnosis throughout the world, and the disease is being diagnosed at an earlier stage, Dr. Gillmore noted.
ATTR-CM results from aggregation and deposition of transthyretin amyloid fibrils in the heart and various tissues. Acoramidis stabilizes the TTR tetramer and avoids the production of the fibrils.
Another similar drug, tafamidis (Vyndaqel, Vyndamax, Pfizer), was approved by the Food and Drug Administration in 2019 for ATTR-CM and is now available in several counties, including Japan and Europe.
BridgeBio Pharma is planning to file for FDA approval for acoramidis toward the end of 2023 and in other countries in 2024, Dr. Gillmore reported.
“It will be a huge benefit to patients to have another effective drug available,” he said.
Tafamidis also showed impressive results with its pivotal trial – ATTR-ACT – including a significant reduction in all-cause mortality, which was not seen in the ATTRibute-CM trial with acoramidis.
Asked about this, Dr. Gillmore replied: “It is difficult to comment on comparison with tafamidis as there isn’t a head-to-head trial. All I can say is that these results with acoramidis are fantastically encouraging, and I think we are going to have two effective drugs to treat this progressive and fatal condition.”
He elaborated that the difference in all-cause mortality results between the trials was “entirely consistent” with differences in the trial populations, with the ATTRibute-CM trial recruiting much lower-risk patients, in line with the earlier diagnosis of the condition that is now occurring.
“The survival in the placebo group in the ATTRibute study was greater than that in the treatment group in the ATTR-ACT study. So, it’s not all that surprising, given the reduced number of events, that mortality alone was not statistically significant in ATTRibute. What is important is that the trend in mortality was in the right direction, with an impressive risk reduction,” Dr. Gillmore noted.
“Incredibly, survival at 30 months and hospitalization rates among patients receiving acoramidis approached that of age-matched individuals who do not have ATTR,” he added.
Noting that more patients in the placebo group started taking tafamidis during the trial, Dr. Gillmore suggested that this would be expected to dilute the treatment effect of acoramidis.
“To have such a strongly positive study despite the change in the patient population and drop-in use of tafamidis is incredibly powerful,” he concluded.
ATTRibute trial
The randomized double-blind ATTRibute-CM trial included 632 patients with ATTR-CM and New York Heart Association class I-III heart failure.
They were randomly assigned 2:1 to acoramidis (800 mg twice daily) or placebo, with a follow-up of 30 months. After the first 12 months, tafamidis was permitted if available. This was more prevalent in the placebo arm (22% vs. 14%).
The trial met the primary endpoint – a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in NT-proBNP and 6-minute walking distance – with a win ratio of 1.8, which was highly statistically significant (P < .0001).
Results were consistent across all components of the primary endpoint and across all subgroups, Dr. Gillmore reported.
“Importantly, 58% of the win ratio ties were broken by the first two components of the hierarchical analysis – all-cause mortality and cardiovascular hospitalizations – and a separate analysis of these two components alone was also statistically significant,” he noted.
A trend was seen toward a treatment effect on all-cause mortality favoring acoramidis, with an 81% survival rate in the treated group, representing an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 25%.
Of the deaths reported in the study, 78% were cardiovascular in nature. Cardiovascular death also showed a trend favoring treatment with the study drug (14.9% in the acoramidis group vs. 21.3% in the placebo group), giving an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 30%.
Acoramidis was also associated with 50% reduction in cardiovascular hospitalizations, which was highly significant (P < .0001).
A treatment effect was also seen in terms of functional status; at 30 months, the difference in 6-minute walk distance between the groups was 40 meters, a “highly statistically significant improvement and clinically important difference, Dr. Gillmore said. Improvement from baseline occurred in 40% of the acoramidis group versus 22% of the placebo group.
Acoramidis recipients showed a blunting of the progressive rise of NT-proBNP, which Dr. Gillmore noted has been shown to be strongly associated with outcomes, with 45% of the acoramidis treated patients showing an improvement in NT-proBNP levels, compared with 9% of placebo group.
There was also a relative preservation of quality of life in the acoramidis group consistent with the separation of NT-proBNP curves, he added.
“Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at therapeutic drug concentrations, serum TTR (an in vivo reflection of TTR stabilization) was promptly and persistently elevated in patients receiving acoramidis,” Dr. Gillmore said.
Safety data showed that treatment-related adverse events were equal between the two groups, and there were fewer treatment emergent serious adverse events in the acoramidis group. The drug was said to be “generally well tolerated, with no findings of potential clinical concern.”
Second primary endpoint not significant
Discussant of the study at the ESC Hotline session, Thibaud Damy, MD, Hospital Henri Mondor, Paris East Creteil University, pointed out that a second primary endpoint of the study, change from baseline to month 12 in the 6-minute walking test, did not significantly differ between acoramidis and placebo.
Dr. Damy also highlighted the significant all-cause mortality reduction seen with tafamidis in ATTR-ACT but not achieved with acoramidis in ATTRibute.
He agreed with Dr. Gillmore’s interpretation that this was probably stemmed from the ATTRibute trial recruiting lower-risk patients, pointing out that patients in this trial had lower levels of NT-proBNP and less severe heart failure.
“It is clear that there is a place for acoramidis in patients with ATTR-CM,” Dr. Damy concluded, adding that many other treatments are in development.
The ATTribute trial was supported by BridgeBio Pharma. Dr. Gillmore reported advisory/consultant roles with BridgeBio, Alnylam, Ionis, AstraZeneca, Intellia, Pfizer, ATTRalus, and Lycia.
A version of this article first appeared on Medscape.com.
AMSTERDAM –
The drug, acoramidis (BridgeBio Pharma), showed a significant reduction, compared with placebo, in the primary endpoint, a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and 6-minute walking distance, in the ATTRibute-CM trial.
The combination of all-cause mortality/cardiovascular hospitalization was also significantly reduced.
The trial was presented at the annual congress of the European Society of Cardiology by Julian Gillmore, MD, head of the University College London Centre for Amyloidosis.
“ATTRibute-CM was a robustly positive trial, showing benefits across the board for acoramidis, and suggest the tantalizing possibility of genuine clinical improvements,” Dr. Gillmore concluded.
ATTR-CM is a debilitating and progressive condition that increases mortality and reduces quality of life. Although this form of cardiomyopathy was considered to be very rare not long ago, improvements in imaging techniques and treatment developments have resulted in an upsurge in diagnosis throughout the world, and the disease is being diagnosed at an earlier stage, Dr. Gillmore noted.
ATTR-CM results from aggregation and deposition of transthyretin amyloid fibrils in the heart and various tissues. Acoramidis stabilizes the TTR tetramer and avoids the production of the fibrils.
Another similar drug, tafamidis (Vyndaqel, Vyndamax, Pfizer), was approved by the Food and Drug Administration in 2019 for ATTR-CM and is now available in several counties, including Japan and Europe.
BridgeBio Pharma is planning to file for FDA approval for acoramidis toward the end of 2023 and in other countries in 2024, Dr. Gillmore reported.
“It will be a huge benefit to patients to have another effective drug available,” he said.
Tafamidis also showed impressive results with its pivotal trial – ATTR-ACT – including a significant reduction in all-cause mortality, which was not seen in the ATTRibute-CM trial with acoramidis.
Asked about this, Dr. Gillmore replied: “It is difficult to comment on comparison with tafamidis as there isn’t a head-to-head trial. All I can say is that these results with acoramidis are fantastically encouraging, and I think we are going to have two effective drugs to treat this progressive and fatal condition.”
He elaborated that the difference in all-cause mortality results between the trials was “entirely consistent” with differences in the trial populations, with the ATTRibute-CM trial recruiting much lower-risk patients, in line with the earlier diagnosis of the condition that is now occurring.
“The survival in the placebo group in the ATTRibute study was greater than that in the treatment group in the ATTR-ACT study. So, it’s not all that surprising, given the reduced number of events, that mortality alone was not statistically significant in ATTRibute. What is important is that the trend in mortality was in the right direction, with an impressive risk reduction,” Dr. Gillmore noted.
“Incredibly, survival at 30 months and hospitalization rates among patients receiving acoramidis approached that of age-matched individuals who do not have ATTR,” he added.
Noting that more patients in the placebo group started taking tafamidis during the trial, Dr. Gillmore suggested that this would be expected to dilute the treatment effect of acoramidis.
“To have such a strongly positive study despite the change in the patient population and drop-in use of tafamidis is incredibly powerful,” he concluded.
ATTRibute trial
The randomized double-blind ATTRibute-CM trial included 632 patients with ATTR-CM and New York Heart Association class I-III heart failure.
They were randomly assigned 2:1 to acoramidis (800 mg twice daily) or placebo, with a follow-up of 30 months. After the first 12 months, tafamidis was permitted if available. This was more prevalent in the placebo arm (22% vs. 14%).
The trial met the primary endpoint – a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in NT-proBNP and 6-minute walking distance – with a win ratio of 1.8, which was highly statistically significant (P < .0001).
Results were consistent across all components of the primary endpoint and across all subgroups, Dr. Gillmore reported.
“Importantly, 58% of the win ratio ties were broken by the first two components of the hierarchical analysis – all-cause mortality and cardiovascular hospitalizations – and a separate analysis of these two components alone was also statistically significant,” he noted.
A trend was seen toward a treatment effect on all-cause mortality favoring acoramidis, with an 81% survival rate in the treated group, representing an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 25%.
Of the deaths reported in the study, 78% were cardiovascular in nature. Cardiovascular death also showed a trend favoring treatment with the study drug (14.9% in the acoramidis group vs. 21.3% in the placebo group), giving an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 30%.
Acoramidis was also associated with 50% reduction in cardiovascular hospitalizations, which was highly significant (P < .0001).
A treatment effect was also seen in terms of functional status; at 30 months, the difference in 6-minute walk distance between the groups was 40 meters, a “highly statistically significant improvement and clinically important difference, Dr. Gillmore said. Improvement from baseline occurred in 40% of the acoramidis group versus 22% of the placebo group.
Acoramidis recipients showed a blunting of the progressive rise of NT-proBNP, which Dr. Gillmore noted has been shown to be strongly associated with outcomes, with 45% of the acoramidis treated patients showing an improvement in NT-proBNP levels, compared with 9% of placebo group.
There was also a relative preservation of quality of life in the acoramidis group consistent with the separation of NT-proBNP curves, he added.
“Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at therapeutic drug concentrations, serum TTR (an in vivo reflection of TTR stabilization) was promptly and persistently elevated in patients receiving acoramidis,” Dr. Gillmore said.
Safety data showed that treatment-related adverse events were equal between the two groups, and there were fewer treatment emergent serious adverse events in the acoramidis group. The drug was said to be “generally well tolerated, with no findings of potential clinical concern.”
Second primary endpoint not significant
Discussant of the study at the ESC Hotline session, Thibaud Damy, MD, Hospital Henri Mondor, Paris East Creteil University, pointed out that a second primary endpoint of the study, change from baseline to month 12 in the 6-minute walking test, did not significantly differ between acoramidis and placebo.
Dr. Damy also highlighted the significant all-cause mortality reduction seen with tafamidis in ATTR-ACT but not achieved with acoramidis in ATTRibute.
He agreed with Dr. Gillmore’s interpretation that this was probably stemmed from the ATTRibute trial recruiting lower-risk patients, pointing out that patients in this trial had lower levels of NT-proBNP and less severe heart failure.
“It is clear that there is a place for acoramidis in patients with ATTR-CM,” Dr. Damy concluded, adding that many other treatments are in development.
The ATTribute trial was supported by BridgeBio Pharma. Dr. Gillmore reported advisory/consultant roles with BridgeBio, Alnylam, Ionis, AstraZeneca, Intellia, Pfizer, ATTRalus, and Lycia.
A version of this article first appeared on Medscape.com.
AMSTERDAM –
The drug, acoramidis (BridgeBio Pharma), showed a significant reduction, compared with placebo, in the primary endpoint, a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and 6-minute walking distance, in the ATTRibute-CM trial.
The combination of all-cause mortality/cardiovascular hospitalization was also significantly reduced.
The trial was presented at the annual congress of the European Society of Cardiology by Julian Gillmore, MD, head of the University College London Centre for Amyloidosis.
“ATTRibute-CM was a robustly positive trial, showing benefits across the board for acoramidis, and suggest the tantalizing possibility of genuine clinical improvements,” Dr. Gillmore concluded.
ATTR-CM is a debilitating and progressive condition that increases mortality and reduces quality of life. Although this form of cardiomyopathy was considered to be very rare not long ago, improvements in imaging techniques and treatment developments have resulted in an upsurge in diagnosis throughout the world, and the disease is being diagnosed at an earlier stage, Dr. Gillmore noted.
ATTR-CM results from aggregation and deposition of transthyretin amyloid fibrils in the heart and various tissues. Acoramidis stabilizes the TTR tetramer and avoids the production of the fibrils.
Another similar drug, tafamidis (Vyndaqel, Vyndamax, Pfizer), was approved by the Food and Drug Administration in 2019 for ATTR-CM and is now available in several counties, including Japan and Europe.
BridgeBio Pharma is planning to file for FDA approval for acoramidis toward the end of 2023 and in other countries in 2024, Dr. Gillmore reported.
“It will be a huge benefit to patients to have another effective drug available,” he said.
Tafamidis also showed impressive results with its pivotal trial – ATTR-ACT – including a significant reduction in all-cause mortality, which was not seen in the ATTRibute-CM trial with acoramidis.
Asked about this, Dr. Gillmore replied: “It is difficult to comment on comparison with tafamidis as there isn’t a head-to-head trial. All I can say is that these results with acoramidis are fantastically encouraging, and I think we are going to have two effective drugs to treat this progressive and fatal condition.”
He elaborated that the difference in all-cause mortality results between the trials was “entirely consistent” with differences in the trial populations, with the ATTRibute-CM trial recruiting much lower-risk patients, in line with the earlier diagnosis of the condition that is now occurring.
“The survival in the placebo group in the ATTRibute study was greater than that in the treatment group in the ATTR-ACT study. So, it’s not all that surprising, given the reduced number of events, that mortality alone was not statistically significant in ATTRibute. What is important is that the trend in mortality was in the right direction, with an impressive risk reduction,” Dr. Gillmore noted.
“Incredibly, survival at 30 months and hospitalization rates among patients receiving acoramidis approached that of age-matched individuals who do not have ATTR,” he added.
Noting that more patients in the placebo group started taking tafamidis during the trial, Dr. Gillmore suggested that this would be expected to dilute the treatment effect of acoramidis.
“To have such a strongly positive study despite the change in the patient population and drop-in use of tafamidis is incredibly powerful,” he concluded.
ATTRibute trial
The randomized double-blind ATTRibute-CM trial included 632 patients with ATTR-CM and New York Heart Association class I-III heart failure.
They were randomly assigned 2:1 to acoramidis (800 mg twice daily) or placebo, with a follow-up of 30 months. After the first 12 months, tafamidis was permitted if available. This was more prevalent in the placebo arm (22% vs. 14%).
The trial met the primary endpoint – a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in NT-proBNP and 6-minute walking distance – with a win ratio of 1.8, which was highly statistically significant (P < .0001).
Results were consistent across all components of the primary endpoint and across all subgroups, Dr. Gillmore reported.
“Importantly, 58% of the win ratio ties were broken by the first two components of the hierarchical analysis – all-cause mortality and cardiovascular hospitalizations – and a separate analysis of these two components alone was also statistically significant,” he noted.
A trend was seen toward a treatment effect on all-cause mortality favoring acoramidis, with an 81% survival rate in the treated group, representing an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 25%.
Of the deaths reported in the study, 78% were cardiovascular in nature. Cardiovascular death also showed a trend favoring treatment with the study drug (14.9% in the acoramidis group vs. 21.3% in the placebo group), giving an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 30%.
Acoramidis was also associated with 50% reduction in cardiovascular hospitalizations, which was highly significant (P < .0001).
A treatment effect was also seen in terms of functional status; at 30 months, the difference in 6-minute walk distance between the groups was 40 meters, a “highly statistically significant improvement and clinically important difference, Dr. Gillmore said. Improvement from baseline occurred in 40% of the acoramidis group versus 22% of the placebo group.
Acoramidis recipients showed a blunting of the progressive rise of NT-proBNP, which Dr. Gillmore noted has been shown to be strongly associated with outcomes, with 45% of the acoramidis treated patients showing an improvement in NT-proBNP levels, compared with 9% of placebo group.
There was also a relative preservation of quality of life in the acoramidis group consistent with the separation of NT-proBNP curves, he added.
“Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at therapeutic drug concentrations, serum TTR (an in vivo reflection of TTR stabilization) was promptly and persistently elevated in patients receiving acoramidis,” Dr. Gillmore said.
Safety data showed that treatment-related adverse events were equal between the two groups, and there were fewer treatment emergent serious adverse events in the acoramidis group. The drug was said to be “generally well tolerated, with no findings of potential clinical concern.”
Second primary endpoint not significant
Discussant of the study at the ESC Hotline session, Thibaud Damy, MD, Hospital Henri Mondor, Paris East Creteil University, pointed out that a second primary endpoint of the study, change from baseline to month 12 in the 6-minute walking test, did not significantly differ between acoramidis and placebo.
Dr. Damy also highlighted the significant all-cause mortality reduction seen with tafamidis in ATTR-ACT but not achieved with acoramidis in ATTRibute.
He agreed with Dr. Gillmore’s interpretation that this was probably stemmed from the ATTRibute trial recruiting lower-risk patients, pointing out that patients in this trial had lower levels of NT-proBNP and less severe heart failure.
“It is clear that there is a place for acoramidis in patients with ATTR-CM,” Dr. Damy concluded, adding that many other treatments are in development.
The ATTribute trial was supported by BridgeBio Pharma. Dr. Gillmore reported advisory/consultant roles with BridgeBio, Alnylam, Ionis, AstraZeneca, Intellia, Pfizer, ATTRalus, and Lycia.
A version of this article first appeared on Medscape.com.
AT THE ESC CONGRESS 2023
Pulsed field ablation challenges conventional devices in AFib
in a head-to-head trial, an outcome that might favor PFA in the context of other considerations.
“The take-home message is that this is a new technology that has important safety benefits. Patients do not have to worry about the possibility – albeit rare – of esophageal fistulae and other problems. It is faster with at least the same efficacy,” reported Vivek Y. Reddy MD, director of cardiac arrhythmia services, Mount Sinai Hospital, New York.
As opposed to conventional catheter-based thermal ablation, which isolates pulmonary veins harboring AF triggers by heating or freezing the tissue, PFA uses microsecond high-voltage electrical fields to produce cellular necrosis. It is largely nonthermal, Dr. Reddy said.
New device might spare adjacent tissue
In experimental studies, PFA has demonstrated a high degree of ablative specificity, limiting effects on adjacent tissues, such as the esophagus and phrenic nerve, he explained.
Several previous clinical studies support the specificity of the PFA ablative effect, but the ADVENT trial, which Dr. Reddy presented Aug. 27 at the annual congress of the European Society of Cardiology, is the first trial in which patients have been randomly assigned to PFA or catheter-based ablation.
The study was published online in the New England Journal of Medicine simultaneously with the ESC presentation.
The primary efficacy endpoint was the absence of a composite of endpoints indicating incomplete ablation. These included an initial procedural failure, atrial tachyarrhythmias arising after a 3-month blanking period, subsequent use of antiarrhythmic drugs, cardioversion, or repeat ablation. The primary safety endpoint involved a composite of procedure-related adverse events.
The 607 patients enrolled in this trial had AF refractory to at least one antiarrhythmic drug class. They were randomly assigned in a 1:1 ratio to PFA with a catheter system (Farapulse–Boston Scientific) or to thermal ablation.
Of the thermal approaches, radiofrequency or cryoablation was permitted, but each center was required to use just one for the control arm. For the comparison to PFA, outcomes for the two thermal techniques, which were used in similar proportions of patients, were combined based on previous evidence that these approaches perform similarly.
At 1 year, 73.3% of patients in the PFA group and 71.3% of those in the control group met the primary outcome, meaning none of the events signaling ablation failure occurred. The numeric advantage of PFA confirmed noninferiority, although an evaluation of superiority for efficacy, which was triggered by the advantage of PFA, was not significant.
As predicted by previous studies, stratification of thermal ablation approaches showed that outcomes were similar, although the proportion of patients who remained free of events at 1 year was numerically higher in the cryoablation group relative to the radiofrequency group (73.6% vs. 69.2%).
An adverse safety event occurred in 2.1% of those who underwent PFA and in 1.5% of those who underwent thermal ablation. This 0.6–percentage point difference placed PFA well within the boundary of noninferiority for safety.
Of notable events, the only death in this study occurred in the PFA group, and the only stroke occurred in the control group. Phrenic nerve palsies occurred only in the control group (2 vs. 0) while pericarditis was seen only in the PFA group (2 vs. 0). One case of pulmonary edema occurred in each group.
“Catheter ablation is quite safe and effective,” said Dr. Reddy, explaining why this comparison was conducted on the basis of noninferiority.
Dr. Reddy emphasized that noninferiority for PFA was achieved by operators with little or no experience with this technology, whereas the catheter ablations were delivered by operators who typically had previously performed hundreds of interventions.
“With experience, one would expect even better rates of success. This is the floor,” Dr. Reddy said.
Procedure time faster with PFA
Despite working with a new technology, the mean procedure performance time with PFA was faster (105 vs. 123 minutes) even though mean fluoroscopy time was longer (21.1 vs 13.9 minutes). Dr. Reddy considers the difference in procedure time a meaningful demonstration of the efficiency of PFA.
“When you look at procedure performance, it is remarkable that the procedure times were statistically significantly shorter for a first-use technology in the hands of multiple operators,” Dr. Reddy said.
There was also a statistically significant advantage for PFA regarding change in the mean pulmonary vein cross-sectional area following the procedures (0.9% vs. 12%). Dr. Reddy acknowledged that small changes in pulmonary vein dimension are not clinically meaningful, but this result “gets at the question of whether we can achieve ablation without tissue proliferation that we see with conventional ablation.”
Overall, Dr. Reddy believes that the data from ADVENT provide several reasons “to get excited about PFA,” including the efficiency of this technique in the context of at least similar efficacy but a potential for fewer adverse events.
The ESC-invited discussant, Samuel Kiil Sørensen, MD, Gentofte University Hospital, Copenhagen, agreed that the ADVENT data support PFA as an alternative to thermal ablation. He suggested that the shorter procedure times are clinically meaningful given comparable safety and efficacy.
“Which property of PFA justifies noninferiority?” he asked. “Many of the complications of AF ablation are not specific to the energy modality. The devastating complications from damage to the esophagus, pulmonary veins, and phrenic nerve that the PFA technology may eliminate are rare, so they would not be expected to change the overall complication rate in a [randomized controlled trial] of realistic size.”
However, he suggested PFA might still prove to be an incremental advance for AF. He cited previous evidence that supports the specificity of its ablative activity and emphasized that ADVENT tested a first-generation device that might not capture the full advantages of the PFA technology.
The trial was supported by Farapulse–Boston Scientific. Dr. Reddy reports financial relationships with more than 30 pharmaceutical or device manufacturers, including Farapulse–Boston Scientific. Dr. Sørensen reports financial relationships with Medtronic and Biosense Webster.
A version of this article first appeared on Medscape.com.
in a head-to-head trial, an outcome that might favor PFA in the context of other considerations.
“The take-home message is that this is a new technology that has important safety benefits. Patients do not have to worry about the possibility – albeit rare – of esophageal fistulae and other problems. It is faster with at least the same efficacy,” reported Vivek Y. Reddy MD, director of cardiac arrhythmia services, Mount Sinai Hospital, New York.
As opposed to conventional catheter-based thermal ablation, which isolates pulmonary veins harboring AF triggers by heating or freezing the tissue, PFA uses microsecond high-voltage electrical fields to produce cellular necrosis. It is largely nonthermal, Dr. Reddy said.
New device might spare adjacent tissue
In experimental studies, PFA has demonstrated a high degree of ablative specificity, limiting effects on adjacent tissues, such as the esophagus and phrenic nerve, he explained.
Several previous clinical studies support the specificity of the PFA ablative effect, but the ADVENT trial, which Dr. Reddy presented Aug. 27 at the annual congress of the European Society of Cardiology, is the first trial in which patients have been randomly assigned to PFA or catheter-based ablation.
The study was published online in the New England Journal of Medicine simultaneously with the ESC presentation.
The primary efficacy endpoint was the absence of a composite of endpoints indicating incomplete ablation. These included an initial procedural failure, atrial tachyarrhythmias arising after a 3-month blanking period, subsequent use of antiarrhythmic drugs, cardioversion, or repeat ablation. The primary safety endpoint involved a composite of procedure-related adverse events.
The 607 patients enrolled in this trial had AF refractory to at least one antiarrhythmic drug class. They were randomly assigned in a 1:1 ratio to PFA with a catheter system (Farapulse–Boston Scientific) or to thermal ablation.
Of the thermal approaches, radiofrequency or cryoablation was permitted, but each center was required to use just one for the control arm. For the comparison to PFA, outcomes for the two thermal techniques, which were used in similar proportions of patients, were combined based on previous evidence that these approaches perform similarly.
At 1 year, 73.3% of patients in the PFA group and 71.3% of those in the control group met the primary outcome, meaning none of the events signaling ablation failure occurred. The numeric advantage of PFA confirmed noninferiority, although an evaluation of superiority for efficacy, which was triggered by the advantage of PFA, was not significant.
As predicted by previous studies, stratification of thermal ablation approaches showed that outcomes were similar, although the proportion of patients who remained free of events at 1 year was numerically higher in the cryoablation group relative to the radiofrequency group (73.6% vs. 69.2%).
An adverse safety event occurred in 2.1% of those who underwent PFA and in 1.5% of those who underwent thermal ablation. This 0.6–percentage point difference placed PFA well within the boundary of noninferiority for safety.
Of notable events, the only death in this study occurred in the PFA group, and the only stroke occurred in the control group. Phrenic nerve palsies occurred only in the control group (2 vs. 0) while pericarditis was seen only in the PFA group (2 vs. 0). One case of pulmonary edema occurred in each group.
“Catheter ablation is quite safe and effective,” said Dr. Reddy, explaining why this comparison was conducted on the basis of noninferiority.
Dr. Reddy emphasized that noninferiority for PFA was achieved by operators with little or no experience with this technology, whereas the catheter ablations were delivered by operators who typically had previously performed hundreds of interventions.
“With experience, one would expect even better rates of success. This is the floor,” Dr. Reddy said.
Procedure time faster with PFA
Despite working with a new technology, the mean procedure performance time with PFA was faster (105 vs. 123 minutes) even though mean fluoroscopy time was longer (21.1 vs 13.9 minutes). Dr. Reddy considers the difference in procedure time a meaningful demonstration of the efficiency of PFA.
“When you look at procedure performance, it is remarkable that the procedure times were statistically significantly shorter for a first-use technology in the hands of multiple operators,” Dr. Reddy said.
There was also a statistically significant advantage for PFA regarding change in the mean pulmonary vein cross-sectional area following the procedures (0.9% vs. 12%). Dr. Reddy acknowledged that small changes in pulmonary vein dimension are not clinically meaningful, but this result “gets at the question of whether we can achieve ablation without tissue proliferation that we see with conventional ablation.”
Overall, Dr. Reddy believes that the data from ADVENT provide several reasons “to get excited about PFA,” including the efficiency of this technique in the context of at least similar efficacy but a potential for fewer adverse events.
The ESC-invited discussant, Samuel Kiil Sørensen, MD, Gentofte University Hospital, Copenhagen, agreed that the ADVENT data support PFA as an alternative to thermal ablation. He suggested that the shorter procedure times are clinically meaningful given comparable safety and efficacy.
“Which property of PFA justifies noninferiority?” he asked. “Many of the complications of AF ablation are not specific to the energy modality. The devastating complications from damage to the esophagus, pulmonary veins, and phrenic nerve that the PFA technology may eliminate are rare, so they would not be expected to change the overall complication rate in a [randomized controlled trial] of realistic size.”
However, he suggested PFA might still prove to be an incremental advance for AF. He cited previous evidence that supports the specificity of its ablative activity and emphasized that ADVENT tested a first-generation device that might not capture the full advantages of the PFA technology.
The trial was supported by Farapulse–Boston Scientific. Dr. Reddy reports financial relationships with more than 30 pharmaceutical or device manufacturers, including Farapulse–Boston Scientific. Dr. Sørensen reports financial relationships with Medtronic and Biosense Webster.
A version of this article first appeared on Medscape.com.
in a head-to-head trial, an outcome that might favor PFA in the context of other considerations.
“The take-home message is that this is a new technology that has important safety benefits. Patients do not have to worry about the possibility – albeit rare – of esophageal fistulae and other problems. It is faster with at least the same efficacy,” reported Vivek Y. Reddy MD, director of cardiac arrhythmia services, Mount Sinai Hospital, New York.
As opposed to conventional catheter-based thermal ablation, which isolates pulmonary veins harboring AF triggers by heating or freezing the tissue, PFA uses microsecond high-voltage electrical fields to produce cellular necrosis. It is largely nonthermal, Dr. Reddy said.
New device might spare adjacent tissue
In experimental studies, PFA has demonstrated a high degree of ablative specificity, limiting effects on adjacent tissues, such as the esophagus and phrenic nerve, he explained.
Several previous clinical studies support the specificity of the PFA ablative effect, but the ADVENT trial, which Dr. Reddy presented Aug. 27 at the annual congress of the European Society of Cardiology, is the first trial in which patients have been randomly assigned to PFA or catheter-based ablation.
The study was published online in the New England Journal of Medicine simultaneously with the ESC presentation.
The primary efficacy endpoint was the absence of a composite of endpoints indicating incomplete ablation. These included an initial procedural failure, atrial tachyarrhythmias arising after a 3-month blanking period, subsequent use of antiarrhythmic drugs, cardioversion, or repeat ablation. The primary safety endpoint involved a composite of procedure-related adverse events.
The 607 patients enrolled in this trial had AF refractory to at least one antiarrhythmic drug class. They were randomly assigned in a 1:1 ratio to PFA with a catheter system (Farapulse–Boston Scientific) or to thermal ablation.
Of the thermal approaches, radiofrequency or cryoablation was permitted, but each center was required to use just one for the control arm. For the comparison to PFA, outcomes for the two thermal techniques, which were used in similar proportions of patients, were combined based on previous evidence that these approaches perform similarly.
At 1 year, 73.3% of patients in the PFA group and 71.3% of those in the control group met the primary outcome, meaning none of the events signaling ablation failure occurred. The numeric advantage of PFA confirmed noninferiority, although an evaluation of superiority for efficacy, which was triggered by the advantage of PFA, was not significant.
As predicted by previous studies, stratification of thermal ablation approaches showed that outcomes were similar, although the proportion of patients who remained free of events at 1 year was numerically higher in the cryoablation group relative to the radiofrequency group (73.6% vs. 69.2%).
An adverse safety event occurred in 2.1% of those who underwent PFA and in 1.5% of those who underwent thermal ablation. This 0.6–percentage point difference placed PFA well within the boundary of noninferiority for safety.
Of notable events, the only death in this study occurred in the PFA group, and the only stroke occurred in the control group. Phrenic nerve palsies occurred only in the control group (2 vs. 0) while pericarditis was seen only in the PFA group (2 vs. 0). One case of pulmonary edema occurred in each group.
“Catheter ablation is quite safe and effective,” said Dr. Reddy, explaining why this comparison was conducted on the basis of noninferiority.
Dr. Reddy emphasized that noninferiority for PFA was achieved by operators with little or no experience with this technology, whereas the catheter ablations were delivered by operators who typically had previously performed hundreds of interventions.
“With experience, one would expect even better rates of success. This is the floor,” Dr. Reddy said.
Procedure time faster with PFA
Despite working with a new technology, the mean procedure performance time with PFA was faster (105 vs. 123 minutes) even though mean fluoroscopy time was longer (21.1 vs 13.9 minutes). Dr. Reddy considers the difference in procedure time a meaningful demonstration of the efficiency of PFA.
“When you look at procedure performance, it is remarkable that the procedure times were statistically significantly shorter for a first-use technology in the hands of multiple operators,” Dr. Reddy said.
There was also a statistically significant advantage for PFA regarding change in the mean pulmonary vein cross-sectional area following the procedures (0.9% vs. 12%). Dr. Reddy acknowledged that small changes in pulmonary vein dimension are not clinically meaningful, but this result “gets at the question of whether we can achieve ablation without tissue proliferation that we see with conventional ablation.”
Overall, Dr. Reddy believes that the data from ADVENT provide several reasons “to get excited about PFA,” including the efficiency of this technique in the context of at least similar efficacy but a potential for fewer adverse events.
The ESC-invited discussant, Samuel Kiil Sørensen, MD, Gentofte University Hospital, Copenhagen, agreed that the ADVENT data support PFA as an alternative to thermal ablation. He suggested that the shorter procedure times are clinically meaningful given comparable safety and efficacy.
“Which property of PFA justifies noninferiority?” he asked. “Many of the complications of AF ablation are not specific to the energy modality. The devastating complications from damage to the esophagus, pulmonary veins, and phrenic nerve that the PFA technology may eliminate are rare, so they would not be expected to change the overall complication rate in a [randomized controlled trial] of realistic size.”
However, he suggested PFA might still prove to be an incremental advance for AF. He cited previous evidence that supports the specificity of its ablative activity and emphasized that ADVENT tested a first-generation device that might not capture the full advantages of the PFA technology.
The trial was supported by Farapulse–Boston Scientific. Dr. Reddy reports financial relationships with more than 30 pharmaceutical or device manufacturers, including Farapulse–Boston Scientific. Dr. Sørensen reports financial relationships with Medtronic and Biosense Webster.
A version of this article first appeared on Medscape.com.
FROM THE ESC CONGRESS 2023
ECMO for shock in acute MI won’t help, may harm: ECLS-SHOCK
Patients with acute myocardial infarction (MI) and shock are often put on extracorporeal membrane oxygenation (ECMO) support before heading to the catheterization laboratory. But the practice, done routinely, doesn’t have much backing from randomized trials. Now it’s being challenged by one of the largest such studies to explore the issue.
ECMO-managed patients, moreover, had sharply increased risks for moderate and severe bleeding and vascular complications.
A challenge to common practice
The results undercut guidelines that promote mechanical circulatory support in MI-related cardiogenic shock primarily based on observational data, and they argue against what’s become common practice, said Holger Thiele, MD, Heart Center Leipzig, University of Leipzig, Germany.
Such use of ECMO could well offer some type of advantage in MI-related shock, but the data so far don’t show it, Dr. Thiele said at a press conference on the new study, called ECLS-SHOCK, at the annual congress of the European Society of Cardiology in Amsterdam. He formally presented the trial at the meeting and is lead author on its simultaneous publication in The New England Journal of Medicine.
Almost half of the trial’s patients died, whether or not they had been put on ECMO. All-cause mortality at 30 days, the primary endpoint, was about the same, at 47.8% and 49.0% for the ECMO and usual-care groups, respectively.
Meanwhile, Dr. Thiele reported, risks for moderate or severe bleeding more than doubled and serious peripheral vascular complications almost tripled with addition of ECMO support.
The findings, he noted, are consistent with a new meta-analysis of trials testing ECMO in MI-related shock that also showed increases in bleeding with survival gains using the devices. Dr. Thiele is senior author on that report, published in The Lancet to coincide with his ECLS-SHOCK presentation.
Would any subgroups benefit?
Importantly, he said in an interview, ECMO’s failure to improve 30-day survival in the trial probably applies across the spectrum of patients with MI-related shock. Subgroup analyses in both ECLS-SHOCK and the meta-analysis didn’t identify any groups that benefit, Dr. Thiele observed.
For example, there were no significant differences for the primary outcome by age, sex, whether the MI was ST-segment elevation MI or non–ST-segment elevation MI or anterior or nonanterior, or whether the patient had diabetes.
If there is a subgroup in MI-related shock that is likely to benefit from the intervention with lower mortality, he said, “it’s less than 1%, if you ask me.”
An accompanying editorial essentially agreed, arguing that ECLS-SHOCK contests the intervention’s broad application in MI-related shock without shedding light on any selective benefits.
“Will the results of the ECLS-SHOCK trial change current clinical practice? If the goal of [ECMO] is to improve 30-day mortality, these data should steer interventional and critical care cardiologists away from its early routine implementation for all or even most patients with myocardial infarction and cardiogenic shock,” the editorialists say.
“There will be some patients in this population for whom [ECMO] is necessary and lifesaving, but the results of the ECLS-SHOCK trial do not tell us which ones,” write Jane A. Leopold, MD, Brigham and Women’s Hospital, Boston, and Darren B. Taichman, MD, PhD, Penn Presbyterian Medical Center, Philadelphia.
“For now, the best course may be to reserve the early initiation of [ECMO] for those patients with infarct-related cardiogenic shock in whom the likely benefits more clearly outweigh the potential harms. We need further studies to tell us who they are,” write Dr. Leopold and Dr. Taichman, who are deputy editors with The New England Journal of Medicine.
ECLS-SHOCK randomly assigned 420 patients with acute MI complicated by shock and slated for coronary revascularization to receive standard care with or without early ECMO at 44 centers in Germany and Slovenia. Their median age was 63 years, and about 81% were men.
The relative risk for death from any cause, ECMO vs. usual care, was flatly nonsignificant at 0.98 (95% confidence interval, 0.80-1.19; P = .81).
ECMO came at the cost of significantly more cases of the primary safety endpoint, moderate or severe bleeding by Bleeding Academic Research Consortium criteria. That endpoint was met by 23.4% of ECMO patients and 9.6% of the control group, for an RR of 2.44 (95% CI, 1.50-3.95).
Rates of stroke or systemic embolization were nonsignificantly different at 3.8% and 2.9%, respectively (RR, 1.33; 95% CI, 0.47-3.76).
Speaking with this news organization, Sripal Bangalore, MD, MHA, pointed out that only 5.8% of the ECMO group but about 32% of those managed with usual care received some form of left ventricular (LV) unloading therapy.
Such measures can include atrial septostomy or the addition of an intra-aortic balloon pump or percutaneous LV-assist pump.
Given that ECMO increases afterload, “which is physiologically detrimental in patients with an ongoing MI, one is left to wonder if the results would have been different with greater use of LV unloading,” said Dr. Bangalore, of NYU Langone Health, New York, who isn’t associated with ECLS-SHOCK.
Also, he pointed out, about 78% of the trial’s patients had experienced some degree of cardiopulmonary resuscitation despite exclusion of anyone who had undergone it for more than 45 minutes. That may make the study more generalizable but also harder to show a benefit from ECMO. “The overall prognosis of that subset of patients despite heroic efforts is bleak at best.”
Dr. Thiele had no disclosures; statements for the other authors can be found at nejm.org. Dr. Bangalore has previously disclosed financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic. Dr. Leopold reports grants from Astellas and personal fees from United Therapeutics, Abbott Vascular, and North America Thrombosis Forum. Dr. Leopold and Dr. Taichman both report employment by The New England Journal of Medicine.
A version of this article appeared on Medscape.com.
Patients with acute myocardial infarction (MI) and shock are often put on extracorporeal membrane oxygenation (ECMO) support before heading to the catheterization laboratory. But the practice, done routinely, doesn’t have much backing from randomized trials. Now it’s being challenged by one of the largest such studies to explore the issue.
ECMO-managed patients, moreover, had sharply increased risks for moderate and severe bleeding and vascular complications.
A challenge to common practice
The results undercut guidelines that promote mechanical circulatory support in MI-related cardiogenic shock primarily based on observational data, and they argue against what’s become common practice, said Holger Thiele, MD, Heart Center Leipzig, University of Leipzig, Germany.
Such use of ECMO could well offer some type of advantage in MI-related shock, but the data so far don’t show it, Dr. Thiele said at a press conference on the new study, called ECLS-SHOCK, at the annual congress of the European Society of Cardiology in Amsterdam. He formally presented the trial at the meeting and is lead author on its simultaneous publication in The New England Journal of Medicine.
Almost half of the trial’s patients died, whether or not they had been put on ECMO. All-cause mortality at 30 days, the primary endpoint, was about the same, at 47.8% and 49.0% for the ECMO and usual-care groups, respectively.
Meanwhile, Dr. Thiele reported, risks for moderate or severe bleeding more than doubled and serious peripheral vascular complications almost tripled with addition of ECMO support.
The findings, he noted, are consistent with a new meta-analysis of trials testing ECMO in MI-related shock that also showed increases in bleeding with survival gains using the devices. Dr. Thiele is senior author on that report, published in The Lancet to coincide with his ECLS-SHOCK presentation.
Would any subgroups benefit?
Importantly, he said in an interview, ECMO’s failure to improve 30-day survival in the trial probably applies across the spectrum of patients with MI-related shock. Subgroup analyses in both ECLS-SHOCK and the meta-analysis didn’t identify any groups that benefit, Dr. Thiele observed.
For example, there were no significant differences for the primary outcome by age, sex, whether the MI was ST-segment elevation MI or non–ST-segment elevation MI or anterior or nonanterior, or whether the patient had diabetes.
If there is a subgroup in MI-related shock that is likely to benefit from the intervention with lower mortality, he said, “it’s less than 1%, if you ask me.”
An accompanying editorial essentially agreed, arguing that ECLS-SHOCK contests the intervention’s broad application in MI-related shock without shedding light on any selective benefits.
“Will the results of the ECLS-SHOCK trial change current clinical practice? If the goal of [ECMO] is to improve 30-day mortality, these data should steer interventional and critical care cardiologists away from its early routine implementation for all or even most patients with myocardial infarction and cardiogenic shock,” the editorialists say.
“There will be some patients in this population for whom [ECMO] is necessary and lifesaving, but the results of the ECLS-SHOCK trial do not tell us which ones,” write Jane A. Leopold, MD, Brigham and Women’s Hospital, Boston, and Darren B. Taichman, MD, PhD, Penn Presbyterian Medical Center, Philadelphia.
“For now, the best course may be to reserve the early initiation of [ECMO] for those patients with infarct-related cardiogenic shock in whom the likely benefits more clearly outweigh the potential harms. We need further studies to tell us who they are,” write Dr. Leopold and Dr. Taichman, who are deputy editors with The New England Journal of Medicine.
ECLS-SHOCK randomly assigned 420 patients with acute MI complicated by shock and slated for coronary revascularization to receive standard care with or without early ECMO at 44 centers in Germany and Slovenia. Their median age was 63 years, and about 81% were men.
The relative risk for death from any cause, ECMO vs. usual care, was flatly nonsignificant at 0.98 (95% confidence interval, 0.80-1.19; P = .81).
ECMO came at the cost of significantly more cases of the primary safety endpoint, moderate or severe bleeding by Bleeding Academic Research Consortium criteria. That endpoint was met by 23.4% of ECMO patients and 9.6% of the control group, for an RR of 2.44 (95% CI, 1.50-3.95).
Rates of stroke or systemic embolization were nonsignificantly different at 3.8% and 2.9%, respectively (RR, 1.33; 95% CI, 0.47-3.76).
Speaking with this news organization, Sripal Bangalore, MD, MHA, pointed out that only 5.8% of the ECMO group but about 32% of those managed with usual care received some form of left ventricular (LV) unloading therapy.
Such measures can include atrial septostomy or the addition of an intra-aortic balloon pump or percutaneous LV-assist pump.
Given that ECMO increases afterload, “which is physiologically detrimental in patients with an ongoing MI, one is left to wonder if the results would have been different with greater use of LV unloading,” said Dr. Bangalore, of NYU Langone Health, New York, who isn’t associated with ECLS-SHOCK.
Also, he pointed out, about 78% of the trial’s patients had experienced some degree of cardiopulmonary resuscitation despite exclusion of anyone who had undergone it for more than 45 minutes. That may make the study more generalizable but also harder to show a benefit from ECMO. “The overall prognosis of that subset of patients despite heroic efforts is bleak at best.”
Dr. Thiele had no disclosures; statements for the other authors can be found at nejm.org. Dr. Bangalore has previously disclosed financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic. Dr. Leopold reports grants from Astellas and personal fees from United Therapeutics, Abbott Vascular, and North America Thrombosis Forum. Dr. Leopold and Dr. Taichman both report employment by The New England Journal of Medicine.
A version of this article appeared on Medscape.com.
Patients with acute myocardial infarction (MI) and shock are often put on extracorporeal membrane oxygenation (ECMO) support before heading to the catheterization laboratory. But the practice, done routinely, doesn’t have much backing from randomized trials. Now it’s being challenged by one of the largest such studies to explore the issue.
ECMO-managed patients, moreover, had sharply increased risks for moderate and severe bleeding and vascular complications.
A challenge to common practice
The results undercut guidelines that promote mechanical circulatory support in MI-related cardiogenic shock primarily based on observational data, and they argue against what’s become common practice, said Holger Thiele, MD, Heart Center Leipzig, University of Leipzig, Germany.
Such use of ECMO could well offer some type of advantage in MI-related shock, but the data so far don’t show it, Dr. Thiele said at a press conference on the new study, called ECLS-SHOCK, at the annual congress of the European Society of Cardiology in Amsterdam. He formally presented the trial at the meeting and is lead author on its simultaneous publication in The New England Journal of Medicine.
Almost half of the trial’s patients died, whether or not they had been put on ECMO. All-cause mortality at 30 days, the primary endpoint, was about the same, at 47.8% and 49.0% for the ECMO and usual-care groups, respectively.
Meanwhile, Dr. Thiele reported, risks for moderate or severe bleeding more than doubled and serious peripheral vascular complications almost tripled with addition of ECMO support.
The findings, he noted, are consistent with a new meta-analysis of trials testing ECMO in MI-related shock that also showed increases in bleeding with survival gains using the devices. Dr. Thiele is senior author on that report, published in The Lancet to coincide with his ECLS-SHOCK presentation.
Would any subgroups benefit?
Importantly, he said in an interview, ECMO’s failure to improve 30-day survival in the trial probably applies across the spectrum of patients with MI-related shock. Subgroup analyses in both ECLS-SHOCK and the meta-analysis didn’t identify any groups that benefit, Dr. Thiele observed.
For example, there were no significant differences for the primary outcome by age, sex, whether the MI was ST-segment elevation MI or non–ST-segment elevation MI or anterior or nonanterior, or whether the patient had diabetes.
If there is a subgroup in MI-related shock that is likely to benefit from the intervention with lower mortality, he said, “it’s less than 1%, if you ask me.”
An accompanying editorial essentially agreed, arguing that ECLS-SHOCK contests the intervention’s broad application in MI-related shock without shedding light on any selective benefits.
“Will the results of the ECLS-SHOCK trial change current clinical practice? If the goal of [ECMO] is to improve 30-day mortality, these data should steer interventional and critical care cardiologists away from its early routine implementation for all or even most patients with myocardial infarction and cardiogenic shock,” the editorialists say.
“There will be some patients in this population for whom [ECMO] is necessary and lifesaving, but the results of the ECLS-SHOCK trial do not tell us which ones,” write Jane A. Leopold, MD, Brigham and Women’s Hospital, Boston, and Darren B. Taichman, MD, PhD, Penn Presbyterian Medical Center, Philadelphia.
“For now, the best course may be to reserve the early initiation of [ECMO] for those patients with infarct-related cardiogenic shock in whom the likely benefits more clearly outweigh the potential harms. We need further studies to tell us who they are,” write Dr. Leopold and Dr. Taichman, who are deputy editors with The New England Journal of Medicine.
ECLS-SHOCK randomly assigned 420 patients with acute MI complicated by shock and slated for coronary revascularization to receive standard care with or without early ECMO at 44 centers in Germany and Slovenia. Their median age was 63 years, and about 81% were men.
The relative risk for death from any cause, ECMO vs. usual care, was flatly nonsignificant at 0.98 (95% confidence interval, 0.80-1.19; P = .81).
ECMO came at the cost of significantly more cases of the primary safety endpoint, moderate or severe bleeding by Bleeding Academic Research Consortium criteria. That endpoint was met by 23.4% of ECMO patients and 9.6% of the control group, for an RR of 2.44 (95% CI, 1.50-3.95).
Rates of stroke or systemic embolization were nonsignificantly different at 3.8% and 2.9%, respectively (RR, 1.33; 95% CI, 0.47-3.76).
Speaking with this news organization, Sripal Bangalore, MD, MHA, pointed out that only 5.8% of the ECMO group but about 32% of those managed with usual care received some form of left ventricular (LV) unloading therapy.
Such measures can include atrial septostomy or the addition of an intra-aortic balloon pump or percutaneous LV-assist pump.
Given that ECMO increases afterload, “which is physiologically detrimental in patients with an ongoing MI, one is left to wonder if the results would have been different with greater use of LV unloading,” said Dr. Bangalore, of NYU Langone Health, New York, who isn’t associated with ECLS-SHOCK.
Also, he pointed out, about 78% of the trial’s patients had experienced some degree of cardiopulmonary resuscitation despite exclusion of anyone who had undergone it for more than 45 minutes. That may make the study more generalizable but also harder to show a benefit from ECMO. “The overall prognosis of that subset of patients despite heroic efforts is bleak at best.”
Dr. Thiele had no disclosures; statements for the other authors can be found at nejm.org. Dr. Bangalore has previously disclosed financial relationships with Abbott Vascular, Amgen, Biotronik, Inari, Pfizer, Reata, and Truvic. Dr. Leopold reports grants from Astellas and personal fees from United Therapeutics, Abbott Vascular, and North America Thrombosis Forum. Dr. Leopold and Dr. Taichman both report employment by The New England Journal of Medicine.
A version of this article appeared on Medscape.com.
FROM ESC CONGRESS 2023
Wegovy scores HFpEF benefits in people with obesity
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AMSTERDAM – Adults with heart failure with preserved ejection fraction (HFpEF) but without diabetes showed significant improvements in their heart failure-related symptoms and physical limitations, exercise function, and weight loss when treated with a weight-reducing dose of semaglutide for 52 weeks, compared with placebo, in the randomized STEP-HFpEF trial.
The results, which also showed the treatment’s safety in these patients, “indicate that treatment with semaglutide is a valuable therapeutic approach in the management of patients with HFpEF and obesity,” Mikhail Kosiborod, MD, said at the annual congress of the European Society of Cardiology.
The findings establish semaglutide, a glucagonlike peptide–1 (GLP-1) receptor agonist, as a second class of medication with proven efficacy and safety for people with HFpEF, joining two agents also proven beneficial for people with HFpEF, dapagliflozin (Farxiga) and empagliflozin (Jardiance), both from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors.
When administered at the approved dose for weight loss of 2.4 mg, injected subcutaneously weekly for 52 weeks, semaglutide (Wegovy) produced an average 7.8-point incremental improvement in patients’ scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated measure of symptoms and functional limitations, compared with controls who received placebo injections, as well as an average incremental weight loss from baseline, compared with placebo, of 10.7%. Both were significant effects, compared with placebo, and clinically meaningful benefits for the study’s two primary endpoints.
Simultaneously with Kosiborod’s report the results also appeared in a report posted online in the New England Journal of Medicine.
A ‘paradigm shift’ for medical weight loss in cardiology
The findings from this study with 529 randomized patients immediately propelled the weight loss formulation of semaglutide into the ranks of agents used to treat and prevent cardiovascular disease events. This evolution in the indications for semaglutide will be driven not only by the STEP-HFpEF results but also by findings from the SELECT trial, which tested the same semaglutide weight-loss dose in people with obesity, established cardiovascular disease, and had positive top-line results for prevention of major cardiovascular adverse events, according to a press release from Novo Nordisk on Aug. 8.
The STEP-HFpEF and SELECT results will trigger “a paradigm shift” for cardiologists, who will now need to consider prescribing a weight-loss medication to many of their patients, agents that until now were not part of the usual pharmacologic toolbox for cardiologists, said Dr. Kosiborod, a cardiologist and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. This shift will require education to bring the clinical cardiology community on board, he added in an interview.
Given that semaglutide administered at this dose already has a Food and Drug Administration–approved indication for weight loss in people with obesity or overweight plus at least one comorbidity, clinicians could immediately start using the treatment in people with obesity and HFpEF, said Dr. Kosiborod and other cardiologists.
Weekly semaglutide injections “could be considered a treatment option right now” for people with obesity and HFpEF, Dr. Kosiborod said during a press briefing.
Other experts agreed, especially because the STEP-HFpEF results confirmed that weight loss treatment with semaglutide was safe in this population.
‘A terrific win for patients’
The new findings are “a terrific win and game changer for patients with HFpEF,” commented Gregg C. Fonarow, MD, professor and cochief of cardiology at the University of California, Los Angeles, who was not involved with the study.
“The magnitude of improvement in the patient-reported health status scores are large and impressive. These data support clinical use of this agent for individuals with HFpEF with a body mass index of 30 kg/m2, patients who already fall within existing indications,” Dr. Fonarow said in an interview.
“Given the improvements in clinical outcomes in the STEP-HFpEF and SELECT trials, cardiologists should be prescribing these medications to eligible patients without conditions,” he added. “The perception of [semaglutide] needs to shift and be viewed as a component of the comprehensive medical therapies provided to individuals with established cardiovascular disease or HFpEF who also have elevated body mass index to improve their clinical outcomes.”
Historically, cardiologists have had a concern that weight loss was potentially harmful in people with heart failure and that obesity was protective, a phenomenon known as the “obesity paradox,” but the STEP-HFpEF data help disprove that notion, commented Nancy K. Sweitzer, MD, PhD, a heart failure specialist and vice chair of clinical research in the department of medicine at Washington University in St. Louis, who also was not involved in the study.
No signal of an obesity paradox
“There’s been a concern in the heart failure community to use weight-loss strategies in people with heart failure because of this, but this evidence provides a lot of confidence that it’s safe to use this weight loss treatment. The results show that patients feel better and lose weight with no signal of harm,” Dr. Sweitzer said in an interview.
The “encouraging findings” for semaglutide in patients with HFpEF “potentially add a much needed extra option for these patients and provide another upstream treatment for patients with signs of this condition plus a high body mass index,” commented Yigal M. Pinto, MD, PhD, in an editorial that accompanied the published report.
“How these findings translate to hard end points remains to be established and will be important in determining the role of GLP-1 agonism,” wrote Dr. Pinto, a professor and heart failure specialist at Amsterdam University Medical Center.
But Dr. Kosiborod said that the improvement seen in the KCCQ score was itself an important benefit for patients. “Heart failure is defined clinically based on symptoms,” he noted, and results in prior studies documented that patients value improvements in symptoms and physical limitations even more than they value “hard endpoints” such as survival.
The new findings, which indicate that two different and expensive classes of medications are now standard of care for many people with HFpEF and obesity – the SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide – also raise concerns over patient access and affordability, as many U.S. insurers have a history of requiring prior authorization, high copays, or coverage denials for these two medical classes.
But Dr. Sweitzer and Dr. Kosiborod both said that the insurance-coverage climate seems, in just the past couple of years or so, to have dramatically improved, although it’s still not ideal.
Prior authorization hoops have decreased
“We still have prior-authorization hoops to jump through, but I expect these will continue to decrease over time as evidence for clinical benefits [from weight loss] continues to accumulate,” said Dr. Sweitzer.
And “the SELECT data mean that cardiologists will need to become comfortable prescribing GLP-1 receptor agonists,” she added.
“It’s not okay for insurers to say we are not going to cover weight loss medications because it’s a cosmetic indication,” said Dr. Kosiborod. “Obesity appears to be very important in the pathogenesis and progression of heart failure, and if patients derive substantial benefit, they should have access to this treatment.”
The improvements in KCCQ score, as well as in several secondary and exploratory endpoints including a significant reduction in C-reactive protein (an indication of a potent anti-inflammatory effect), an average 20 m increase in 6-minute walk distance, a significant average drop in N-terminal pro-brain natriuretic peptide, and a drop in heart failure hospitalizations or urgent heart failure visits (although the trial was not powered to show differences in clinical events), “were the largest benefits in these outcomes we’ve seen,” compared with any other medical intervention in people with HFpEF, he noted.
“About 80% of U.S. patients with HFpEF have obesity or overweight,” Dr. Kosiborod noted. Using semaglutide on these patients “is an issue of access and insurance coverage. My hope is that these and other data will favorably change this.”
A related trial with a similar design, STEP-HFpEF DM, is still in progress and testing the same semaglutide treatment in adults with HFpEF, obesity, and type 2 diabetes, noted Dr. Kosiborod, who is also lead investigator for that study. He said those results will likely become available before the end of 2023.
The study was funded by Novo Nordisk, the company that markets semaglutide (Wegovy). Dr. Kosiborod has been a consultant and adviser to and has received honoraria from Novo Nordisk. He has also been a consultant to numerous other companies, received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, honoraria from AstraZeneca, and is a stockholder in Artera Health and Saghmos Therapeutics. Dr. Fonarow has been a consultant to Abbott, Amgen, AstraZeneca, CHF Solutions, Cytokinetics, Edwards, Janssen, Medtronic, Merck, Novartis, and Regeneron. Dr. Sweitzer reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT THE ESC CONGRESS 2023