Interventional Cardiology & Surgery

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

The American College of Cardiology/American Heart Association have issued a set of data standards for chest pain and acute myocardial infarction to accompany the 2021 guidelines for evaluation and diagnosis of chest pain.

In October 2021, the AHA/ACC issued a joint clinical practice guideline encouraging clinicians to use standardized risk assessments, clinical pathways, and tools to evaluate and communicate with patients who present with chest pain, as reported by this news organization.

The writing group underscored the need to reach a consensus for the definitions of chest pain. The new document standardizes related data elements for consistent reporting on chest pain syndromes.

“This is an appendix to the guidelines and a planned effort to try to harmonize and bring uniformity to the language applied,” writing committee chair H.V. “Skip” Anderson, MD, with UT Health Science Center, Houston, told this news organization.

“You want heart attack to mean the same thing in Miami Beach as in Western Pennsylvania, as in Oregon and Washington and every place in between,” Dr. Anderson explained. “You want everybody to be using the same language, so that’s what these data standards are meant to do.”

In the document, data elements are grouped into three broad categories: chest pain, myocardial injury, and MI.

“We deliberately followed the plans contained in the new guideline and focused on potentially serious cardiovascular causes of chest pain as might be encountered in emergency departments,” the writing group notes in the document.

The terms “typical” and “atypical” as descriptors of chest pain or anginal syndromes are not used in the new document, in line with the 2021 guidance to abandon these terms.

Instead, the new document divides chest pain syndromes into three categories: “cardiac,” “possible cardiac,” and “noncardiac” – again, in keeping with the chest pain guideline.

The document also includes data elements for risk stratification scoring according to several common risk scoring algorithms and for procedure-related myocardial injury and procedure-related MI.

Each year, chest pain sends more than 7 million adults to the emergency department in the United States. Although noncardiac causes of chest pain make up a large majority of these cases, there are several life-threatening causes of chest pain that must be identified and treated promptly.

Distinguishing between serious and nonserious causes of chest pain is an urgent imperative, the writing group says.

Overall, they say this new clinical lexicon and set of data standards should be “broadly applicable” in various settings, including clinical trials and observational studies, patient care, electronic health records (EHRs), quality and performance improvement initiatives, registries, and public reporting programs.

The 2022 ACC/AHA Key Data Elements and Definitions for Chest Pain and Acute Myocardial Infarction was simultaneously published online in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.

It was developed in collaboration with the American College of Emergency Physicians and the Society for Cardiac Angiography and Interventions and endorsed by the Society for Academic Emergency Medicine.

Dr. Anderson noted that “almost all of the guidelines that come out now, certainly in the last few years, have been followed after a certain interval by a set of data standards applicable to the guidelines.”

“It would be really great if it could actually be attached as an appendix, but the nature of the development of these things is such that there will always be a bit of a time lag between the writing group that develops the guidelines and the work group that develops the data standards; you can’t really have them working in parallel at the same time,” Dr. Anderson said in an interview.

This research had no commercial funding. The authors have no relevant disclosures.

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

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

New randomized trial results show no benefit in clinical outcomes from active surveillance using functional testing over usual care among high-risk patients with previous percutaneous coronary intervention (PCI).

At 2 years, there was no difference in a composite outcome of death from any cause, MI, or hospitalization for unstable angina between patients who had routine functional testing at 1 year and patients receiving standard care in the POST-PCI trial.

“Our trial does not support active surveillance with routine functional testing for follow-up strategy in high-risk patients who undergo PCI,” first author Duk-Woo Park, MD, division of cardiology, Asan Medical Center, University of Ulsan, Seoul, South Korea, said in an interview.

The researchers said their results should be interpreted in the context of previous findings from the ISCHEMIA trial that showed no difference in death or ischemic events with an initial invasive versus an initial conservative approach in patients with stable coronary artery disease and moderate to severe ischemia on stress testing.

“Both the ISCHEMIA and POST-PCI trials show the benefits of a ‘less is more’ concept (i.e., if more invasive strategies or testing are performed less frequently, it will result in better patient outcomes),” the authors wrote. Although characteristics of the patients in these trials “were quite different, a more invasive therapeutic approach (in the ISCHEMIA trial) as well as a more aggressive follow-up approach (in the POST-PCI trial) did not provide an additional treatment effect beyond a conservative strategy on the basis of guideline-directed medical therapy.”

Results were presented at the annual congress of the European Society of Cardiology and published online simultaneously in the New England Journal of Medicine.
 

‘Compelling new evidence’

In an editorial accompanying the publication, Jacqueline E. Tamis-Holland, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Morningside Hospital, New York, also agreed that this new result “builds on the findings” from the ISCHEMIA trial. “Collectively, these trials highlight the lack of benefit of routine stress testing in asymptomatic patients.”

Dr. Tamis-Holland pointed out that many of the deaths in this trial occurred before the 1-year stress test, possibly related to stent thrombosis, and therefore would not have been prevented by routine testing at 1 year. And overall, event rates were “quite low, and most likely reflect adherence to guideline recommendations” in the trial. For example, 99% of patients were receiving statins, and 74% of the procedures used intravascular imaging for the PCI procedures, “a much greater proportion of use than most centers in the United States,” she noted.

“The POST-PCI trial provides compelling new evidence for a future class III recommendation for routine surveillance testing after PCI,” Dr. Tamis-Holland concluded “Until then, we must refrain from prescribing surveillance stress testing to our patients after PCI, in the absence of other clinical signs or symptoms suggestive of stent failure.”

Commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, said that for decades it’s been thought that patients who had high-risk PCI needed to be followed more closely for potential future events. 

“And it actually turned out there was no difference in outcomes between the groups,” he said in an interview.

“So, I think it’s a good study – well conducted, good numbers –  that answers the question that routine functional stress testing, even for high-risk PCI patients, is not effective or cost effective or beneficial on a yearly basis,” he said. “I think it will help frame care that patients will just be followed with best medical therapy and then if they have recurrence of symptoms they would be considered for further evaluation, either with stress testing or angiography.”
 

High-risk characteristics

Current guidelines do not advocate the use of routine stress testing after revascularization, the authors wrote in their paper. “However, surveillance with the use of imaging-based stress testing may be considered in high-risk patients at 6 months after a revascularization procedure (class IIb recommendation), and routine imaging-based stress testing may be considered at 1 year after PCI and more than 5 years after CABG [coronary artery bypass graft] (class IIb recommendation).”

But in real-world clinical practice, Dr. Park said, “follow-up strategy for patients who underwent PCI or CABG is still undetermined.” Particularly, “it could be more problematic in high-risk PCI patients with high-risk anatomical or clinical characteristics. Thus, we performed this POST-PCI trial comparing routine stress testing follow-up strategy versus standard-care follow-up strategy in high-risk PCI patients.”

The researchers randomly assigned 1,706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing, including nuclear stress testing, exercise electrocardiography, or stress echocardiography at 1 year, or to standard care alone.

High-risk anatomical features included left main or bifurcation disease; restenotic or long, diffuse lesions; or bypass graft disease. High-risk clinical characteristics included diabetes mellitus, chronic kidney disease, or enzyme-positive acute coronary syndrome.

Mean age of the patients was 64.7 years; 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents.

At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval, 0.61-1.35; P = .62). There were no between-group differences in the components of the primary outcome.

Secondary endpoints included invasive coronary angiography or repeat revascularization. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, −0.01 to 5.99 percentage points), and 8.1% and 5.8% of patients, respectively, had a repeat revascularization procedure (difference, 2.23 percentage points; 95% CI, −0.22 to 4.68 percentage points).

Positive results on stress tests were more common with nuclear imaging than with exercise ECG or stress echocardiography, the authors noted. Subsequent coronary angiography and repeat revascularization were more common in patients with positive results on nuclear stress imaging and exercise ECG than in those with discordant results between nuclear imaging and exercise ECG.

POST-PCI was funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Park reported grants from the Cardiovascular Research Foundation and Daewoong Pharmaceutical Company. Dr. Tamis-Holland reported “other” funding from Pfizer  outside the submitted work. Dr. Wilson reported no relevant disclosures.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Comprehensive image-based cardiovascular screening in men aged 65-74 years did not significantly reduce all-cause mortality in a new Danish study, although there were strong suggestions of benefit in some cardiovascular endpoints in the whole group and also in mortality in those aged younger than 70.

The DANCAVAS study was presented at the annual congress of the European Society of Cardiology, being held in Barcelona. It was also simultaneously published online in The New England Journal of Medicine.

“I do believe there is something in this study,” lead investigator Axel Diederichsen, PhD, Odense University Hospital, Denmark, told this news organization.

“We can decrease all-cause mortality by screening in men younger than 70. That’s amazing, I think. And in the entire group the composite endpoint of all-cause mortality/MI/stroke was significantly reduced by 7%.”

He pointed out that only 63% of the screening group actually attended the tests. “So that 63% had to account for the difference of 100% of the screening group, with an all-cause mortality endpoint. That is very ambitious. But even so, we were very close to meeting the all-cause mortality primary endpoint.”

Dr. Diederichsen believes the data could support such cardiovascular screening in men younger than 70. “In Denmark, I think this would be feasible, and our study suggests it would be cost effective compared to cancer screening,” he said.

Noting that Denmark has a relatively healthy population with good routine care, he added: “In other countries where it can be more difficult to access care or where cardiovascular health is not so good, such a screening program would probably have a greater effect.”

The population-based DANCAVAS trial randomly assigned 46,611 Danish men aged 65-74 years in a 1:2 ratio to undergo screening (invited group) or not to undergo screening (control group) for subclinical cardiovascular disease.

Screening included non-contrast electrocardiography-gated CT to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation; ankle–brachial blood-pressure measurements to detect peripheral artery disease and hypertension; and a blood sample to detect diabetes and hypercholesterolemia. Of the 16,736 men who were invited to the screening group, 10,471 (62.6%) actually attended for the screening.

In intention-to-treat analyses, after a median follow-up of 5.6 years, the primary endpoint (all cause death) had occurred in 2,106 men (12.6%) in the invited group and 3,915 men (13.1%) in the control group (hazard ratio, 0.95; 95% confidence interval, 0.90-1.00; P = .06).

The hazard ratio for stroke in the invited group, compared with the control group, was 0.93 (95% confidence interval, 0.86-0.99); for MI, 0.91 (95% CI, 0.81-1.03); for aortic dissection, 0.95 (95% CI, 0.61-1.49); and for aortic rupture, 0.81 (95% CI, 0.49-1.35).

The post-hoc composite endpoint of all-cause mortality/stroke/MI was reduced by 7%, with a hazard ratio of 0.93 (95% CI, 0.89-0.97).

There were no significant between-group differences in safety outcomes.

Subgroup analysis showed that the primary outcome of all-cause mortality was significantly reduced in men invited to screening who were aged 65-69 years (HR, 0.89; 95% CI, 0.83-0.96), with no effect in men aged 70-74.

Other findings showed that in the group invited to screening, there was a large increase in use of antiplatelet medication (HR, 3.12) and in lipid lowering agents (HR, 2.54) but no difference in use of anticoagulants, antihypertensives, and diabetes drugs or in coronary or aortic revascularization.  

In terms of cost-effectiveness, the total additional health care costs were €207 ($206 U.S.) per person in the invited group, which included the screening, medication, and all physician and hospital visits.

The quality-adjusted life-year (QALY) gained per person was 0.023, with an incremental cost-effectiveness ratio of €9,075 ($9,043) per QALY in the whole cohort and €3,860 ($3,846) in the men aged 65-69.

Dr. Diederichsen said these figures compared favorably to cancer screening, with breast cancer screening having a cost-effectiveness ratio of €22,000 ($21,923) per QALY.

“This study is a step in the right direction,” Dr. Diederichsen said in an interview. But governments will have to decide if they want to spend public money on this type of screening. I would like this to happen. We can make a case for it with this data.”

He said the study had also collected some data on younger men – aged 60-64 – and in a small group of women, which has not been analyzed yet. “We would like to look at this to help us formulate recommendations,” he added.
 

Increased medical therapy

Designated discussant of the study at the ESC session, Harriette Van Spall, MD, McMaster University, Hamilton, Ont., congratulated the DANCAVAS investigators for the trial, which she said was “implemented perfectly.”

“This is the kind of trial that is very difficult to run but comes from a big body of research from this remarkable group,” she commented.

Dr. Van Spall pointed out that it looked likely that any benefits from the screening approach were brought about by increased use of medical therapy alone (antiplatelet and lipid-lowering drugs). She added that the lack of an active screening comparator group made it unclear whether full CT imaging is more effective than active screening for traditional risk factors or assessment of global cardiovascular risk scores, and there was a missed opportunity to screen for and treat cigarette smoking in the intervention group.

“Aspects of the screening such as a full CT could be considered resource-intensive and not feasible in some health care systems. A strength of restricting the abdominal aorta iliac screening to a risk-enriched group – perhaps cigarette smokers – could have conserved additional resources,” she suggested.

Because 37% of the invited group did not attend for screening and at baseline these non-attendees had more comorbidities, this may have caused a bias in the intention to treat analysis toward the control group, thus underestimating the benefit of screening. There is therefore a role for a secondary on-treatment analysis, she noted.

Dr. Van Spall also pointed out that because of the population involved in this study, inferences can only be made to Danish men aged 65-74. 

Noting that cardiovascular disease is relevant to everyone, accounting for 24% of deaths in Danish females and 25% of deaths in Danish males, she asked the investigators to consider eliminating sex-based eligibility criteria in their next big cardiovascular prevention trial.

Susanna Price, MD, Royal Brompton Hospital, London, and cochair of the ESC session at which DANCAVAS was presented, described the study as “really interesting” and useful in planning future screening approaches.

“Although the primary endpoint was neutral, and so the results may not change practice at this time, it should promote a look at different predefined endpoints in a larger population, including both men and women, to see what the best screening interventions would be,” she commented.

“What is interesting is that we are seeing huge amounts of money being spent on acute cardiac patients after having an event, but here we are beginning to shift the focus on how to prevent cardiovascular morbidity and mortality. That is starting to be the trend in cardiovascular medicine.”

Also commenting for this news organization, Dipti Itchhaporia, MD, University of California, Irvine, and immediate past president of the American College of Cardiology, said: “This study is asking the important question of whether comprehensive cardiovascular screening is needed, but I don’t think it has fully given the answer, although there did appear to be some benefit in those under 70.”

Dr. Itchhaporia questioned whether the 5-year follow up was long enough to show the true benefit of screening, and she suggested that a different approach with a longer monitoring period may have been better to detect AFib.

The DANCAVAS study was supported by the Southern Region of Denmark, the Danish Heart Foundation, and the Danish Independent Research Councils.

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

Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

Copyright American Heart Association copyright American Heart Association copyright American Heart Association

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

Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

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

Percutaneous coronary intervention (PCI) with optimal medical therapy (OMT) does not prolong survival or improve ventricular function, compared with OMT alone, in patients with severe ischemic cardiomyopathy, according to results from the REVIVED-BCIS2 trial.

The primary composite outcome of all-cause death or heart failure hospitalization occurred in 37.2% of the PCI group and 38% of the OMT group (hazard ratio, 0.99; P = .96) over a median of 3.4 years follow-up. The treatment effect was consistent across all subgroups.

There were no significant differences in left ventricular ejection fraction (LVEF) at 6 and 12 months.

Quality of life scores favored PCI early on, but there was catch-up over time with medical therapy, and this advantage disappeared by 2 years, principal investigator Divaka Perera, MD, King’s College London, reported at the annual congress of the European Society of Cardiology.

“The takeaway is that we should not be offering PCI to patients who have stable, well-medicated left ventricular dysfunction,” Dr. Perera told this news organization. “But we should still consider revascularization in patients presenting with acute coronary syndromes or who have lots of angina, because they were not included in the trial.”

The study, published simultaneously in the New England Journal of Medicine, provides the first randomized evidence on PCI for ischemic cardiomyopathy.

Revascularization guidelines in the United States make no recommendation for PCI, whereas those in Europe recommend coronary artery bypass grafting (CABG) first for patients with multivessel disease (class 1); they have a class 2a, level of evidence C indication for PCI in select patients. U.S. and European heart failure guidelines also support guideline directed therapy and CABG in select patients with ejection fractions of 35% or less.

This guidance is based on consensus opinion and the STICH trial, in which CABG plus OMT failed to provide a mortality benefit over OMT alone at 5 years but improved survival at 10 years in the extension STICHES study.

“Medical therapy for heart failure works, and this trial’s results are another important reminder of that,” said Eric Velazquez, MD, who led STICH and was invited to comment on the findings.

Mortality will only get better with the use of SGLT2 inhibitors, he noted, which were not included in the trial. Utilization of ACE inhibitors/ARBs/ARNIs and beta-blockers was similar to STICH and excellent in REVIVED. “They did do a better job in utilization of ICD and CRTs than the STICH trial, and I think that needs to be explored further about the impact of those changes.”

Nevertheless, ischemic cardiomyopathy patients have “unacceptably high mortality,” with the observed mortality about 20% at 3 years and about 35% at 5 years, said Dr. Velazquez, with Yale University, New Haven, Conn.

In most heart failure trials, HF hospitalization drives the primary composite endpoint, but the opposite was true here and in STICH, he observed. “You had twice the risk of dying during the 3.4 years than you did of being hospitalized for heart failure, and ... that is [an important] distinction we must realize is evident in our ischemic cardiomyopathy patients.”

The findings will likely not lead to a change in the guidelines, he added. “I think we continue as status quo for now and get more data.”

Despite the lack of randomized evidence, he cautioned that PCI is increasingly performed in patients with ischemic cardiomyopathy, with registry data suggesting nearly 60% of patients received the procedure.

Reached for comment, Clyde Yancy, MD, chief of cardiology and vice dean of diversity & inclusion at Northwestern University Feinberg School of Medicine, Chicago, said, “For now, the current guidelines are correct. Best application of guideline-directed medical and device therapy is the gold standard for heart failure, and that includes heart failure due to ischemic etiologies.

Detailed results

Between August 2013 and March 2020, REVIVED-BCIS2 enrolled 700 patients at 40 U.K. centers who had an LVEF of 35% or less, extensive CAD (defined by a British Cardiovascular Intervention Society myocardial Jeopardy Score [BCIS-JS] of at least 6), and viability in at least four myocardial segments amenable to PCI. Patients were evenly randomly assigned to individually adjusted pharmacologic and device therapy for heart failure alone or with PCI.

The average age was about 70, only 12.3% women, 344 patients had 2-vessel CAD, and 281 had 3-vessel CAD. The mean LVEF was 27% and median BCIS-JS score 10.

During follow-up, which reached 8.5 years in some patients due to the long enrollment, 31.7% of patients in the PCI group and 32.6% patients in the OMT group died from any cause and 14.7% and 15.3%, respectively, were admitted for heart failure.

LVEF improved by 1.8% at 6 months and 2% at 12 months in the PCI group and by 3.4% and 1.1%, respectively, in the OMT group. The mean between-group difference was –1.6% at 6 months and 0.9% at 12 months.

With regard to quality of life, the Kansas City Cardiomyopathy Questionnaire overall summary score favored the PCI group by 6.5 points at 6 months and by 4.5 points at 12 months, but by 24 months the between-group difference was 2.6 points (95% confidence interval, –0.7 to 5.8). Scores on the EuroQol Group 5-Dimensions 5-Level Questionnaire followed a similar pattern.

Unplanned revascularization was more common in the OMT group (HR, 0.27; 95% CI, 0.13-0.53). Acute myocardial infarction rates were similar in the two groups (HR, 1.01, 95% CI, 0.64-1.60), with the PCI group having more periprocedural infarcts and slightly fewer spontaneous infarcts.

Possible reasons for the discordant results between STICH and REVIVED are the threefold excess mortality within 30 days of CABG, whereas no such early hit occurred with PCI, lead investigator Dr. Perera said in an interview. Medical therapy has also evolved over time and REVIVED enrolled a more “real-world” population, with a median age close to 70 years versus 59 in STICH.
 

‘Modest’ degree of CAD?

An accompanying editorial, however, points out that despite considerable ventricular dysfunction, about half the patients in REVIVED had only 2-vessel disease and a median of two lesions treated.

“This relatively modest degree of coronary artery disease seems unusual for patients selected to undergo revascularization with the hope of restoring or normalizing ventricular function,” writes Ajay Kirtane, MD, from Columbia University Irving Medical Center, NewYork-Presbyterian Hospital.

He said more details are needed on completeness of the revascularization, severity of stenosis, physiologic assessment of the lesion and, “most importantly, the correlation of stenosis with previous ischemic or viability testing.”

Asked about the editorial, Dr. Perera agreed that information on the type of revascularization and myocardial viability are important and said they hope to share analyses of the only recently unblinded data at the American College of Cardiology meeting next spring. Importantly, about 71% of viability testing was done by cardiac MR and the rest largely by dobutamine stress echocardiogram.

He disagreed, however, that participants had relatively modest CAD based on the 2- or 3-vessel classification and said the median score on the more granular BCIS-JS was 10, with maximum 12 indicating the entire myocardium is supplied by diseased vessels.

The trial also included almost 100 patients with left main disease, a group not included in previous medical therapy trials, including STICH and ISCHEMIA, Dr. Perera noted. “So, I think it was pretty, pretty severe coronary disease but a cohort that was better treated medically.”

George Dangas, MD, PhD, a professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said the study provides valuable information but also expressed concerns that the chronic heart failure in the trial was much more advanced than the CAD.

Copyright American Heart Association copyright American Heart Association copyright American Heart Association

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