Lipid Disorders

Large-scale scanning of serum proteins offers a potential method for noninvasive screening and monitoring of patients with nonalcoholic steatohepatitis (NASH), the technique’s developers claim.

By scanning for about 5,000 proteins in nearly 3,000 samples from patients enrolled in studies from the Clinical Research Network in NASH (NASH CRN), Rachel Ostroff, PhD, and colleagues from SomaLogic in Boulder, Colo., created four protein models that mimic results of the major pathologic findings in liver tissue biopsy.

“Concurrent positive results from the protein models had performance characteristics of ‘rule-out’ tests for pathologists’ diagnosis of NASH. These tests may assist in new drug development and medical intervention decisions,” they wrote in a late-breaking poster presented at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“There is no single noninvasive method that can accurately and simultaneously capture steatosis, inflammation, hepatocyte ballooning and fibrosis, the four major pathologic components assessed by biopsy. Each of these is relevant to the multiple mechanisms targeted in drug development for NASH,” they wrote.

To see whether large-scale protemoics could serve as an alternative to invasive liver biopsy for use in clinical trials or in longitudinal studies of NASH, they used a modified aptamer proteomics platform to scan for liver-related proteins. Aptamers are olignonucleotide or peptide molecules designed to home in on a specific target.

They scanned for approximately 5,000 proteins in 2,852 serum samples from 638 patients in a NASH CRN natural history cohort, and in patients enrolled in two NASH treatment trials: the PIVENS trial, which is evaluating pioglitazone versus vitamin E and placebo in nondiabetic patients, and the FLINT trial, which is comparing obeticholic acid with placebo. All of the patients in the natural history cohort and half of all patients in the clinical trial cohorts were included in the training sets, with the remaining half included in the validation set.

The accuracy of the models, as measured by the area under the curve (AUC) of receiver operating characteristics in the training and validation sets, respectively, were as follows:

• Fibrosis: AUC 0.92/0.85.
• Steatosis: AUC 0.95/0.79.
• Inflammation: AUC 0.83/0.72.
• Hepatocyte Ballooning: AUC 0.87/0.83.

“A concurrent positive score for steatosis, inflammation and ballooning predicted the biopsy diagnosis of NASH with an accuracy of 73%,” Ostroff and colleagues wrote.

They also found that model scores applied over time showed improvements in symptoms in the patients on active therapies in the clinical trials, compared with patients on placebo.

A specialist in liver pathology and nonalcoholic fatty liver disease who was not involved in the study said in an interview that she finds the results highly promising.
 

Impressive results

Elizabeth M. Brunt, MD, emeritus professor of pathology and immunology at Washington University in St. Louis, was a member of the NASH CRN when SomaLogic first proposed using the groups’ data for this study.

“I was impressed with them then, and I am very impressed with what they’re presenting here, and I can’t say that about all the noninvasive tests,” she said. “I think a lot of noninvasive tests are way over-simplifying what NASH is.”

She acknowledged that, although she spent much of her career performing liver biopsies, “you can’t biopsy every single patients who you suspect of having NASH, or certainly if you want to follow them over time – it’s unrealistic,” she said in an interview.

Although the protein scanning method cannot – and is not intended to – replace a well-conducted biopsy with the interpretation of a skilled pathologist, the proteins the company investigators identified can reflect the dynamic nature of liver disease and the liver’s ability to heal itself with a high degree of accuracy and hold promise for both screening patients and for monitoring responses to therapy, Dr. Brunt said.

The study was sponsored by SomaLogic. The authors are employees of the company. Dr. Brunt had no relevant disclosures.

SOURCE: Ostroff R et al. The Liver Disease Meeting Digital Experience, Abstract LP11

Large-scale scanning of serum proteins offers a potential method for noninvasive screening and monitoring of patients with nonalcoholic steatohepatitis (NASH), the technique’s developers claim.

By scanning for about 5,000 proteins in nearly 3,000 samples from patients enrolled in studies from the Clinical Research Network in NASH (NASH CRN), Rachel Ostroff, PhD, and colleagues from SomaLogic in Boulder, Colo., created four protein models that mimic results of the major pathologic findings in liver tissue biopsy.

“Concurrent positive results from the protein models had performance characteristics of ‘rule-out’ tests for pathologists’ diagnosis of NASH. These tests may assist in new drug development and medical intervention decisions,” they wrote in a late-breaking poster presented at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“There is no single noninvasive method that can accurately and simultaneously capture steatosis, inflammation, hepatocyte ballooning and fibrosis, the four major pathologic components assessed by biopsy. Each of these is relevant to the multiple mechanisms targeted in drug development for NASH,” they wrote.

To see whether large-scale protemoics could serve as an alternative to invasive liver biopsy for use in clinical trials or in longitudinal studies of NASH, they used a modified aptamer proteomics platform to scan for liver-related proteins. Aptamers are olignonucleotide or peptide molecules designed to home in on a specific target.

They scanned for approximately 5,000 proteins in 2,852 serum samples from 638 patients in a NASH CRN natural history cohort, and in patients enrolled in two NASH treatment trials: the PIVENS trial, which is evaluating pioglitazone versus vitamin E and placebo in nondiabetic patients, and the FLINT trial, which is comparing obeticholic acid with placebo. All of the patients in the natural history cohort and half of all patients in the clinical trial cohorts were included in the training sets, with the remaining half included in the validation set.

The accuracy of the models, as measured by the area under the curve (AUC) of receiver operating characteristics in the training and validation sets, respectively, were as follows:

• Fibrosis: AUC 0.92/0.85.
• Steatosis: AUC 0.95/0.79.
• Inflammation: AUC 0.83/0.72.
• Hepatocyte Ballooning: AUC 0.87/0.83.

“A concurrent positive score for steatosis, inflammation and ballooning predicted the biopsy diagnosis of NASH with an accuracy of 73%,” Ostroff and colleagues wrote.

They also found that model scores applied over time showed improvements in symptoms in the patients on active therapies in the clinical trials, compared with patients on placebo.

A specialist in liver pathology and nonalcoholic fatty liver disease who was not involved in the study said in an interview that she finds the results highly promising.
 

Impressive results

Elizabeth M. Brunt, MD, emeritus professor of pathology and immunology at Washington University in St. Louis, was a member of the NASH CRN when SomaLogic first proposed using the groups’ data for this study.

“I was impressed with them then, and I am very impressed with what they’re presenting here, and I can’t say that about all the noninvasive tests,” she said. “I think a lot of noninvasive tests are way over-simplifying what NASH is.”

She acknowledged that, although she spent much of her career performing liver biopsies, “you can’t biopsy every single patients who you suspect of having NASH, or certainly if you want to follow them over time – it’s unrealistic,” she said in an interview.

Although the protein scanning method cannot – and is not intended to – replace a well-conducted biopsy with the interpretation of a skilled pathologist, the proteins the company investigators identified can reflect the dynamic nature of liver disease and the liver’s ability to heal itself with a high degree of accuracy and hold promise for both screening patients and for monitoring responses to therapy, Dr. Brunt said.

The study was sponsored by SomaLogic. The authors are employees of the company. Dr. Brunt had no relevant disclosures.

SOURCE: Ostroff R et al. The Liver Disease Meeting Digital Experience, Abstract LP11

Large-scale scanning of serum proteins offers a potential method for noninvasive screening and monitoring of patients with nonalcoholic steatohepatitis (NASH), the technique’s developers claim.

By scanning for about 5,000 proteins in nearly 3,000 samples from patients enrolled in studies from the Clinical Research Network in NASH (NASH CRN), Rachel Ostroff, PhD, and colleagues from SomaLogic in Boulder, Colo., created four protein models that mimic results of the major pathologic findings in liver tissue biopsy.

“Concurrent positive results from the protein models had performance characteristics of ‘rule-out’ tests for pathologists’ diagnosis of NASH. These tests may assist in new drug development and medical intervention decisions,” they wrote in a late-breaking poster presented at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“There is no single noninvasive method that can accurately and simultaneously capture steatosis, inflammation, hepatocyte ballooning and fibrosis, the four major pathologic components assessed by biopsy. Each of these is relevant to the multiple mechanisms targeted in drug development for NASH,” they wrote.

To see whether large-scale protemoics could serve as an alternative to invasive liver biopsy for use in clinical trials or in longitudinal studies of NASH, they used a modified aptamer proteomics platform to scan for liver-related proteins. Aptamers are olignonucleotide or peptide molecules designed to home in on a specific target.

They scanned for approximately 5,000 proteins in 2,852 serum samples from 638 patients in a NASH CRN natural history cohort, and in patients enrolled in two NASH treatment trials: the PIVENS trial, which is evaluating pioglitazone versus vitamin E and placebo in nondiabetic patients, and the FLINT trial, which is comparing obeticholic acid with placebo. All of the patients in the natural history cohort and half of all patients in the clinical trial cohorts were included in the training sets, with the remaining half included in the validation set.

The accuracy of the models, as measured by the area under the curve (AUC) of receiver operating characteristics in the training and validation sets, respectively, were as follows:

• Fibrosis: AUC 0.92/0.85.
• Steatosis: AUC 0.95/0.79.
• Inflammation: AUC 0.83/0.72.
• Hepatocyte Ballooning: AUC 0.87/0.83.

“A concurrent positive score for steatosis, inflammation and ballooning predicted the biopsy diagnosis of NASH with an accuracy of 73%,” Ostroff and colleagues wrote.

They also found that model scores applied over time showed improvements in symptoms in the patients on active therapies in the clinical trials, compared with patients on placebo.

A specialist in liver pathology and nonalcoholic fatty liver disease who was not involved in the study said in an interview that she finds the results highly promising.
 

Impressive results

Elizabeth M. Brunt, MD, emeritus professor of pathology and immunology at Washington University in St. Louis, was a member of the NASH CRN when SomaLogic first proposed using the groups’ data for this study.

“I was impressed with them then, and I am very impressed with what they’re presenting here, and I can’t say that about all the noninvasive tests,” she said. “I think a lot of noninvasive tests are way over-simplifying what NASH is.”

She acknowledged that, although she spent much of her career performing liver biopsies, “you can’t biopsy every single patients who you suspect of having NASH, or certainly if you want to follow them over time – it’s unrealistic,” she said in an interview.

Although the protein scanning method cannot – and is not intended to – replace a well-conducted biopsy with the interpretation of a skilled pathologist, the proteins the company investigators identified can reflect the dynamic nature of liver disease and the liver’s ability to heal itself with a high degree of accuracy and hold promise for both screening patients and for monitoring responses to therapy, Dr. Brunt said.

The study was sponsored by SomaLogic. The authors are employees of the company. Dr. Brunt had no relevant disclosures.

SOURCE: Ostroff R et al. The Liver Disease Meeting Digital Experience, Abstract LP11

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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

Treatment with evinacumab, an investigational lipid-lowering drug with a novel mechanism of action, safely led to roughly a halving of LDL cholesterol levels in patients with treatment-refractory hypercholesterolemia in a multicenter, phase 2 study of 272 patients treated for 16 weeks.

The study enrolled patients with either heterozygous familial hypercholesterolemia (FH) (72% of patients), or patients with hypercholesterolemia and clinical evidence of atherosclerotic cardiovascular disease who had failed to reached their recommended level of LDL cholesterol by treatment (when tolerated) with a statin, ezetimibe, and a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

Notably, only 8 of the 272 randomized patients entered the study not on treatment with a PCSK9 inhibitor. Despite these background treatments, all enrolled patients were above their goal LDL-cholesterol level, with an average level of 148 mg/dL.

The study’s primary endpoint was the percent change from baseline in LDL cholesterol after 16 weeks compared with placebo among patients treated with subcutaneous drug delivery either weekly or every other week, and among patients treated with intravenous delivery every 4 weeks. Results of the dose-ranging study showed that the highest subcutaneous dosage tested produced a 56% cut in LDL cholesterol, while the highest IV dosage led to a 51% drop, Robert S. Rosenson, MD, said at the virtual scientific sessions of the American Heart Association. Concurrently with his report, the results were published online in the New England Journal of Medicine.

The drug’s safety among 194 patients who received evinacumab was “reassuring,” said Dr. Rosenson, professor of medicine and director of the cardiometabolic disorders unit at Icahn School of Medicine at Mount Sinai in New York. “I see no concerning signals in the safety profile,” he said in an interview, an assessment that other experts shared.

“Safety looks pretty good. I don’t see any major concerns,” said lipidologist and endocrinologist Anne C. Goldberg, MD, professor of medicine at Washington University in St. Louis. The LDL-cholesterol effect shown was “very, very impressive in these hard to treat patients,” added Dr. Goldberg, who was a coinvestigator on the study.

“Nothing stands out” as a safety concern in the new data, agreed Robert H. Eckel, MD, an endocrinologist and lipid specialist at the University of Colorado in Aurora.

Drug’s unique mechanism extends potential benefits

The phase 2 study included dose-ranging assessments of both subcutaneous and intravenous treatment with evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, an enzyme that inhibits two different lipases involved in metabolizing LDL cholesterol and other lipoproteins including triglycerides. When the drug inhibits angiopoietin-like 3, the lipases remain more active and further reduce levels of their target lipoproteins.

“The powerful contribution of this drug is that it works by a pathway independent of the LDL receptor,” said Dr. Rosenson.

By this mechanism evinacumab cut not only LDL cholesterol, but also lowered triglycerides by 53%-62% at the highest dosages, an effect seen as a potential plus. “Prospects are favorable for a drug that not only lowers atherogenic lipoproteins but also lowers triglycerides [TGs]. That’s a distinguishing feature of this treatment,” compared with other agents that lower LDL cholesterol, Dr. Rosenson said. It could make evinacumab especially attractive for treating patients with diabetes, who often have elevated TG levels, he noted. But Dr. Eckel cautioned that a clinical benefit directly linked to TG lowering has not yet been proven.

The drug also cut HDL cholesterol by an average of as much as 31% from baseline, though the consequence of this effect isn’t clear. “I’m not worried about the HDL levels,” said Dr. Goldberg, who noted that changes in HDL cholesterol produced by drug treatment have often not shown discernible effects.

Reaching goals by IV or subcutaneous delivery

Another measure of evinacumab’s efficacy was the percentage of patients who fell below the LDL-cholesterol threshold of 70 mg/dL set by recommendations of the American Heart Association and American College of Cardiology for the highest risk patients, and the less than 55 mg/dL goal set for similar patients by the European Society of Cardiology. Among the subcutaneously-treated patients, 64% achieved the goal of less than 70 mg/dL, and 49% hit the goal of less than 55 mg/dL. Among those who received IV treatment, 71% fell below the 70 mg/dL threshold, and 50% dropped below 55 mg/dL.

The good efficacy shown with subcutaneous dosing is critical, noted Dr. Eckel, as this represents a new dimension for evinacumab that had previously been tested only as an IV agent in patients with homozygous FH (N Engl J Med. 2020 Aug 20;383[8]:711-20).

“Subcutaneous delivery is needed for wide real world use,” Dr. Eckel noted in an interview.

Evinacumab’s role hangs on further studies

The path that evinacumab takes from here into U.S. practice is not yet clear, said Dr. Rosenson. He cited the approval earlier in 2020 of another LDL-lowering drug, bempedoic acid (Nexletol) that received U.S. regulatory approval for a similar patient population after studies that proved only lipid-lowering safety and efficacy, without any clinical-endpoint data. He wondered: “Will the [Food and Drug Administration] require a cardiovascular outcomes trial” for evinacumab?

The growing experience using the PCSK9 inhibitor antibodies to treat hyperlipidemia has made clinicians comfortable with this general approach to lipid management, but if evinacumab never accumulates similar efficacy evidence that may relegate it to the backseat compared with the PCSK9 inhibitors for quite some time, suggested Dr. Goldberg, though she said she’d be willing to prescribe evinacumab to selected patients based on lipid-lowering evidence alone.

By providing an alternative mechanism for lipid lowering, evinacumab can serve as a useful add-on for patients not reaching their LDL-cholesterol goal with more established agents, thereby providing an alternative to LDL apheresis, which now serves as the lipid-lowering therapy of last resort, said both Dr. Rosenson and Dr. Goldberg.

The study was sponsored by Regeneron, the company developing evinacumab. Dr. Rosenson has been a consultant to Regeneron, and has also  been a consultant to or received research funding from Amgen, 89Bio, Corvidia, CVS Caremark, Kowa, Novartis, and The Medicines Company. Dr. Goldberg has received research grants, personal fees, and nonfinancial support from Regeneron and Sanofi, research grants from Amarin, Amgen, Ionis/AKCEA, Novartis, and Pfizer, and personal fees from AKCEA, Esperion, Merck and Novartis. Dr. Eckel has been a consultant to KOWA and Novo Nordisk.

[email protected] 

Treatment with evinacumab, an investigational lipid-lowering drug with a novel mechanism of action, safely led to roughly a halving of LDL cholesterol levels in patients with treatment-refractory hypercholesterolemia in a multicenter, phase 2 study of 272 patients treated for 16 weeks.

The study enrolled patients with either heterozygous familial hypercholesterolemia (FH) (72% of patients), or patients with hypercholesterolemia and clinical evidence of atherosclerotic cardiovascular disease who had failed to reached their recommended level of LDL cholesterol by treatment (when tolerated) with a statin, ezetimibe, and a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

Notably, only 8 of the 272 randomized patients entered the study not on treatment with a PCSK9 inhibitor. Despite these background treatments, all enrolled patients were above their goal LDL-cholesterol level, with an average level of 148 mg/dL.

The study’s primary endpoint was the percent change from baseline in LDL cholesterol after 16 weeks compared with placebo among patients treated with subcutaneous drug delivery either weekly or every other week, and among patients treated with intravenous delivery every 4 weeks. Results of the dose-ranging study showed that the highest subcutaneous dosage tested produced a 56% cut in LDL cholesterol, while the highest IV dosage led to a 51% drop, Robert S. Rosenson, MD, said at the virtual scientific sessions of the American Heart Association. Concurrently with his report, the results were published online in the New England Journal of Medicine.

The drug’s safety among 194 patients who received evinacumab was “reassuring,” said Dr. Rosenson, professor of medicine and director of the cardiometabolic disorders unit at Icahn School of Medicine at Mount Sinai in New York. “I see no concerning signals in the safety profile,” he said in an interview, an assessment that other experts shared.

“Safety looks pretty good. I don’t see any major concerns,” said lipidologist and endocrinologist Anne C. Goldberg, MD, professor of medicine at Washington University in St. Louis. The LDL-cholesterol effect shown was “very, very impressive in these hard to treat patients,” added Dr. Goldberg, who was a coinvestigator on the study.

“Nothing stands out” as a safety concern in the new data, agreed Robert H. Eckel, MD, an endocrinologist and lipid specialist at the University of Colorado in Aurora.

Drug’s unique mechanism extends potential benefits

The phase 2 study included dose-ranging assessments of both subcutaneous and intravenous treatment with evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, an enzyme that inhibits two different lipases involved in metabolizing LDL cholesterol and other lipoproteins including triglycerides. When the drug inhibits angiopoietin-like 3, the lipases remain more active and further reduce levels of their target lipoproteins.

“The powerful contribution of this drug is that it works by a pathway independent of the LDL receptor,” said Dr. Rosenson.

By this mechanism evinacumab cut not only LDL cholesterol, but also lowered triglycerides by 53%-62% at the highest dosages, an effect seen as a potential plus. “Prospects are favorable for a drug that not only lowers atherogenic lipoproteins but also lowers triglycerides [TGs]. That’s a distinguishing feature of this treatment,” compared with other agents that lower LDL cholesterol, Dr. Rosenson said. It could make evinacumab especially attractive for treating patients with diabetes, who often have elevated TG levels, he noted. But Dr. Eckel cautioned that a clinical benefit directly linked to TG lowering has not yet been proven.

The drug also cut HDL cholesterol by an average of as much as 31% from baseline, though the consequence of this effect isn’t clear. “I’m not worried about the HDL levels,” said Dr. Goldberg, who noted that changes in HDL cholesterol produced by drug treatment have often not shown discernible effects.

Reaching goals by IV or subcutaneous delivery

Another measure of evinacumab’s efficacy was the percentage of patients who fell below the LDL-cholesterol threshold of 70 mg/dL set by recommendations of the American Heart Association and American College of Cardiology for the highest risk patients, and the less than 55 mg/dL goal set for similar patients by the European Society of Cardiology. Among the subcutaneously-treated patients, 64% achieved the goal of less than 70 mg/dL, and 49% hit the goal of less than 55 mg/dL. Among those who received IV treatment, 71% fell below the 70 mg/dL threshold, and 50% dropped below 55 mg/dL.

The good efficacy shown with subcutaneous dosing is critical, noted Dr. Eckel, as this represents a new dimension for evinacumab that had previously been tested only as an IV agent in patients with homozygous FH (N Engl J Med. 2020 Aug 20;383[8]:711-20).

“Subcutaneous delivery is needed for wide real world use,” Dr. Eckel noted in an interview.

Evinacumab’s role hangs on further studies

The path that evinacumab takes from here into U.S. practice is not yet clear, said Dr. Rosenson. He cited the approval earlier in 2020 of another LDL-lowering drug, bempedoic acid (Nexletol) that received U.S. regulatory approval for a similar patient population after studies that proved only lipid-lowering safety and efficacy, without any clinical-endpoint data. He wondered: “Will the [Food and Drug Administration] require a cardiovascular outcomes trial” for evinacumab?

The growing experience using the PCSK9 inhibitor antibodies to treat hyperlipidemia has made clinicians comfortable with this general approach to lipid management, but if evinacumab never accumulates similar efficacy evidence that may relegate it to the backseat compared with the PCSK9 inhibitors for quite some time, suggested Dr. Goldberg, though she said she’d be willing to prescribe evinacumab to selected patients based on lipid-lowering evidence alone.

By providing an alternative mechanism for lipid lowering, evinacumab can serve as a useful add-on for patients not reaching their LDL-cholesterol goal with more established agents, thereby providing an alternative to LDL apheresis, which now serves as the lipid-lowering therapy of last resort, said both Dr. Rosenson and Dr. Goldberg.

The study was sponsored by Regeneron, the company developing evinacumab. Dr. Rosenson has been a consultant to Regeneron, and has also  been a consultant to or received research funding from Amgen, 89Bio, Corvidia, CVS Caremark, Kowa, Novartis, and The Medicines Company. Dr. Goldberg has received research grants, personal fees, and nonfinancial support from Regeneron and Sanofi, research grants from Amarin, Amgen, Ionis/AKCEA, Novartis, and Pfizer, and personal fees from AKCEA, Esperion, Merck and Novartis. Dr. Eckel has been a consultant to KOWA and Novo Nordisk.

[email protected] 

Treatment with evinacumab, an investigational lipid-lowering drug with a novel mechanism of action, safely led to roughly a halving of LDL cholesterol levels in patients with treatment-refractory hypercholesterolemia in a multicenter, phase 2 study of 272 patients treated for 16 weeks.

The study enrolled patients with either heterozygous familial hypercholesterolemia (FH) (72% of patients), or patients with hypercholesterolemia and clinical evidence of atherosclerotic cardiovascular disease who had failed to reached their recommended level of LDL cholesterol by treatment (when tolerated) with a statin, ezetimibe, and a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

Notably, only 8 of the 272 randomized patients entered the study not on treatment with a PCSK9 inhibitor. Despite these background treatments, all enrolled patients were above their goal LDL-cholesterol level, with an average level of 148 mg/dL.

The study’s primary endpoint was the percent change from baseline in LDL cholesterol after 16 weeks compared with placebo among patients treated with subcutaneous drug delivery either weekly or every other week, and among patients treated with intravenous delivery every 4 weeks. Results of the dose-ranging study showed that the highest subcutaneous dosage tested produced a 56% cut in LDL cholesterol, while the highest IV dosage led to a 51% drop, Robert S. Rosenson, MD, said at the virtual scientific sessions of the American Heart Association. Concurrently with his report, the results were published online in the New England Journal of Medicine.

The drug’s safety among 194 patients who received evinacumab was “reassuring,” said Dr. Rosenson, professor of medicine and director of the cardiometabolic disorders unit at Icahn School of Medicine at Mount Sinai in New York. “I see no concerning signals in the safety profile,” he said in an interview, an assessment that other experts shared.

“Safety looks pretty good. I don’t see any major concerns,” said lipidologist and endocrinologist Anne C. Goldberg, MD, professor of medicine at Washington University in St. Louis. The LDL-cholesterol effect shown was “very, very impressive in these hard to treat patients,” added Dr. Goldberg, who was a coinvestigator on the study.

“Nothing stands out” as a safety concern in the new data, agreed Robert H. Eckel, MD, an endocrinologist and lipid specialist at the University of Colorado in Aurora.

Drug’s unique mechanism extends potential benefits

The phase 2 study included dose-ranging assessments of both subcutaneous and intravenous treatment with evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, an enzyme that inhibits two different lipases involved in metabolizing LDL cholesterol and other lipoproteins including triglycerides. When the drug inhibits angiopoietin-like 3, the lipases remain more active and further reduce levels of their target lipoproteins.

“The powerful contribution of this drug is that it works by a pathway independent of the LDL receptor,” said Dr. Rosenson.

By this mechanism evinacumab cut not only LDL cholesterol, but also lowered triglycerides by 53%-62% at the highest dosages, an effect seen as a potential plus. “Prospects are favorable for a drug that not only lowers atherogenic lipoproteins but also lowers triglycerides [TGs]. That’s a distinguishing feature of this treatment,” compared with other agents that lower LDL cholesterol, Dr. Rosenson said. It could make evinacumab especially attractive for treating patients with diabetes, who often have elevated TG levels, he noted. But Dr. Eckel cautioned that a clinical benefit directly linked to TG lowering has not yet been proven.

The drug also cut HDL cholesterol by an average of as much as 31% from baseline, though the consequence of this effect isn’t clear. “I’m not worried about the HDL levels,” said Dr. Goldberg, who noted that changes in HDL cholesterol produced by drug treatment have often not shown discernible effects.

Reaching goals by IV or subcutaneous delivery

Another measure of evinacumab’s efficacy was the percentage of patients who fell below the LDL-cholesterol threshold of 70 mg/dL set by recommendations of the American Heart Association and American College of Cardiology for the highest risk patients, and the less than 55 mg/dL goal set for similar patients by the European Society of Cardiology. Among the subcutaneously-treated patients, 64% achieved the goal of less than 70 mg/dL, and 49% hit the goal of less than 55 mg/dL. Among those who received IV treatment, 71% fell below the 70 mg/dL threshold, and 50% dropped below 55 mg/dL.

The good efficacy shown with subcutaneous dosing is critical, noted Dr. Eckel, as this represents a new dimension for evinacumab that had previously been tested only as an IV agent in patients with homozygous FH (N Engl J Med. 2020 Aug 20;383[8]:711-20).

“Subcutaneous delivery is needed for wide real world use,” Dr. Eckel noted in an interview.

Evinacumab’s role hangs on further studies

The path that evinacumab takes from here into U.S. practice is not yet clear, said Dr. Rosenson. He cited the approval earlier in 2020 of another LDL-lowering drug, bempedoic acid (Nexletol) that received U.S. regulatory approval for a similar patient population after studies that proved only lipid-lowering safety and efficacy, without any clinical-endpoint data. He wondered: “Will the [Food and Drug Administration] require a cardiovascular outcomes trial” for evinacumab?

The growing experience using the PCSK9 inhibitor antibodies to treat hyperlipidemia has made clinicians comfortable with this general approach to lipid management, but if evinacumab never accumulates similar efficacy evidence that may relegate it to the backseat compared with the PCSK9 inhibitors for quite some time, suggested Dr. Goldberg, though she said she’d be willing to prescribe evinacumab to selected patients based on lipid-lowering evidence alone.

By providing an alternative mechanism for lipid lowering, evinacumab can serve as a useful add-on for patients not reaching their LDL-cholesterol goal with more established agents, thereby providing an alternative to LDL apheresis, which now serves as the lipid-lowering therapy of last resort, said both Dr. Rosenson and Dr. Goldberg.

The study was sponsored by Regeneron, the company developing evinacumab. Dr. Rosenson has been a consultant to Regeneron, and has also  been a consultant to or received research funding from Amgen, 89Bio, Corvidia, CVS Caremark, Kowa, Novartis, and The Medicines Company. Dr. Goldberg has received research grants, personal fees, and nonfinancial support from Regeneron and Sanofi, research grants from Amarin, Amgen, Ionis/AKCEA, Novartis, and Pfizer, and personal fees from AKCEA, Esperion, Merck and Novartis. Dr. Eckel has been a consultant to KOWA and Novo Nordisk.

[email protected] 

Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.  

Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).

Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions. 

The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up. 

In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks: 

• SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
• Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
• HIV: HR for CHD, 1.38; for MI, 1.69.
• Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
• Psoriasis: no significant increase.
• Inflammatory bowel disease: no significant increase.

In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups. 

In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation. 

These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type. 

But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease. 

“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained. 

Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis. 

In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median. 

A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award. 

He reported having no financial conflicts regarding his study. 

[email protected] 

Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.  

Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).

Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions. 

The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up. 

In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks: 

• SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
• Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
• HIV: HR for CHD, 1.38; for MI, 1.69.
• Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
• Psoriasis: no significant increase.
• Inflammatory bowel disease: no significant increase.

In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups. 

In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation. 

These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type. 

But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease. 

“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained. 

Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis. 

In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median. 

A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award. 

He reported having no financial conflicts regarding his study. 

[email protected] 

Not all chronic systemic inflammatory diseases are equal enhancers of atherosclerotic cardiovascular disease risk, according to a large case-control study.  

Current AHA/American College of Cardiology guidelines cite three chronic inflammatory diseases as atherosclerotic cardiovascular disease risk enhancers: rheumatoid arthritis, psoriasis, and HIV infection. But this study of those three diseases, along with three others marked by elevated high sensitivity C-reactive protein (systemic sclerosis, inflammatory bowel disease, and systemic lupus erythematosus [SLE]), showed that chronic inflammatory diseases are not monolithic in terms of their associated risk of incident coronary heart disease (CHD).

Indeed, two of the six inflammatory diseases – psoriasis and inflammatory bowel disease – turned out to be not at all associated with increased cardiovascular risk in the 37,117-patient study. The highest-risk disease was SLE, not specifically mentioned in the guidelines, Arjun Sinha, MD, a cardiology fellow at Northwestern University, Chicago, noted in his presentation at the virtual American Heart Association scientific sessions. 

The study included 18,129 patients with one of the six chronic inflammatory diseases and 18,988 matched controls, none with CHD at baseline. All regularly received outpatient care at Northwestern during 2000-2019. There were 1,011 incident CHD events during a median of 3.5 years of follow-up. 

In a Cox proportional hazards analysis adjusted for demographics, insurance status, hypertension, diabetes, current smoking, total cholesterol, and estimated glomerular filtration rate, here’s how the chronic inflammatory diseases stacked up in terms of incident CHD and MI risks: 

• SLE: hazard ratio for CHD, 2.85; for MI, 4.76.
• Systemic sclerosis: HR for CHD, 2.14; for MI, 3.19.
• HIV: HR for CHD, 1.38; for MI, 1.69.
• Rheumatoid arthritis: HR for CHD, 1.22; for MI, 1.45.
• Psoriasis: no significant increase.
• Inflammatory bowel disease: no significant increase.

In an exploratory analysis, Dr. Sinha and coinvestigators evaluated the risk of incident CHD stratified by disease severity. For lack of standardized disease severity scales, the investigators relied upon tertiles of CD4 T cell count in the HIV group and CRP in the others. The HR for new-onset CHD in the more than 5,000 patients with psoriasis didn’t vary by CRP tertile. However, there was a nonsignificant trend for greater disease severity, as reflected by CRP tertile, to be associated with increased incident CHD risk in the HIV and inflammatory bowel disease groups. 

In contrast, patients with rheumatoid arthritis or systemic sclerosis who were in the top CRP tertile had a significantly greater risk of developing CHD than that of controls, with HRs of 2.11 in the rheumatoid arthritis group and 4.59 with systemic sclerosis, although patients in the other two tertiles weren’t at significantly increased risk. But all three tertiles of CRP in patients with SLE were associated with significantly increased CHD risk: 3.17-fold in the lowest tertile of lupus severity, 5.38-fold in the middle tertile, and 4.04-fold in the top tertile for inflammation. 

These findings could be used in clinical practice to fine-tune atherosclerotic cardiovascular disease risk assessment based upon chronic inflammatory disease type and severity. That’s information which in turn can help guide the timing and intensity of preventive therapy for patients with each disease type. 

But studying the association between chronic systemic inflammatory diseases and CHD risk can be useful in additional ways, according to Dr. Sinha. These inflammatory diseases can serve as models of atherosclerosis that shed light on the non–lipid-related mechanisms involved in cardiovascular disease. 

“The gradient in risk may be hypothesis-generating with respect to which specific inflammatory pathways may contribute to CHD,” he explained. 

Each of these six chronic inflammatory diseases is characterized by a different form of major immune dysfunction, Dr. Sinha continued. A case in point is SLE, the inflammatory disease associated with the highest risk of CHD and MI. Lupus is characterized by a form of neutrophil dysfunction marked by increased formation and reduced degradation of neutrophil extracellular traps, or NETs, as well as by an increase in autoreactive B cells and dysfunctional CD4+ T helper cells. The increase in NETs of of particular interest because NETs have also been shown to contribute to the development of atherosclerosis, endothelial dysfunction, plaque erosion, and thrombosis. 

In another exploratory analysis, Dr. Sinha and coworkers found that SLE patients with a neutrophil count above the median level were twice as likely to develop CHD than were those with a neutrophil count below the median. 

A better understanding of the upstream pathways linking NET formation in SLE and atherosclerosis could lead to development of new or repurposed medications that target immune dysfunction in order to curb atherosclerosis, said Dr. Sinha, whose study won the AHA’s Samuel A. Levine Early Career Clinical Investigator Award. 

He reported having no financial conflicts regarding his study. 

[email protected] 

Individuals in the general population with high levels of silent coronary atherosclerosis can be successfully identified with a simple questionnaire that they can complete themselves at home, a new study suggests.  

The Swedish CardioPulmonary BioImage Study (SCAPIS) found that 40% of middle-aged adults without known heart disease had evidence of coronary atherosclerosis on coronary CT angiography (CCTA), and 13% had extensive atherosclerotic disease.

The authors found that the screening questionnaire could identify individuals who had extensive coronary atherosclerosis with a reasonably high predictive value.

Initial results from the study were presented today at the virtual American Heart Association (AHA) Scientific Sessions 2020.

“Our study is looking to see if we can estimate how many people in the general population have significant coronary atherosclerosis and therefore could benefit from preventative treatment,” lead author, Göran Bergström, MD, explained to Medscape Medical News. 

Bergström, who is professor and lead physician at Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden, said there are no good data on this as yet. “There are studies of atherosclerosis burden in patients who have had a cardiovascular event, but our study was conducted in a random selection of the middle-aged general population who did not have symptoms of heart disease.”

“Our study also suggests that in future we may be able to identify these people with an online questionnaire, and those that reached a certain score could be referred for an imaging test,” he added.
SCAPIS included more than 30,000 men and women, age 50 to 64 years, who had no history of cardiovascular events or cardiac intervention. They were asked questions about sex, age, lifestyle, smoking, body measurements, cholesterol medication, and blood pressure to predict their risk for coronary artery disease.

Researchers then used CCTA images to examine patients’ arteries for the presence of plaque. More than 25,000 individuals from the original sample were successfully imaged.

Results showed that 40% of the middle-aged population had some coronary atherosclerosis and 5% had severe atherosclerosis, defined as the presence of a stenosis blocking 50% or more of blood flow in one of the coronary arteries.   

A second aim of the study was to use data from the questionnaire to develop a prediction model to identify people with widespread atherosclerosis — those with any type of stenosis in four different segments of their coronary arteries, who made up 13% of the population. 

The questionnaire included data on 120 different variables. Of these variables, around 100 could be assessed by the patients themselves and another 20 measurements could be performed in the clinic, such as blood pressure and cholesterol levels.

The researchers then used artificial intelligence to assess which variables were associated with widespread atherosclerosis. This had an area under the curve (AUC, a measure of the predictive value) of 0.8.  

“An AUC of 1.0 would show a perfect prediction, and a value of 0.5 shows no value. A result of 0.8 shows reasonable predictive potential. This is an encouraging result and suggests this strategy could work,” Bergström said. 

“We know silent atherosclerosis is a big problem and causes sudden cardiac events in people who have not shown symptoms,” he said.

The goal is to identify these patients before they have an event and offer them preventive treatments. “At present we try and identify patients at high risk of cardiovascular events by using cholesterol and blood pressure measurements and cardiovascular risk scores such as Framingham. But this is not so effective,” Bergström explained.

“Using imaging such as CCTA, where you can actually see atherosclerotic plaque, could be better for prediction, but we can’t image everyone. So, we wanted to see whether we could narrow down the population who should receive imaging with a detailed questionnaire, and it looks like we can.”

The study found that including clinical measurements such as blood pressure and cholesterol did not add much to the predictive value for identifying people with extensive coronary atherosclerosis, a result that Bergström said was surprising.   

Which population to target?

Discussant of the study, Pamela Douglas, MD, professor of research in cardiovascular diseases at Duke University, Durham, North Carolina, congratulated the SCAPIS investigators on creating “a very rich data set for current and future study.”

“The SCAPIS study has already yielded novel data on the prevalence of coronary artery disease in the general population, and will address many critical questions over the long term,” she said.
But Douglas suggested that individuals with extensive coronary atherosclerosis were not the most appropriate target population to identify.

“The rationale for choosing this cutpoint is unclear as clinical risk/mortality is higher in all nonobstructive coronary artery disease, starting at one-vessel involvement,” she noted. “Therefore, effective preventive strategies likely need to start with detection and treatment of patients with even minimal plaque.”

Responding to Medscape Medical News, Bergström said this was a valid argument. “We plan to reanalyze our results with different populations as the target — that is something that we can do in the future.

But targeting everyone with just one coronary plaque is going to identify a large group — it was 40% of the population in our study. This will be too many people in whom to perform confirmatory CCTA imaging. It would be impractical to try and conduct cardiac imaging on that many people.”

Bergström noted that more data are needed on the danger of various levels of coronary atherosclerosis in this population who have not had any symptoms. 

“We don’t have this information at present, but we are continuing to follow our population and we will have data on cardiac events in a few years’ time. Then we will know which level of atherosclerosis we need to target. It will probably be somewhere in between the extensive levels we used in this first analysis (which occurred in 13% of people) and the 40% of people who showed just one area of plaque.”

This study is the first report from SCAPIS, a collaborative project between six Swedish universities with the following vision statement: to “reduce the risk of cardiovascular and respiratory diseases for generations to come.”

The SCAPIS project is funded by the Swedish Heart and Lung Foundation. Bergström reports no disclosures. 

This article first appeared on Medscape.com.

Individuals in the general population with high levels of silent coronary atherosclerosis can be successfully identified with a simple questionnaire that they can complete themselves at home, a new study suggests.  

The Swedish CardioPulmonary BioImage Study (SCAPIS) found that 40% of middle-aged adults without known heart disease had evidence of coronary atherosclerosis on coronary CT angiography (CCTA), and 13% had extensive atherosclerotic disease.

The authors found that the screening questionnaire could identify individuals who had extensive coronary atherosclerosis with a reasonably high predictive value.

Initial results from the study were presented today at the virtual American Heart Association (AHA) Scientific Sessions 2020.

“Our study is looking to see if we can estimate how many people in the general population have significant coronary atherosclerosis and therefore could benefit from preventative treatment,” lead author, Göran Bergström, MD, explained to Medscape Medical News. 

Bergström, who is professor and lead physician at Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden, said there are no good data on this as yet. “There are studies of atherosclerosis burden in patients who have had a cardiovascular event, but our study was conducted in a random selection of the middle-aged general population who did not have symptoms of heart disease.”

“Our study also suggests that in future we may be able to identify these people with an online questionnaire, and those that reached a certain score could be referred for an imaging test,” he added.
SCAPIS included more than 30,000 men and women, age 50 to 64 years, who had no history of cardiovascular events or cardiac intervention. They were asked questions about sex, age, lifestyle, smoking, body measurements, cholesterol medication, and blood pressure to predict their risk for coronary artery disease.

Researchers then used CCTA images to examine patients’ arteries for the presence of plaque. More than 25,000 individuals from the original sample were successfully imaged.

Results showed that 40% of the middle-aged population had some coronary atherosclerosis and 5% had severe atherosclerosis, defined as the presence of a stenosis blocking 50% or more of blood flow in one of the coronary arteries.   

A second aim of the study was to use data from the questionnaire to develop a prediction model to identify people with widespread atherosclerosis — those with any type of stenosis in four different segments of their coronary arteries, who made up 13% of the population. 

The questionnaire included data on 120 different variables. Of these variables, around 100 could be assessed by the patients themselves and another 20 measurements could be performed in the clinic, such as blood pressure and cholesterol levels.

The researchers then used artificial intelligence to assess which variables were associated with widespread atherosclerosis. This had an area under the curve (AUC, a measure of the predictive value) of 0.8.  

“An AUC of 1.0 would show a perfect prediction, and a value of 0.5 shows no value. A result of 0.8 shows reasonable predictive potential. This is an encouraging result and suggests this strategy could work,” Bergström said. 

“We know silent atherosclerosis is a big problem and causes sudden cardiac events in people who have not shown symptoms,” he said.

The goal is to identify these patients before they have an event and offer them preventive treatments. “At present we try and identify patients at high risk of cardiovascular events by using cholesterol and blood pressure measurements and cardiovascular risk scores such as Framingham. But this is not so effective,” Bergström explained.

“Using imaging such as CCTA, where you can actually see atherosclerotic plaque, could be better for prediction, but we can’t image everyone. So, we wanted to see whether we could narrow down the population who should receive imaging with a detailed questionnaire, and it looks like we can.”

The study found that including clinical measurements such as blood pressure and cholesterol did not add much to the predictive value for identifying people with extensive coronary atherosclerosis, a result that Bergström said was surprising.   

Which population to target?

Discussant of the study, Pamela Douglas, MD, professor of research in cardiovascular diseases at Duke University, Durham, North Carolina, congratulated the SCAPIS investigators on creating “a very rich data set for current and future study.”

“The SCAPIS study has already yielded novel data on the prevalence of coronary artery disease in the general population, and will address many critical questions over the long term,” she said.
But Douglas suggested that individuals with extensive coronary atherosclerosis were not the most appropriate target population to identify.

“The rationale for choosing this cutpoint is unclear as clinical risk/mortality is higher in all nonobstructive coronary artery disease, starting at one-vessel involvement,” she noted. “Therefore, effective preventive strategies likely need to start with detection and treatment of patients with even minimal plaque.”

Responding to Medscape Medical News, Bergström said this was a valid argument. “We plan to reanalyze our results with different populations as the target — that is something that we can do in the future.

But targeting everyone with just one coronary plaque is going to identify a large group — it was 40% of the population in our study. This will be too many people in whom to perform confirmatory CCTA imaging. It would be impractical to try and conduct cardiac imaging on that many people.”

Bergström noted that more data are needed on the danger of various levels of coronary atherosclerosis in this population who have not had any symptoms. 

“We don’t have this information at present, but we are continuing to follow our population and we will have data on cardiac events in a few years’ time. Then we will know which level of atherosclerosis we need to target. It will probably be somewhere in between the extensive levels we used in this first analysis (which occurred in 13% of people) and the 40% of people who showed just one area of plaque.”

This study is the first report from SCAPIS, a collaborative project between six Swedish universities with the following vision statement: to “reduce the risk of cardiovascular and respiratory diseases for generations to come.”

The SCAPIS project is funded by the Swedish Heart and Lung Foundation. Bergström reports no disclosures. 

This article first appeared on Medscape.com.

Individuals in the general population with high levels of silent coronary atherosclerosis can be successfully identified with a simple questionnaire that they can complete themselves at home, a new study suggests.  

The Swedish CardioPulmonary BioImage Study (SCAPIS) found that 40% of middle-aged adults without known heart disease had evidence of coronary atherosclerosis on coronary CT angiography (CCTA), and 13% had extensive atherosclerotic disease.

The authors found that the screening questionnaire could identify individuals who had extensive coronary atherosclerosis with a reasonably high predictive value.

Initial results from the study were presented today at the virtual American Heart Association (AHA) Scientific Sessions 2020.

“Our study is looking to see if we can estimate how many people in the general population have significant coronary atherosclerosis and therefore could benefit from preventative treatment,” lead author, Göran Bergström, MD, explained to Medscape Medical News. 

Bergström, who is professor and lead physician at Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden, said there are no good data on this as yet. “There are studies of atherosclerosis burden in patients who have had a cardiovascular event, but our study was conducted in a random selection of the middle-aged general population who did not have symptoms of heart disease.”

“Our study also suggests that in future we may be able to identify these people with an online questionnaire, and those that reached a certain score could be referred for an imaging test,” he added.
SCAPIS included more than 30,000 men and women, age 50 to 64 years, who had no history of cardiovascular events or cardiac intervention. They were asked questions about sex, age, lifestyle, smoking, body measurements, cholesterol medication, and blood pressure to predict their risk for coronary artery disease.

Researchers then used CCTA images to examine patients’ arteries for the presence of plaque. More than 25,000 individuals from the original sample were successfully imaged.

Results showed that 40% of the middle-aged population had some coronary atherosclerosis and 5% had severe atherosclerosis, defined as the presence of a stenosis blocking 50% or more of blood flow in one of the coronary arteries.   

A second aim of the study was to use data from the questionnaire to develop a prediction model to identify people with widespread atherosclerosis — those with any type of stenosis in four different segments of their coronary arteries, who made up 13% of the population. 

The questionnaire included data on 120 different variables. Of these variables, around 100 could be assessed by the patients themselves and another 20 measurements could be performed in the clinic, such as blood pressure and cholesterol levels.

The researchers then used artificial intelligence to assess which variables were associated with widespread atherosclerosis. This had an area under the curve (AUC, a measure of the predictive value) of 0.8.  

“An AUC of 1.0 would show a perfect prediction, and a value of 0.5 shows no value. A result of 0.8 shows reasonable predictive potential. This is an encouraging result and suggests this strategy could work,” Bergström said. 

“We know silent atherosclerosis is a big problem and causes sudden cardiac events in people who have not shown symptoms,” he said.

The goal is to identify these patients before they have an event and offer them preventive treatments. “At present we try and identify patients at high risk of cardiovascular events by using cholesterol and blood pressure measurements and cardiovascular risk scores such as Framingham. But this is not so effective,” Bergström explained.

“Using imaging such as CCTA, where you can actually see atherosclerotic plaque, could be better for prediction, but we can’t image everyone. So, we wanted to see whether we could narrow down the population who should receive imaging with a detailed questionnaire, and it looks like we can.”

The study found that including clinical measurements such as blood pressure and cholesterol did not add much to the predictive value for identifying people with extensive coronary atherosclerosis, a result that Bergström said was surprising.   

Which population to target?

Discussant of the study, Pamela Douglas, MD, professor of research in cardiovascular diseases at Duke University, Durham, North Carolina, congratulated the SCAPIS investigators on creating “a very rich data set for current and future study.”

“The SCAPIS study has already yielded novel data on the prevalence of coronary artery disease in the general population, and will address many critical questions over the long term,” she said.
But Douglas suggested that individuals with extensive coronary atherosclerosis were not the most appropriate target population to identify.

“The rationale for choosing this cutpoint is unclear as clinical risk/mortality is higher in all nonobstructive coronary artery disease, starting at one-vessel involvement,” she noted. “Therefore, effective preventive strategies likely need to start with detection and treatment of patients with even minimal plaque.”

Responding to Medscape Medical News, Bergström said this was a valid argument. “We plan to reanalyze our results with different populations as the target — that is something that we can do in the future.

But targeting everyone with just one coronary plaque is going to identify a large group — it was 40% of the population in our study. This will be too many people in whom to perform confirmatory CCTA imaging. It would be impractical to try and conduct cardiac imaging on that many people.”

Bergström noted that more data are needed on the danger of various levels of coronary atherosclerosis in this population who have not had any symptoms. 

“We don’t have this information at present, but we are continuing to follow our population and we will have data on cardiac events in a few years’ time. Then we will know which level of atherosclerosis we need to target. It will probably be somewhere in between the extensive levels we used in this first analysis (which occurred in 13% of people) and the 40% of people who showed just one area of plaque.”

This study is the first report from SCAPIS, a collaborative project between six Swedish universities with the following vision statement: to “reduce the risk of cardiovascular and respiratory diseases for generations to come.”

The SCAPIS project is funded by the Swedish Heart and Lung Foundation. Bergström reports no disclosures. 

This article first appeared on Medscape.com.

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

[email protected]

On Twitter @mitchelzoler

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

[email protected]

On Twitter @mitchelzoler

Omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, safely produced a significant but modest improvement in heart failure events or cardiovascular death in a pivotal trial with HFrEF patients, leaving experts unsure about the role this drug could have on top of an already crowded list of four first-line drug classes for this condition.

“It remains to be investigated and discussed where omecamtiv mecarbil fits in” the overall approach to treating patients with heart failure with reduced ejection fraction (HFrEF), commented Paul Heidenreich, MD, designated discussant for the report at the virtual scientific sessions of the American Heart Association.

Room for a fifth HFrEF drug?

In addition to the limited benefit, another question raised by the trial is how OM would perform when used on top of what is now considered standard, quadruple therapy for most HFrEF patients: a beta-blocker, a mineralocorticoid receptor antagonist, sacubitril-valsartan (Entresto), and an agent from the sodium glucose co-transporter 2 (SGLT2) inhibitor class, specifically dapagliflozin (Farxiga) or empagliflozin (Jardiance). During the period when the new OM trial was run, 2017-2019, the SGLT2 inhibitors had not yet been established as a key part of standard HFrEF treatment, and hence fewer than 3% of enrolled patients were on one of these drugs.

Because of this evidence gap, OM “can’t be across the board a fifth drug on top of standard treatment,” based on the new results, cautioned Dr. Heidenreich, a cardiologist and professor of medicine at Stanford (Calif.) University School of Medicine.

The positives of omecamtiv mercarbil

But in addition to its positive result in the GALACTIC-HF trial, treatment with OM showed other attractive characteristics in a study that treated a wide spectrum of 4,120 patients with HFrEF as well as including 4,112 patients randomized to placebo. Most notably, OM had a very clean safety profile, with adverse event rates similar to placebo patients across all adverse event subtypes, as well as causing no drop in blood pressure and actually an average 2.0–mm Hg increase in systolic blood pressure, no increase in potassium, no apparent impact on renal function, and a small but significant decline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

This coupled with the novel mechanism of action of OM – direct augmentation of cardiac sarcomere function by increasing myosin attachment to actin – suggests that OM can be safely added on top of existing HFrEF treatment to provide an unique and incremental benefit.

“Other heart failure drugs [like beta-blockers and sacubitril-valsartan] lower blood pressure, so what can happen is that clinicians run out of room to add full dosages” when patients’ pressures fall too low, commented Gregory D. Lewis, MD, head of Heart Failure at Massachusetts General Hospital in Boston. He is principle investigator for another OM trial, METEORIC-HF, which is examining the possible impact of the drug on exercise capacity in a randomized study with about 270 HFrEF patients.

If the METEORIC-HF results can could confirm some of the GALACTIC-HF results that suggested improvements in patient function, the combined data could potentially lead to regulatory approval for U.S. marketing of the drug, Dr. Lewis suggested. Results from that study are expected in 2021, he said in an interview.

The GALACTIC-HF results hinted at possible functional improvement after 24 weeks on treatment among patients who required hospitalization as measured by the Kansas City Cardiomyopathy Questionnaire, which measures quality life. However, this difference failed to meet the study’s prespecified definition of a significant effect.

Another intriguing suggestion of focused benefit was in patients with a left ventricular ejection fraction at or below the median in GALACTIC-HF of 28%. In that subgroup, OM treatment was linked with a significant 16% relative reduction in the primary endpoint compared with placebo, while it had no significant effect in the other 50% of patients with higher ejection fractions. (The maximum left ventricular ejection fraction for enrollment was 35%.) This apparent subgroup interaction was statistically significant, reported Dr. Teerlink, a professor of medicine at the University of California, San Francisco, and director of Heart Failure at the San Francisco V.A. Medical Center.

Further analysis of the study data “will provide greater insight into subgroups who may demonstrate greater benefit, such as patients with lower ejection fraction in whom improving cardiac function may have a greater role,” he said. The idea that a drug that improves myocyte function at the molecular level could especially benefit patients with the lowest ejection fractions is “biologically plausible,” Dr. Teerlink said.

This scenario looks reasonable, and could make OM something of a niche drug for at least the near term, said Dr. Mann.

The world’s first myotropic drug

Possibly the most notable aspect of GALACTIC-HF is that it proved the efficacy, modest though it was, of a novel drug mechanism that fulfills a decades-long quest of heart failure researchers: a safe way to improve the heart’s pumping action.

“For years, the heart failure community struggled with treatment to improve cardiac performance, but invariably it ended in disaster by worsening cardiac deaths,” problems that led to abandonment of early inotropic drugs more than a generation ago, noted Dr. Mann.

But a more nuanced approach to inotropic agents recently has emerged from Dr. Teerlink and his associates, built on the premise that the dangers seen years ago related to the calcium modulations they caused. Their new paradigm is that the dangers of these “calcitropic” agents can be sidestepped with different agents that either mediate their effects via myosin, the myotropes like OM, or mitochondrial effects from mitotropic drugs.

The inotrope debacle from the 1990s made that drug-class name “a dirty word that causes fear and loathing in the heart failure community,” observed Dr. Mann. While the term myotrope has not yet really caught on, “If omecamtiv mecarbil starts getting used in routine practice, then I think you’ll start seeing uptake of the term myotrope,” he predicted.

GALACTIC-HF was sponsored by Amgen, Cytokinetics, and Servier, the companies developing omecamtiv mecarbil. Dr. Teerlink has received research support from and been a consultant to Amgen, Cytokinetics, and Servier, as well as Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Merck, and Novartis. Dr. Heidenreich had no disclosures. Dr. Mann is on a steering committee for a trial sponsored by Novartis and has no other commercial disclosures. Dr. Lewis is principal investigator for a trial of omecamtiv mecarbil and has no other commercial disclosures.

[email protected]

On Twitter @mitchelzoler

Both obese and nonobese individuals can develop nonalcoholic fatty liver disease (NAFLD), and lipid profiles were effective predictors in both groups, based on data from a cross-sectional study of 361 individuals.

Nephron/Wikimedia/Creative Commons License

Given the strong association between obesity and NAFLD, previous research on lipidomic profiles have focused on obese White patients, wrote Youngae Jung, MD, of the Korea Basic Science Institute, Seoul, and colleagues.

“However, there are insufficient data on circulating lipidomics of nonobese NAFLD patients,” they added.

In a study published in Alimentary Pharmacology and Therapeutics, the researchers identified 295 adults with NAFLD and 66 controls. Overall, 130 participants were nonobese (body mass index <25 kg/m²) and 231 were obese (BMI, 25 or higher). The nonobese group included 51 patients with NAFL, 31 with nonalcoholic steatohepatitis , and 48 controls; the obese group included 106 patients with NAFL, 107 with NASH, and 18 controls.

Lipid profiles show predictive promise

Overall, changes in diacylglycerol (DAG) and triacylglycerol (TAG) appeared in both obese and nonobese patients with increases from NAFL to NASH, the researchers noted.

“Levels of DAGs with relatively short chains and a low degree of desaturation significantly increased in NAFL versus no NAFLD, regardless of obesity,” the researchers said. “In contrast, levels of DAGs with relatively long chains and a high degree of desaturation significantly decreased in NASH versus NAFL in the obese group, which was not observed in the nonobese group,” they noted.

In addition, saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in nonobese NAFLD patients, but not in obese NAFLD patients, and SM levels were significantly associated with both systemic and adipose tissue insulin resistance.

The researchers identified five potential lipid metabolites for nonobese subjects and seven potential lipids for obese subjects that included DAGs, TAGs, and SMs that were distinct between NAFL and NASH patients in order to predict the histologic severity of NAFLD. Overall, these metabolite combinations were effective predictors of NAFLD/NASH in nonobese and obese patients. The areas under the receiver operator characteristic curve were 0.916 versus 0.813 for NAFLD versus non-NAFLD in nonobese patients, and 0.967 versus 0.812 for NAFLD versus non-NAFLD in the obese patients.
 

More BMI groups may yield more information

The key study limitation was the cross-sectional study design, the researchers noted. In addition, dividing patients into only two groups based on BMI may not reveal any distinct biology among lean NAFLD patients, who were included with overweight patients in the nonobese group.

However, the results were strengthened by the large amount of data and the confirmed diagnoses of NASH and fibrosis by an expert liver pathologist, they added.

“Therefore, our findings provide new insights that aid in the understanding of pathophysiological mechanisms responsible for the development and severity of nonobese NAFLD, which are relevant to precision medicine and personalized therapy based on various phenotypes of NAFLD,” they concluded.
 

Validation needed in other populations

“Liver biopsy remains the gold standard for diagnosing NAFLD/NASH but has its own limitations and risks, so many researchers in this field are looking for a noninvasive alternative to help with diagnosis,” Zachary Henry, MD, of the University of Virginia, Charlottesville, said in an interview. “Imaging methods such as transient elastography and MR-elastography have been introduced and many biochemical markers have been evaluated, yet all have their limitations. In the current study, the authors report a high diagnostic accuracy for evaluating NAFLD using lipidomic profiles, which could introduce a new noninvasive measurement of NAFLD.”

Dr. Henry said that he was not surprised by the study findings. However, “I believe they are important as they define a lipid profile that shows differences between patients with NASH versus patients with NAFLD versus patients without NAFLD,” he said. “NAFLD is a disease of disordered lipid metabolism in hepatocytes, and although it stands to reason there would be differences in lipid profiles, it is interesting to see the changes between DAGs and TAGs especially as disease progresses from NAFLD to NASH.

“Clinically, I do not think this really changes practice right now since it needs to be validated in other populations of NAFLD. However, it certainly adds to a growing armamentarium of noninvasive testing. Hopefully, we are able to combine some of these noninvasive tests in the future to better predict NAFLD and NASH as well as outcomes such as cirrhosis and hepatocellular carcinoma,” he said.

“I think these lipidomic profiles need to be validated in non-Korean populations of patients with NAFLD to determine if these changes are ubiquitous to everyone or if a different profile exists based upon different genetics and environment,” Dr. Henry added. “As the authors note in their paper, there have been previously published differences between populations of NAFLD in Asia as compared to Western countries and it is unclear how, if at all, these lipidomic profiles relate to those differences.”

The study was funded by the Korea Basic Science Institute, the Korea Health Industry Department Institute, and the National Research Foundation of Korea. The researchers had no financial conflicts to disclose. Dr. Henry had no financial conflicts to disclose.

SOURCE: Jung Y et al. Aliment Pharmacol Ther. 2020 Sep 6. doi: 10.1111/apt.16066.

Both obese and nonobese individuals can develop nonalcoholic fatty liver disease (NAFLD), and lipid profiles were effective predictors in both groups, based on data from a cross-sectional study of 361 individuals.

Nephron/Wikimedia/Creative Commons License

Given the strong association between obesity and NAFLD, previous research on lipidomic profiles have focused on obese White patients, wrote Youngae Jung, MD, of the Korea Basic Science Institute, Seoul, and colleagues.

“However, there are insufficient data on circulating lipidomics of nonobese NAFLD patients,” they added.

In a study published in Alimentary Pharmacology and Therapeutics, the researchers identified 295 adults with NAFLD and 66 controls. Overall, 130 participants were nonobese (body mass index <25 kg/m²) and 231 were obese (BMI, 25 or higher). The nonobese group included 51 patients with NAFL, 31 with nonalcoholic steatohepatitis , and 48 controls; the obese group included 106 patients with NAFL, 107 with NASH, and 18 controls.

Lipid profiles show predictive promise

Overall, changes in diacylglycerol (DAG) and triacylglycerol (TAG) appeared in both obese and nonobese patients with increases from NAFL to NASH, the researchers noted.

“Levels of DAGs with relatively short chains and a low degree of desaturation significantly increased in NAFL versus no NAFLD, regardless of obesity,” the researchers said. “In contrast, levels of DAGs with relatively long chains and a high degree of desaturation significantly decreased in NASH versus NAFL in the obese group, which was not observed in the nonobese group,” they noted.

In addition, saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in nonobese NAFLD patients, but not in obese NAFLD patients, and SM levels were significantly associated with both systemic and adipose tissue insulin resistance.

The researchers identified five potential lipid metabolites for nonobese subjects and seven potential lipids for obese subjects that included DAGs, TAGs, and SMs that were distinct between NAFL and NASH patients in order to predict the histologic severity of NAFLD. Overall, these metabolite combinations were effective predictors of NAFLD/NASH in nonobese and obese patients. The areas under the receiver operator characteristic curve were 0.916 versus 0.813 for NAFLD versus non-NAFLD in nonobese patients, and 0.967 versus 0.812 for NAFLD versus non-NAFLD in the obese patients.
 

More BMI groups may yield more information

The key study limitation was the cross-sectional study design, the researchers noted. In addition, dividing patients into only two groups based on BMI may not reveal any distinct biology among lean NAFLD patients, who were included with overweight patients in the nonobese group.

However, the results were strengthened by the large amount of data and the confirmed diagnoses of NASH and fibrosis by an expert liver pathologist, they added.

“Therefore, our findings provide new insights that aid in the understanding of pathophysiological mechanisms responsible for the development and severity of nonobese NAFLD, which are relevant to precision medicine and personalized therapy based on various phenotypes of NAFLD,” they concluded.
 

Validation needed in other populations

“Liver biopsy remains the gold standard for diagnosing NAFLD/NASH but has its own limitations and risks, so many researchers in this field are looking for a noninvasive alternative to help with diagnosis,” Zachary Henry, MD, of the University of Virginia, Charlottesville, said in an interview. “Imaging methods such as transient elastography and MR-elastography have been introduced and many biochemical markers have been evaluated, yet all have their limitations. In the current study, the authors report a high diagnostic accuracy for evaluating NAFLD using lipidomic profiles, which could introduce a new noninvasive measurement of NAFLD.”

Dr. Henry said that he was not surprised by the study findings. However, “I believe they are important as they define a lipid profile that shows differences between patients with NASH versus patients with NAFLD versus patients without NAFLD,” he said. “NAFLD is a disease of disordered lipid metabolism in hepatocytes, and although it stands to reason there would be differences in lipid profiles, it is interesting to see the changes between DAGs and TAGs especially as disease progresses from NAFLD to NASH.

“Clinically, I do not think this really changes practice right now since it needs to be validated in other populations of NAFLD. However, it certainly adds to a growing armamentarium of noninvasive testing. Hopefully, we are able to combine some of these noninvasive tests in the future to better predict NAFLD and NASH as well as outcomes such as cirrhosis and hepatocellular carcinoma,” he said.

“I think these lipidomic profiles need to be validated in non-Korean populations of patients with NAFLD to determine if these changes are ubiquitous to everyone or if a different profile exists based upon different genetics and environment,” Dr. Henry added. “As the authors note in their paper, there have been previously published differences between populations of NAFLD in Asia as compared to Western countries and it is unclear how, if at all, these lipidomic profiles relate to those differences.”

The study was funded by the Korea Basic Science Institute, the Korea Health Industry Department Institute, and the National Research Foundation of Korea. The researchers had no financial conflicts to disclose. Dr. Henry had no financial conflicts to disclose.

SOURCE: Jung Y et al. Aliment Pharmacol Ther. 2020 Sep 6. doi: 10.1111/apt.16066.

Both obese and nonobese individuals can develop nonalcoholic fatty liver disease (NAFLD), and lipid profiles were effective predictors in both groups, based on data from a cross-sectional study of 361 individuals.

Nephron/Wikimedia/Creative Commons License

Given the strong association between obesity and NAFLD, previous research on lipidomic profiles have focused on obese White patients, wrote Youngae Jung, MD, of the Korea Basic Science Institute, Seoul, and colleagues.

“However, there are insufficient data on circulating lipidomics of nonobese NAFLD patients,” they added.

In a study published in Alimentary Pharmacology and Therapeutics, the researchers identified 295 adults with NAFLD and 66 controls. Overall, 130 participants were nonobese (body mass index <25 kg/m²) and 231 were obese (BMI, 25 or higher). The nonobese group included 51 patients with NAFL, 31 with nonalcoholic steatohepatitis , and 48 controls; the obese group included 106 patients with NAFL, 107 with NASH, and 18 controls.

Lipid profiles show predictive promise

Overall, changes in diacylglycerol (DAG) and triacylglycerol (TAG) appeared in both obese and nonobese patients with increases from NAFL to NASH, the researchers noted.

“Levels of DAGs with relatively short chains and a low degree of desaturation significantly increased in NAFL versus no NAFLD, regardless of obesity,” the researchers said. “In contrast, levels of DAGs with relatively long chains and a high degree of desaturation significantly decreased in NASH versus NAFL in the obese group, which was not observed in the nonobese group,” they noted.

In addition, saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in nonobese NAFLD patients, but not in obese NAFLD patients, and SM levels were significantly associated with both systemic and adipose tissue insulin resistance.

The researchers identified five potential lipid metabolites for nonobese subjects and seven potential lipids for obese subjects that included DAGs, TAGs, and SMs that were distinct between NAFL and NASH patients in order to predict the histologic severity of NAFLD. Overall, these metabolite combinations were effective predictors of NAFLD/NASH in nonobese and obese patients. The areas under the receiver operator characteristic curve were 0.916 versus 0.813 for NAFLD versus non-NAFLD in nonobese patients, and 0.967 versus 0.812 for NAFLD versus non-NAFLD in the obese patients.
 

More BMI groups may yield more information

The key study limitation was the cross-sectional study design, the researchers noted. In addition, dividing patients into only two groups based on BMI may not reveal any distinct biology among lean NAFLD patients, who were included with overweight patients in the nonobese group.

However, the results were strengthened by the large amount of data and the confirmed diagnoses of NASH and fibrosis by an expert liver pathologist, they added.

“Therefore, our findings provide new insights that aid in the understanding of pathophysiological mechanisms responsible for the development and severity of nonobese NAFLD, which are relevant to precision medicine and personalized therapy based on various phenotypes of NAFLD,” they concluded.
 

Validation needed in other populations

“Liver biopsy remains the gold standard for diagnosing NAFLD/NASH but has its own limitations and risks, so many researchers in this field are looking for a noninvasive alternative to help with diagnosis,” Zachary Henry, MD, of the University of Virginia, Charlottesville, said in an interview. “Imaging methods such as transient elastography and MR-elastography have been introduced and many biochemical markers have been evaluated, yet all have their limitations. In the current study, the authors report a high diagnostic accuracy for evaluating NAFLD using lipidomic profiles, which could introduce a new noninvasive measurement of NAFLD.”

Dr. Henry said that he was not surprised by the study findings. However, “I believe they are important as they define a lipid profile that shows differences between patients with NASH versus patients with NAFLD versus patients without NAFLD,” he said. “NAFLD is a disease of disordered lipid metabolism in hepatocytes, and although it stands to reason there would be differences in lipid profiles, it is interesting to see the changes between DAGs and TAGs especially as disease progresses from NAFLD to NASH.

“Clinically, I do not think this really changes practice right now since it needs to be validated in other populations of NAFLD. However, it certainly adds to a growing armamentarium of noninvasive testing. Hopefully, we are able to combine some of these noninvasive tests in the future to better predict NAFLD and NASH as well as outcomes such as cirrhosis and hepatocellular carcinoma,” he said.

“I think these lipidomic profiles need to be validated in non-Korean populations of patients with NAFLD to determine if these changes are ubiquitous to everyone or if a different profile exists based upon different genetics and environment,” Dr. Henry added. “As the authors note in their paper, there have been previously published differences between populations of NAFLD in Asia as compared to Western countries and it is unclear how, if at all, these lipidomic profiles relate to those differences.”

The study was funded by the Korea Basic Science Institute, the Korea Health Industry Department Institute, and the National Research Foundation of Korea. The researchers had no financial conflicts to disclose. Dr. Henry had no financial conflicts to disclose.

SOURCE: Jung Y et al. Aliment Pharmacol Ther. 2020 Sep 6. doi: 10.1111/apt.16066.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

Dietary patterns with higher inflammatory potential were significantly associated with a higher incidence of cardiovascular disease (CVD) and stroke in a new pooled analysis of three prospective cohort studies.

The analysis included 210,145 U.S. women and men followed for up to 32 years in the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study.

After adjustment for use of anti-inflammatory medications and CVD risk factors, those whose dietary pattern ranked in the highest quintile of inflammatory potential had a 38% higher risk of CVD (hazard ratio comparing highest with lowest quintiles, 1.38), a 46% higher risk of coronary heart disease (HR, 1.46), and a 28% higher risk of stroke (HR, 1.28) (all P for trend < .001).

Jun Li, MD, PhD, and colleagues at Harvard School of Public Health and Harvard Medical School, Boston, published the findings of their study in the Nov. 10 issue of the Journal of the American College of Cardiology.

The inflammatory potential of a diet was assessed using a food-based, dietary index called the “empirical dietary inflammatory pattern” or EDIP.

In an interview, Dr. Li explained that the EDIP was developed 4 years ago by many of the same authors involved with this study, including nutrition heavyweights Walter C. Willett, MD, DrPH, and Frank B. Hu, MD, PhD, both from Harvard.

“We summarized all the foods people eat into 39 defined food groups and did a reduced-rank regression analysis that looked at these 39 food groups and three inflammatory markers – interleukin-6, C-reactive protein, and tumor necrosis factor–alpha receptor 2. We found 18 food groups that are most predictive of these biomarkers, and the EDIP was calculated as the weighted sum of these 18 food groups.”

Individuals who had higher intakes of green-leafy vegetables (kale, spinach, arugula), dark-yellow vegetables (pumpkin, yellow peppers, carrots), whole grains, fruits, tea, coffee and wine had lower long-term CVD risk than those with higher intakes of red meat, processed meat, organ meat, refined carbohydrates, and sweetened beverages. 

The associations were consistent across cohorts and between sexes and remained significant in multiple sensitivity analysis that adjusted for alcohol consumption, smoking pack-years, use of lipid-lowering and antihypertensive medications, sodium intake, and blood pressure.

In a secondary analysis, diets with higher inflammatory potential were also associated with significantly higher biomarker levels indicative of more systemic, vascular, and metabolic inflammation, as well as less favorable lipid profiles.

“We wanted to be able to provide guidance on dietary patterns and food combinations,” said Dr. Li. “If you tell people to eat more polyunsaturated fats instead of saturated fat or trans fat, most people don’t know what foods are higher and lower in those nutrients. Also, many foods have different nutrients – some of which are good and some of which are bad – so we wanted to help people find the foods with the higher proportion of healthy nutrients rather than point out specific nutrients to avoid.”

Researchers used prospectively gathered data from the Nurses’ Health Studies I and II starting from 1984 and from the Health Professionals Follow-up Study. After excluding participants with missing diet information or previously diagnosed heart disease, stroke or cancer, over 210,000 participants were included in the analysis. Participants completed a survey every 4 years to ascertain dietary intake. 
 

Prevention, not treatment

In an editorial comment, Ramon Estruch, MD, PhD, from the Hospital Clinic in Barcelona, and colleagues suggested that it might be time for better dietary guidelines.

“A better knowledge of health protection provided by different foods and dietary patterns, mainly their anti-inflammatory properties, should provide the basis for designing even healthier dietary patterns to protect against heart disease,” the editorialists wrote.

They added extra-virgin olive oil, fatty fish, and tomatoes to the list of foods with “established anti-inflammatory activity.”

In a comment, Dr. Estruch said the findings of this new study are confirmatory of the PREDIMED trial, which showed a reduction in risk of major CV events in individuals at high cardiovascular risk assigned to an anti-inflammatory Mediterranean diet pattern supplemented with extra-virgin olive oil or nuts as compared with those assigned to a reduced-fat diet. 

“The study of Jun Li et al. confirms that an anti-inflammatory diet is useful to prevent cardiovascular events and, more important, that healthy dietary patterns may be even healthier if subjects increase consumption of foods with the highest anti-inflammatory potential,” he said, adding that “mechanistic explanations add plausibility to the results of observational studies.”

Dr. Estruch was the principal investigator of PREDIMED. This trial was originally published in 2013 and then retracted and republished in 2018, with some required corrections, but the results had not materially changed.

Dr. Li is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Boston Nutrition Obesity Research Center. Dr. Estruch disclosed no financial relationships relevant to the contents of this article.  

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

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.