MDedge Cardiology

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.
 

The Moderna mRNA-1273 vaccine, in development to prevent COVID-19, yielded 94.5% efficacy in early results and is generally well tolerated, the company announced early Monday. The product can be stored at refrigeration temperatures common to many physician offices, pharmacies, and hospitals.

The first interim results of the phase 3 COVE trial included 95 participants with confirmed COVID-19. An independent data safety monitoring board, which was appointed by the National Institutes of Health, informed Moderna that 90 of the patients who were positive for COVID-19 were in a placebo group and that 5 patients were in the mRNA-1273 vaccine group, resulting in a vaccine efficacy of 94.5% (P < .0001).

Interim data included 11 patients with severe COVID-19, all of whom were in the placebo group.

“This positive interim analysis from our phase 3 study has given us the first clinical validation that our vaccine can prevent COVID-19 disease, including severe disease,” said Stéphane Bancel, CEO of Moderna, said in a statement.

The vaccine met its primary study endpoint, which was based on adjudicated data that were collected starting 2 weeks after the second dose of mRNA-1273. The interim study population included people who could be at higher risk for COVID-19, including 15 adults aged 65 years and older and 20 participants from diverse communities.
 

Safety data

The DSMB also reviewed safety data for the COVE study interim results. The vaccine was generally safe and well tolerated, as determined on the basis of solicited adverse events. Most adverse events were mild to moderate and were generally short-lived, according to a company news release.

Injection-site pain was reported in 2.7% of participants after the first dose. After the second dose, 9.7% of participants reported fatigue, 8.9% reported myalgia, 5.2% reported arthralgia, 4.5% reported headache, 4.1% reported pain, and 2.0% reported erythema or redness at the injection site.

Moderna plans to request emergency-use authorization (EUA) from the Food and Drug Administration in the coming weeks. The company expects that the EUA will be based on more data from the COVE study, including a final analysis of 151 patients with a median follow-up of more than 2 months. Moderna also plans to seek authorizations from global regulatory agencies.

The company expects to have approximately 20 million doses of mRNA-1273 ready to ship in the United States by the end of the year. In addition, the company says it remains on track to manufacture between 500 million and 1 billion doses globally in 2021.

Moderna is developing distribution plans in conjunction with the Centers for Disease Control and Prevention, the federal government’s Operation Warp Speed, and McKesson, a COVID-19 vaccine distributor contracted by the U.S. government.
 

Refrigeration requirements

The mRNA-1273 vaccine can be shipped and stored for up to 6 months at –20° C (about –4° F), a temperature maintained in most home or medical freezers, according to Moderna. The company expects that, after the product thaws, it will remain stable at standard refrigerator temperatures of 2°-8° C (36°-46° F) for up to 30 days within the 6-month shelf life.

Because the mRNA-1273 vaccine is stable at these refrigerator temperatures, it can be stored at most physicians’ offices, pharmacies, and hospitals, the company noted. In contrast, the similar Pfizer BTN162b2 vaccine – early results for which showed a 90% efficacy rate – requires shipment and storage at “deep-freeze” conditions of –70° C or –80° C, which is more challenging from a logistic point of view.

Moderna’s mRNA-1273 can be kept at room temperature for up to 12 hours after removal from a refrigerator for patient administration. The vaccine will not require dilution prior to use.

More than 30,000 people aged older than 18 years in the United States are enrolled in the COVE study. The research is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority, part of the Office of the Assistant Secretary for Preparedness and Response at the Department of Health & Human Services.

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

The Moderna mRNA-1273 vaccine, in development to prevent COVID-19, yielded 94.5% efficacy in early results and is generally well tolerated, the company announced early Monday. The product can be stored at refrigeration temperatures common to many physician offices, pharmacies, and hospitals.

The first interim results of the phase 3 COVE trial included 95 participants with confirmed COVID-19. An independent data safety monitoring board, which was appointed by the National Institutes of Health, informed Moderna that 90 of the patients who were positive for COVID-19 were in a placebo group and that 5 patients were in the mRNA-1273 vaccine group, resulting in a vaccine efficacy of 94.5% (P < .0001).

Interim data included 11 patients with severe COVID-19, all of whom were in the placebo group.

“This positive interim analysis from our phase 3 study has given us the first clinical validation that our vaccine can prevent COVID-19 disease, including severe disease,” said Stéphane Bancel, CEO of Moderna, said in a statement.

The vaccine met its primary study endpoint, which was based on adjudicated data that were collected starting 2 weeks after the second dose of mRNA-1273. The interim study population included people who could be at higher risk for COVID-19, including 15 adults aged 65 years and older and 20 participants from diverse communities.
 

Safety data

The DSMB also reviewed safety data for the COVE study interim results. The vaccine was generally safe and well tolerated, as determined on the basis of solicited adverse events. Most adverse events were mild to moderate and were generally short-lived, according to a company news release.

Injection-site pain was reported in 2.7% of participants after the first dose. After the second dose, 9.7% of participants reported fatigue, 8.9% reported myalgia, 5.2% reported arthralgia, 4.5% reported headache, 4.1% reported pain, and 2.0% reported erythema or redness at the injection site.

Moderna plans to request emergency-use authorization (EUA) from the Food and Drug Administration in the coming weeks. The company expects that the EUA will be based on more data from the COVE study, including a final analysis of 151 patients with a median follow-up of more than 2 months. Moderna also plans to seek authorizations from global regulatory agencies.

The company expects to have approximately 20 million doses of mRNA-1273 ready to ship in the United States by the end of the year. In addition, the company says it remains on track to manufacture between 500 million and 1 billion doses globally in 2021.

Moderna is developing distribution plans in conjunction with the Centers for Disease Control and Prevention, the federal government’s Operation Warp Speed, and McKesson, a COVID-19 vaccine distributor contracted by the U.S. government.
 

Refrigeration requirements

The mRNA-1273 vaccine can be shipped and stored for up to 6 months at –20° C (about –4° F), a temperature maintained in most home or medical freezers, according to Moderna. The company expects that, after the product thaws, it will remain stable at standard refrigerator temperatures of 2°-8° C (36°-46° F) for up to 30 days within the 6-month shelf life.

Because the mRNA-1273 vaccine is stable at these refrigerator temperatures, it can be stored at most physicians’ offices, pharmacies, and hospitals, the company noted. In contrast, the similar Pfizer BTN162b2 vaccine – early results for which showed a 90% efficacy rate – requires shipment and storage at “deep-freeze” conditions of –70° C or –80° C, which is more challenging from a logistic point of view.

Moderna’s mRNA-1273 can be kept at room temperature for up to 12 hours after removal from a refrigerator for patient administration. The vaccine will not require dilution prior to use.

More than 30,000 people aged older than 18 years in the United States are enrolled in the COVE study. The research is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority, part of the Office of the Assistant Secretary for Preparedness and Response at the Department of Health & Human Services.

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

The Moderna mRNA-1273 vaccine, in development to prevent COVID-19, yielded 94.5% efficacy in early results and is generally well tolerated, the company announced early Monday. The product can be stored at refrigeration temperatures common to many physician offices, pharmacies, and hospitals.

The first interim results of the phase 3 COVE trial included 95 participants with confirmed COVID-19. An independent data safety monitoring board, which was appointed by the National Institutes of Health, informed Moderna that 90 of the patients who were positive for COVID-19 were in a placebo group and that 5 patients were in the mRNA-1273 vaccine group, resulting in a vaccine efficacy of 94.5% (P < .0001).

Interim data included 11 patients with severe COVID-19, all of whom were in the placebo group.

“This positive interim analysis from our phase 3 study has given us the first clinical validation that our vaccine can prevent COVID-19 disease, including severe disease,” said Stéphane Bancel, CEO of Moderna, said in a statement.

The vaccine met its primary study endpoint, which was based on adjudicated data that were collected starting 2 weeks after the second dose of mRNA-1273. The interim study population included people who could be at higher risk for COVID-19, including 15 adults aged 65 years and older and 20 participants from diverse communities.
 

Safety data

The DSMB also reviewed safety data for the COVE study interim results. The vaccine was generally safe and well tolerated, as determined on the basis of solicited adverse events. Most adverse events were mild to moderate and were generally short-lived, according to a company news release.

Injection-site pain was reported in 2.7% of participants after the first dose. After the second dose, 9.7% of participants reported fatigue, 8.9% reported myalgia, 5.2% reported arthralgia, 4.5% reported headache, 4.1% reported pain, and 2.0% reported erythema or redness at the injection site.

Moderna plans to request emergency-use authorization (EUA) from the Food and Drug Administration in the coming weeks. The company expects that the EUA will be based on more data from the COVE study, including a final analysis of 151 patients with a median follow-up of more than 2 months. Moderna also plans to seek authorizations from global regulatory agencies.

The company expects to have approximately 20 million doses of mRNA-1273 ready to ship in the United States by the end of the year. In addition, the company says it remains on track to manufacture between 500 million and 1 billion doses globally in 2021.

Moderna is developing distribution plans in conjunction with the Centers for Disease Control and Prevention, the federal government’s Operation Warp Speed, and McKesson, a COVID-19 vaccine distributor contracted by the U.S. government.
 

Refrigeration requirements

The mRNA-1273 vaccine can be shipped and stored for up to 6 months at –20° C (about –4° F), a temperature maintained in most home or medical freezers, according to Moderna. The company expects that, after the product thaws, it will remain stable at standard refrigerator temperatures of 2°-8° C (36°-46° F) for up to 30 days within the 6-month shelf life.

Because the mRNA-1273 vaccine is stable at these refrigerator temperatures, it can be stored at most physicians’ offices, pharmacies, and hospitals, the company noted. In contrast, the similar Pfizer BTN162b2 vaccine – early results for which showed a 90% efficacy rate – requires shipment and storage at “deep-freeze” conditions of –70° C or –80° C, which is more challenging from a logistic point of view.

Moderna’s mRNA-1273 can be kept at room temperature for up to 12 hours after removal from a refrigerator for patient administration. The vaccine will not require dilution prior to use.

More than 30,000 people aged older than 18 years in the United States are enrolled in the COVE study. The research is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority, part of the Office of the Assistant Secretary for Preparedness and Response at the Department of Health & Human Services.

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

Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.

The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).

It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.

Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.

These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.

“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.

The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.  

Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.

The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.

“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.

Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”

Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.

“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.

A “manufactured controversy”

The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”

In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”

Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.

Dr. Lincoff outlined other possible explanations for the difference between the two trials. 

He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”   

There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”  

Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.  

STRENGTH trial

The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.

They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.

The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment. 

At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).

A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69). 
 

Uncertainty prevails

The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.

“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.    

Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.

“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”  

In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.

“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.

“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”

The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.

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

Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.

The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).

It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.

Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.

These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.

“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.

The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.  

Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.

The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.

“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.

Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”

Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.

“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.

A “manufactured controversy”

The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”

In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”

Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.

Dr. Lincoff outlined other possible explanations for the difference between the two trials. 

He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”   

There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”  

Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.  

STRENGTH trial

The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.

They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.

The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment. 

At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).

A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69). 
 

Uncertainty prevails

The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.

“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.    

Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.

“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”  

In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.

“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.

“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”

The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.

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

Questions about the cardiovascular benefit of omega-3 fatty acids and the high-dose eicosapentaenoic acid (EPA) product, icosapent ethyl (Vascepa, Amarin), have resurfaced with the presentation and publication of the STRENGTH trial using a combined high-dose omega-3 fatty acid product.

The STRENGTH trial showed no benefit on cardiovascular event rates of a high-dose combination of EPA and docosahexaenoic acid (DHA) in a new branded product (Epanova, AstraZeneca).

It was announced in January that the trial was being stopped because of a low likelihood of showing any benefit.

Full results were presented Nov. 15 at the virtual American Heart Association scientific sessions and simultaneously published online in JAMA.

These results showed similar cardiovascular event rates with the high-dose EPA/DHA product and placebo, with a hazard ratio for the primary endpoint of 0.99. In addition to no benefit, more adverse effects occurred in the active treatment arm, with a higher rate of gastrointestinal adverse events and atrial fibrillation.

“We found no benefit of a high-dose combination of EPA and DHA. Despite a 270% to 300% increase in EPA, the hazard curves for the active and placebo groups were superimposable,” STRENGTH investigator A. Michael Lincoff, MD, of the Cleveland Clinic, said at the AHA meeting.

The big question is how the negative results of the STRENGTH trial can be reconciled with the very positive results of the REDUCE-IT trial, which showed an impressive 25% relative risk reduction in major adverse cardiovascular events with the high-dose purified EPA product, icosapent ethyl.  

Dr. Lincoff proposed several possible explanations for the different results between these two trials, although he cautioned that all explanations were speculative.

The one explanation that Dr. Lincoff highlighted in particular was the different placebos used in the two trials. REDUCE-IT used a placebo of mineral oil, which Dr. Lincoff noted increases LDL, apolipoprotein B, and high-sensitivity C-reactive protein, whereas the corn oil placebo used in STRENGTH “is truly neutral on a broad range lipid and cardiovascular biomarkers,” he said.

“It must therefore be considered that at least part of the benefit in REDUCE-IT is due to an increase in adverse cardiovascular event rate in the control arm, and our results from STRENGTH cast uncertainly on the net benefit or harm of any omega-3 fatty acid preparation,” Dr. Lincoff said.

Asked whether he used omega-3 fatty acids in his practice, Dr. Lincoff replied, “Aside from patients with triglycerides greater than 500 – for which there is other evidence of benefit – I do not routinely prescribe omega-3 fatty acids. For the reasons discussed, I think there are questions about whether the risks and benefits have a favorable ratio.”

Asked at an AHA press conference what advice he would give to other physicians on the use of Vascepa, Dr. Lincoff said, “On the one hand, we could take the REDUCE-IT study results at face value, but there are potential concerns on the construct of that trial and whether the effects were exaggerated. That having been said, the [Food and Drug Administration] has approved that initial indication, so this is not a straightforward issue of whether or not that trial result is valid.

“What I would like to see is a trial in future with a clearly neutral comparator. It’s hard to recommend taking your patients off Vascepa now, but I have a high threshold at this point to start patients on it because of these concerns,” he added.

A “manufactured controversy”

The lead investigator of the REDUCE-IT trial, Deepak L. Bhatt, MD, professor of medicine, Harvard Medical School, Boston, described Dr. Lincoff’s comments as “absurd.”

In an interview, he said the Japanese JELIS trial, while having some limitations, also showed a benefit of icosapent ethyl, which “in the context of this manufactured controversy about the mineral oil placebo in REDUCE-IT, completely rebuts concerns about the placebo in REDUCE-IT being toxic.”

Dr. Bhatt also suggested that DHA may counter some of the benefits of EPA. “It appears that the STRENGTH trial leadership is trying to stir up controversy, rather than just reporting objectively that they have a negative trial,” he added.

Dr. Lincoff outlined other possible explanations for the difference between the two trials. 

He noted that icosapent ethyl increased levels of EPA by 45% in REDUCE-IT more than did the combined product used in STRENGTH. “But this moderate difference seems insufficient to account for the markedly different results of the two trials,” Dr. Lincoff added, “and both trials showed a 19% reduction in triglycerides, suggesting they have similar biochemical effects.”   

There is also the possibility of an adverse effect of DHA, he noted, “but this has never been seen in previous studies.”  

Another explanation could be differences in trial populations, with REDUCE-IT including more patients with established cardiovascular disease. “But the results were no different in this group compared to the patients without established cardiovascular disease, so this explanation is unlikely,” Dr. Lincoff suggested.  

STRENGTH trial

The STRENGTH trial included 13,078 statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL cholesterol from 22 countries.

They were randomly assigned to a 4 g per day of carboxylic acid formulation of EPA and DHA or to corn oil as an inert comparator.

The trial was halted when 1,384 patients had experienced a primary endpoint event (of a planned 1,600 events), based on an interim analysis that indicated a low probability of clinical benefit of the active treatment. 

At this point, the primary efficacy endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization – occurred in 12.0% of patients treated with the omega-3 product vs. 12.2% of those who received corn oil (hazard ratio [HR], 0.99; P = .84).

A greater rate of gastrointestinal adverse events was observed in the omega-3 group (24.7%) than in corn oil–treated patients (14.7%). An increased rate of new-onset atrial fibrillation was also observed in the omega-3 group (2.2% vs 1.3%; HR, 1.69). 
 

Uncertainty prevails

The moderator of an AHA press conference at which the STRENGTH trial was discussed, Amit Khera, MD, professor of medicine and director of preventive cardiology at UT Southwestern Medical Center, Dallas, said in an interview that questions about how Vascepa brought about the benefits shown in REDUCE-IT have been ongoing since that trial was published.

“I think for now, we have to accept the REDUCE-IT results as a positive finding. However, the STRENGTH trial did amplify these questions a bit since there was no signal at all for benefit, and this heightens the call for additional trials of high-dose EPA formulations, including icosapent ethyl, versus corn oil or another neutral comparator,” he said.    

Discussant of the STRENGTH trial at the AHA late-breaker session, Alberico Catapano, MD, PhD, University of Milan, noted that DHA may have less biological activity than EPA.

“We don’t know for certain, but there are studies suggesting that EPA may have more effect on stabilizing plaque membranes,” Dr. Catapano said. “Certainly, the dose of EPA was different in the two studies, and in my view this could be part of the explanation. But we are still in place where we need more evidence.”  

In an editorial accompanying the JAMA publication of STRENGTH, Garima Sharma, MD, Seth S. Martin, MD, and Roger S. Blumenthal, MD, Johns Hopkins University, Baltimore, said the trial’s findings “may invigorate further investigation regarding IPE [icosapent ethyl], generate additional constructive debate around the optimal placebo control, and should prompt reconsideration of over-the-counter mixed omega-3 fatty acid products for ASCVD [atherosclerotic cardiovascular disease] prevention.

“This latter point is especially important given the lack of evidence for benefit, and the potential for harm due to increased AF [atrial fibrillation],” they noted.

“The reasons the findings from the REDUCE-IT trial were positive and the STRENGTH trial were not, and that EPA levels correlated with outcomes in REDUCE-IT but did not in STRENGTH, remain uncertain,” they concluded. “The importance of the specific omega-3 formulation in achieving ASCVD risk reduction and the degree to which the placebo (i.e., mineral oil vs corn oil) may have affected outcomes remain unresolved.”

The STRENGTH trial was sponsored by AstraZeneca. Dr. Lincoff reported receiving grants from AstraZeneca during the conduct of the study. Dr. Catapano has received honoraria, lecture fees, or research grants from Sigma-Tau, Manarini, Kowa Pharmaceuticals, Recordati, Eli Lilly, AstraZeneca, Mediolanum, Pfizer, Merck, Sanofi, Aegerion, Amgen, Genzyme, Bayer, Sanofi, Regeneron Daiichi Sankyo, and Amarin. Dr. Martin reports receiving consulting fees from AstraZeneca, Amgen, Esperion, and REGENXBIO, and has a patent pending for a system of LDL-C estimation filed by Johns Hopkins University. Dr. Bhatt reports serving as principal investigator for REDUCE-IT and that Brigham and Women’s Hospital has received research funding from Amarin.

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.

Optical CT (OCT) plus cardiac MRI (CMR) provides a more specific diagnosis in the majority of women presenting with myocardial infarction with nonobstructive coronary arteries (MINOCA).

The multimodal imaging strategy identified the underlying cause of MINOCA in 85% of women in the HARP-MINOCA study. Overall, 64% of women had a true MI and 21% had an alternate nonischemic diagnosis, most commonly myocarditis.

The results were presented at the virtual American Heart Association (AHA) Scientific Sessions 2020 and published simultaneously in Circulation.  

MINOCA occurs in up to 15% of patients with MI and is defined as MI meeting the universal definition but with less than 50% stenosis in all major epicardial arteries on angiography and no specific alternate diagnosis to explain the presentation.

It is three times more common in women than in men and also disproportionately affects Black, Hispanic, Maori, and Pacific persons. MINOCA has several causes, leading to uncertainty in diagnostic testing and treatment.

“Different doctors tell patients different messages about MINOCA and may incorrectly say the event wasn’t a heart attack,” Dr. Reynolds said in an earlier press briefing. “I had a patient who was told ‘your arteries are open,’ and they gave her Xanax.”

As part of the Women’s Heart Attack Research Program (HARP), researchers enrolled 301 women with a clinical diagnosis of MI, of whom 170 were diagnosed with MINOCA during angiography and underwent OCT at that time, followed by CMR within 1 week of the acute presentation.

All images were interpreted by an independent core laboratory blinded to results of the other tests and clinical information. The final cohort included 145 women with interpretable OCT images.

Their median age was 60 years, 49.7% were white non-Hispanic, and 97% presented with a provisional diagnosis of non–ST-segment MI. Their median peak troponin level was 0.94 ng/mL.

OCT identified a definite or probable culprit lesion in 46% of women, most commonly atherosclerosis or thrombosis. On multivariable analysis, having a culprit lesion was associated with older age, abnormal angiography findings at the site, and diabetes, but not peak troponin level or severity of angiographic stenosis.

CMR available in 116 women showed evidence of infarction or regional injury in 69%. Multivariate predictors of an abnormal CMR were higher peak troponin and diastolic blood pressure but not an OCT culprit lesion or angiographic stenosis severity.

When the OCT and CMR results were combined, a cause of MINOCA was identified in 84.5% of women. Three-fourths of the causes were ischemic (64% MI) and one-quarter were nonischemic (15% myocarditis, 3% Takotsubo syndrome, and 3% nonischemic cardiomyopathy). In the remaining 15%, no cause of MINOCA was identified.

To emphasize the effect multimodal imaging can have on treatment, Dr. Reynolds highlighted a 44-year-old woman with no risk factors for coronary artery disease who had chest pain in the context of heavy menstrual bleeding, a low hemoglobin level, and peak troponin level of 3.25 ng/mL.

Unexpectedly, imaging revealed a left anterior descending (LAD) plaque rupture in a thin-cap fibroatheroma, causing a small transmural infarction at the terminus of the LAD.

“Without this diagnosis, it’s unlikely she would have received antiplatelet therapy or statins and might have been given a diagnosis of supply/demand mismatch, when the real diagnosis was MI,” Dr. Reynolds observed.

“Finally we can say this is not just crazy women. There is really something going on,” said panelist Roxana Mehran, MD, of the Icahn School of Medicine at Mount Sinai in New York. “You have now told us this is most likely atherosclerosis for pretty much 85% of the cases. So make the diagnosis and, of course, make sure you treat these patients accordingly for risk factor modification, really thinking about a ruptured plaque.”

Combining OCT and MRI may result in a more specific diagnosis and better treatment but also raises costs and logistical considerations.

“Implementation challenges are that not every form of testing is available in every medical center,” Dr. Reynolds said in an interview. “Many centers have cardiac MRI,” whereas “OCT is not currently available at most medical centers where heart attack patients are treated but is available at specialized centers.”

Asked during the session about the use of CT angiography, invited discussant Martha Gulati, MD, president-elect of the American Society for Preventive Cardiology, said, “For me, CT is helpful when I’m not sure if there’s any plaque because the angiogram looked really normal and there was no opportunity to do intracoronary imaging. And sometimes that will help me, in particular, if a patient doesn’t want to take a statin.”

Dr. Gulati pointed out that the European Society of Cardiology MINOCA guidelines recommend OCT and CMR, whereas the 2019 AHA statement on MINOCA, which she coauthored, also recommends OCT and CMR, but almost as one or the other.

“We already said that you should do cardiac MR to try to make a diagnosis, but I think the combination of the two needs to be emphasized when we next draft these guidelines. It really will help,” Dr. Gulati said in an interview.

“But using OCT, particularly, needs to be in the setting of the MI. I don’t think you want to do a procedure again,” she said. “So we really need it to become more widely available because at the time of an MI, you won’t necessarily know that you’re not going to find an obstructive lesion.”

Dr. Gulati pointed out several unanswered questions, including whether the diagnosis was missed in some patients, because OCT of all three vessels was available in only 59%, and how the use of high-sensitivity troponin, which was left up to the individual institution, might affect the usefulness of OCT and CMR.

It’s also unknown whether the mechanism is different for ST-segment elevation MI, as the trial included very few cases, although MINOCA often occurs in this setting. Future OCT/CMR studies will also need to enroll men to determine potential sex differences, if any.

Commenting on the study, B. Hadley Wilson, MD, Sanger Heart & Vascular Institute in Charlotte, N.C., said, “There would need to be further justification of this invasive interventional procedure to be sure that the benefit outweighed the risk of putting a wire and an OCT catheter down patients without any significant angiographic blockage and to assure interventional cardiologists of its value here.”

He pointed out that noninvasive CMR appears helpful in the diagnosis of nearly three-quarters of these patients and perhaps could be done first to direct which of those with an ischemic cause might benefit from invasive OCT at catheterization. This seems most pertinent in patients with a high suspicion of coronary artery disease or recurrent MINOCA.

“Overall, we need to consider the expense, logistics, and small risk of these combined modalities, particularly in everyday practice, before making recommendations,” Dr. Wilson said. “ Since OCT is much less available than intravascular ultrasound, it would require a challenging marketplace paradigm shift to implement this multimodality imaging strategy regionally and locally in the U.S., including the added costs. However, further study to direct the more judicious use of either CMR and/or combined with OCT is warranted in these patients.”

The study was funded by the AHA through a grant from the Go Red for Women Strategically Focused Research Network. Dr. Reynolds reported in-kind donations from Abbott Vascular and Siemens related to the study and nonfinancial support from BioTelemetry outside the study. Dr. Gulati and Dr. Wilson reported having no relevant disclosures.

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

Optical CT (OCT) plus cardiac MRI (CMR) provides a more specific diagnosis in the majority of women presenting with myocardial infarction with nonobstructive coronary arteries (MINOCA).

The multimodal imaging strategy identified the underlying cause of MINOCA in 85% of women in the HARP-MINOCA study. Overall, 64% of women had a true MI and 21% had an alternate nonischemic diagnosis, most commonly myocarditis.

The results were presented at the virtual American Heart Association (AHA) Scientific Sessions 2020 and published simultaneously in Circulation.  

MINOCA occurs in up to 15% of patients with MI and is defined as MI meeting the universal definition but with less than 50% stenosis in all major epicardial arteries on angiography and no specific alternate diagnosis to explain the presentation.

It is three times more common in women than in men and also disproportionately affects Black, Hispanic, Maori, and Pacific persons. MINOCA has several causes, leading to uncertainty in diagnostic testing and treatment.

“Different doctors tell patients different messages about MINOCA and may incorrectly say the event wasn’t a heart attack,” Dr. Reynolds said in an earlier press briefing. “I had a patient who was told ‘your arteries are open,’ and they gave her Xanax.”

As part of the Women’s Heart Attack Research Program (HARP), researchers enrolled 301 women with a clinical diagnosis of MI, of whom 170 were diagnosed with MINOCA during angiography and underwent OCT at that time, followed by CMR within 1 week of the acute presentation.

All images were interpreted by an independent core laboratory blinded to results of the other tests and clinical information. The final cohort included 145 women with interpretable OCT images.

Their median age was 60 years, 49.7% were white non-Hispanic, and 97% presented with a provisional diagnosis of non–ST-segment MI. Their median peak troponin level was 0.94 ng/mL.

OCT identified a definite or probable culprit lesion in 46% of women, most commonly atherosclerosis or thrombosis. On multivariable analysis, having a culprit lesion was associated with older age, abnormal angiography findings at the site, and diabetes, but not peak troponin level or severity of angiographic stenosis.

CMR available in 116 women showed evidence of infarction or regional injury in 69%. Multivariate predictors of an abnormal CMR were higher peak troponin and diastolic blood pressure but not an OCT culprit lesion or angiographic stenosis severity.

When the OCT and CMR results were combined, a cause of MINOCA was identified in 84.5% of women. Three-fourths of the causes were ischemic (64% MI) and one-quarter were nonischemic (15% myocarditis, 3% Takotsubo syndrome, and 3% nonischemic cardiomyopathy). In the remaining 15%, no cause of MINOCA was identified.

To emphasize the effect multimodal imaging can have on treatment, Dr. Reynolds highlighted a 44-year-old woman with no risk factors for coronary artery disease who had chest pain in the context of heavy menstrual bleeding, a low hemoglobin level, and peak troponin level of 3.25 ng/mL.

Unexpectedly, imaging revealed a left anterior descending (LAD) plaque rupture in a thin-cap fibroatheroma, causing a small transmural infarction at the terminus of the LAD.

“Without this diagnosis, it’s unlikely she would have received antiplatelet therapy or statins and might have been given a diagnosis of supply/demand mismatch, when the real diagnosis was MI,” Dr. Reynolds observed.

“Finally we can say this is not just crazy women. There is really something going on,” said panelist Roxana Mehran, MD, of the Icahn School of Medicine at Mount Sinai in New York. “You have now told us this is most likely atherosclerosis for pretty much 85% of the cases. So make the diagnosis and, of course, make sure you treat these patients accordingly for risk factor modification, really thinking about a ruptured plaque.”

Combining OCT and MRI may result in a more specific diagnosis and better treatment but also raises costs and logistical considerations.

“Implementation challenges are that not every form of testing is available in every medical center,” Dr. Reynolds said in an interview. “Many centers have cardiac MRI,” whereas “OCT is not currently available at most medical centers where heart attack patients are treated but is available at specialized centers.”

Asked during the session about the use of CT angiography, invited discussant Martha Gulati, MD, president-elect of the American Society for Preventive Cardiology, said, “For me, CT is helpful when I’m not sure if there’s any plaque because the angiogram looked really normal and there was no opportunity to do intracoronary imaging. And sometimes that will help me, in particular, if a patient doesn’t want to take a statin.”

Dr. Gulati pointed out that the European Society of Cardiology MINOCA guidelines recommend OCT and CMR, whereas the 2019 AHA statement on MINOCA, which she coauthored, also recommends OCT and CMR, but almost as one or the other.

“We already said that you should do cardiac MR to try to make a diagnosis, but I think the combination of the two needs to be emphasized when we next draft these guidelines. It really will help,” Dr. Gulati said in an interview.

“But using OCT, particularly, needs to be in the setting of the MI. I don’t think you want to do a procedure again,” she said. “So we really need it to become more widely available because at the time of an MI, you won’t necessarily know that you’re not going to find an obstructive lesion.”

Dr. Gulati pointed out several unanswered questions, including whether the diagnosis was missed in some patients, because OCT of all three vessels was available in only 59%, and how the use of high-sensitivity troponin, which was left up to the individual institution, might affect the usefulness of OCT and CMR.

It’s also unknown whether the mechanism is different for ST-segment elevation MI, as the trial included very few cases, although MINOCA often occurs in this setting. Future OCT/CMR studies will also need to enroll men to determine potential sex differences, if any.

Commenting on the study, B. Hadley Wilson, MD, Sanger Heart & Vascular Institute in Charlotte, N.C., said, “There would need to be further justification of this invasive interventional procedure to be sure that the benefit outweighed the risk of putting a wire and an OCT catheter down patients without any significant angiographic blockage and to assure interventional cardiologists of its value here.”

He pointed out that noninvasive CMR appears helpful in the diagnosis of nearly three-quarters of these patients and perhaps could be done first to direct which of those with an ischemic cause might benefit from invasive OCT at catheterization. This seems most pertinent in patients with a high suspicion of coronary artery disease or recurrent MINOCA.

“Overall, we need to consider the expense, logistics, and small risk of these combined modalities, particularly in everyday practice, before making recommendations,” Dr. Wilson said. “ Since OCT is much less available than intravascular ultrasound, it would require a challenging marketplace paradigm shift to implement this multimodality imaging strategy regionally and locally in the U.S., including the added costs. However, further study to direct the more judicious use of either CMR and/or combined with OCT is warranted in these patients.”

The study was funded by the AHA through a grant from the Go Red for Women Strategically Focused Research Network. Dr. Reynolds reported in-kind donations from Abbott Vascular and Siemens related to the study and nonfinancial support from BioTelemetry outside the study. Dr. Gulati and Dr. Wilson reported having no relevant disclosures.

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

Optical CT (OCT) plus cardiac MRI (CMR) provides a more specific diagnosis in the majority of women presenting with myocardial infarction with nonobstructive coronary arteries (MINOCA).

The multimodal imaging strategy identified the underlying cause of MINOCA in 85% of women in the HARP-MINOCA study. Overall, 64% of women had a true MI and 21% had an alternate nonischemic diagnosis, most commonly myocarditis.

The results were presented at the virtual American Heart Association (AHA) Scientific Sessions 2020 and published simultaneously in Circulation.  

MINOCA occurs in up to 15% of patients with MI and is defined as MI meeting the universal definition but with less than 50% stenosis in all major epicardial arteries on angiography and no specific alternate diagnosis to explain the presentation.

It is three times more common in women than in men and also disproportionately affects Black, Hispanic, Maori, and Pacific persons. MINOCA has several causes, leading to uncertainty in diagnostic testing and treatment.

“Different doctors tell patients different messages about MINOCA and may incorrectly say the event wasn’t a heart attack,” Dr. Reynolds said in an earlier press briefing. “I had a patient who was told ‘your arteries are open,’ and they gave her Xanax.”

As part of the Women’s Heart Attack Research Program (HARP), researchers enrolled 301 women with a clinical diagnosis of MI, of whom 170 were diagnosed with MINOCA during angiography and underwent OCT at that time, followed by CMR within 1 week of the acute presentation.

All images were interpreted by an independent core laboratory blinded to results of the other tests and clinical information. The final cohort included 145 women with interpretable OCT images.

Their median age was 60 years, 49.7% were white non-Hispanic, and 97% presented with a provisional diagnosis of non–ST-segment MI. Their median peak troponin level was 0.94 ng/mL.

OCT identified a definite or probable culprit lesion in 46% of women, most commonly atherosclerosis or thrombosis. On multivariable analysis, having a culprit lesion was associated with older age, abnormal angiography findings at the site, and diabetes, but not peak troponin level or severity of angiographic stenosis.

CMR available in 116 women showed evidence of infarction or regional injury in 69%. Multivariate predictors of an abnormal CMR were higher peak troponin and diastolic blood pressure but not an OCT culprit lesion or angiographic stenosis severity.

When the OCT and CMR results were combined, a cause of MINOCA was identified in 84.5% of women. Three-fourths of the causes were ischemic (64% MI) and one-quarter were nonischemic (15% myocarditis, 3% Takotsubo syndrome, and 3% nonischemic cardiomyopathy). In the remaining 15%, no cause of MINOCA was identified.

To emphasize the effect multimodal imaging can have on treatment, Dr. Reynolds highlighted a 44-year-old woman with no risk factors for coronary artery disease who had chest pain in the context of heavy menstrual bleeding, a low hemoglobin level, and peak troponin level of 3.25 ng/mL.

Unexpectedly, imaging revealed a left anterior descending (LAD) plaque rupture in a thin-cap fibroatheroma, causing a small transmural infarction at the terminus of the LAD.

“Without this diagnosis, it’s unlikely she would have received antiplatelet therapy or statins and might have been given a diagnosis of supply/demand mismatch, when the real diagnosis was MI,” Dr. Reynolds observed.

“Finally we can say this is not just crazy women. There is really something going on,” said panelist Roxana Mehran, MD, of the Icahn School of Medicine at Mount Sinai in New York. “You have now told us this is most likely atherosclerosis for pretty much 85% of the cases. So make the diagnosis and, of course, make sure you treat these patients accordingly for risk factor modification, really thinking about a ruptured plaque.”

Combining OCT and MRI may result in a more specific diagnosis and better treatment but also raises costs and logistical considerations.

“Implementation challenges are that not every form of testing is available in every medical center,” Dr. Reynolds said in an interview. “Many centers have cardiac MRI,” whereas “OCT is not currently available at most medical centers where heart attack patients are treated but is available at specialized centers.”

Asked during the session about the use of CT angiography, invited discussant Martha Gulati, MD, president-elect of the American Society for Preventive Cardiology, said, “For me, CT is helpful when I’m not sure if there’s any plaque because the angiogram looked really normal and there was no opportunity to do intracoronary imaging. And sometimes that will help me, in particular, if a patient doesn’t want to take a statin.”

Dr. Gulati pointed out that the European Society of Cardiology MINOCA guidelines recommend OCT and CMR, whereas the 2019 AHA statement on MINOCA, which she coauthored, also recommends OCT and CMR, but almost as one or the other.

“We already said that you should do cardiac MR to try to make a diagnosis, but I think the combination of the two needs to be emphasized when we next draft these guidelines. It really will help,” Dr. Gulati said in an interview.

“But using OCT, particularly, needs to be in the setting of the MI. I don’t think you want to do a procedure again,” she said. “So we really need it to become more widely available because at the time of an MI, you won’t necessarily know that you’re not going to find an obstructive lesion.”

Dr. Gulati pointed out several unanswered questions, including whether the diagnosis was missed in some patients, because OCT of all three vessels was available in only 59%, and how the use of high-sensitivity troponin, which was left up to the individual institution, might affect the usefulness of OCT and CMR.

It’s also unknown whether the mechanism is different for ST-segment elevation MI, as the trial included very few cases, although MINOCA often occurs in this setting. Future OCT/CMR studies will also need to enroll men to determine potential sex differences, if any.

Commenting on the study, B. Hadley Wilson, MD, Sanger Heart & Vascular Institute in Charlotte, N.C., said, “There would need to be further justification of this invasive interventional procedure to be sure that the benefit outweighed the risk of putting a wire and an OCT catheter down patients without any significant angiographic blockage and to assure interventional cardiologists of its value here.”

He pointed out that noninvasive CMR appears helpful in the diagnosis of nearly three-quarters of these patients and perhaps could be done first to direct which of those with an ischemic cause might benefit from invasive OCT at catheterization. This seems most pertinent in patients with a high suspicion of coronary artery disease or recurrent MINOCA.

“Overall, we need to consider the expense, logistics, and small risk of these combined modalities, particularly in everyday practice, before making recommendations,” Dr. Wilson said. “ Since OCT is much less available than intravascular ultrasound, it would require a challenging marketplace paradigm shift to implement this multimodality imaging strategy regionally and locally in the U.S., including the added costs. However, further study to direct the more judicious use of either CMR and/or combined with OCT is warranted in these patients.”

The study was funded by the AHA through a grant from the Go Red for Women Strategically Focused Research Network. Dr. Reynolds reported in-kind donations from Abbott Vascular and Siemens related to the study and nonfinancial support from BioTelemetry outside the study. Dr. Gulati and Dr. Wilson reported having no relevant disclosures.

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

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

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

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

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

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

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

Treatment with the SGLT2 inhibitor empagliflozin led to significant reductions in both left ventricular end systolic and diastolic volumes in two independent randomized studies of patients with heart failure with reduced ejection fraction.

These results provide important new evidence that one way a drug from this class exerts its beneficial effects on cardiovascular outcomes in these patients is by producing favorable left-ventricular remodeling.

One of the two studies involved only patients with heart failure with reduced ejection fraction (HFrEF) with diabetes and examined treatment impact after 36 weeks. The second study focused exclusively on HFrEF patients without diabetes and followed patients for 6 months. Both studies also generated additional significant evidence of favorable left-ventricular effects. 

“The results of these two new trials are incredibly important, as they tell cardiologists one of the mechanisms by which SGLT2 [sodium glucose co-transporter 2] inhibitors reduce heart failure hospitalizations and cardiovascular death,” said Mark C. Petrie,  MBChB, professor at the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, and principal investigator for one of the two studies.

“Many cardiologists want to know mechanisms as well as clinical benefit. These remodeling data showing that these drugs reduce the size of abnormally large hearts [and] are also very important for patients,” Dr. Petrie said in an interview. “There have been more than 50 publications on potential mechanisms of benefit of SGLT2 inhibitors in HFrEF, but these are the first randomized, mechanistic data.”

Mechanistic clues follow large cardiovascular outcome trials

Results from a large randomized trial, EMPEROR-Reduced, recently showed that treatment with empagliflozin (Jardiance) on top of standard HFrEF treatment led to significant benefits in patients with or without type 2 diabetes (T2D), compared with placebo, for major cardiovascular and renal endpoints, including the combination of cardiovascular death or hospitalization for heart failure. And results from a second large randomized trial, DAPA-HF, showed similar results with a different drug from the same class, dapagliflozin (Farxiga), in an earlier report.

But while these reports led to quick uptake of these two drugs for the treatment of patients with HFrEF, the means by which these agents exert their HFrEF benefits have been unclear.

“Our study identifies why this drug [empagliflozin] is effective – because it improves heart function, something that has not been understood until now,” Carlos G. Santos-Gallego, MD, lead investigator for the second new report, said in a written statement. “Many doctors are afraid of prescribing a drug they do not understand, and our findings will help clinicians feel more comfortable giving this to patients once approved.”

On the strength of the DAPA-HF results, dapagliflozin received a revised U.S. label in May 2020 that added the indication for treating patients with HFrEF regardless of the whether patients also have T2D, the original indication for prescribing the drug. Many experts anticipate that a similar addition to the label for empagliflozin will soon occur.

EMPA-TROPISM examines patients with no T2D

The single-center study reported by Dr. Santos-Gallego randomized 84 patients with HFrEF and no diabetes to standard treatment with empagliflozin or placebo and measured several parameters in 80 patients who completed the planned 6 months of treatment. The primary endpoints were the changes in both left ventricular end systolic and diastolic volume from baseline in the empagliflozin-treated patients compared with patients on placebo, measured by cardiac MR.

The results showed an average reduction of end systolic volume of 26.6 mL from baseline compared with a small rise in the placebo patients, and an average drop in end diastolic volume of 25.1 mL from baseline compared again with a small increase in the controls. Both differences were statistically significant, reported the senior author of the study, Juan J. Badimon, PhD, in a talk at the virtual scientific sessions of the American Heart Association. Concurrently, the results were published online in the Journal of the American College of Cardiology.

Results from the EMPA-TROPISM study also showed several other significant benefits from empagliflozin treatment, both to left ventricular shape and function as well as to other measures of patient well being. The drug regimen led to an increase in left ventricular ejection fraction, a decrease in left ventricular mass, reduced myocardial fibrosis and aortic stiffness, increased peak oxygen consumption, an increased distance traveled in a 6-minute walk test, and improved quality of life, said Dr. Badimon, professor of medicine and director of the Atherothrombosis Research Unit at the Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai in New York.

SUGAR-DM-HF enrolled only T2D patients

The second study, SUGAR-DM-HF, randomized 105 patients with HFrEF and T2D to treatment with empagliflozin or placebo at any of 15 centers in Scotland, with 92 patients completing the full 36 weeks on treatment. One of the study’s two primary endpoints was the change in left ventricular end systolic volume index, which dropped by an average of 7.9 mL/m2 in patients who received empagliflozin and by 1.5 mL/m2 in the controls, a significant average between-group difference of 6.0 mL/m2, reported Matthew M.Y. Lee, MBChB, at the same meeting.

However, the second primary endpoint, change in left ventricular global longitudinal strain, showed no significant difference in effect on empagliflozin compared with placebo, said Dr. Lee, a cardiologist at the University of Glasgow. Concurrently with his report the results appeared in an article published online in Circulation.

The results also showed a significant drop in left ventricular end diastolic volume index from baseline compared with the control patients, with an average between-group difference in the reduction from baseline of 8.2 mL/m2.
“Reverse cardiac remodeling is a mechanism by which SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular mortality,” Dr. Lee concluded during his presentation at the meeting.

Although the findings from both studies together provide strong evidence for an effect by empagliflozin on left ventricular shape and function, neither study provides much insight into how this drug exerts these effects. The authors of both studies agreed on several potential explanations, including reductions in cardiac preload and afterload that could reduce left ventricular stretch and volume; a change triggered in myocardial energetics that switches from a metabolism mostly dependent on glucose to one more geared to using fatty acids, ketone bodies, and branched chain amino acids; and a possible drug-induced reduction in oxidative stress and inflammation.

SUGAR-DM-HF was sponsored by a grant from Boehringer Ingelheim, the company that along with Eli Lilly markets empagliflozin (Jardiance). Dr. Lee had no disclosures. Dr. Petrie has been a consultant to Boehringer Ingelheim and Eli Lilly and to several other companies. EMPA-TROPISM was sponsored by a grant from Boehringer Ingelheim. Dr. Badimon and Dr. Santos-Gallego had no disclosures.

[email protected] 

Treatment with the SGLT2 inhibitor empagliflozin led to significant reductions in both left ventricular end systolic and diastolic volumes in two independent randomized studies of patients with heart failure with reduced ejection fraction.

These results provide important new evidence that one way a drug from this class exerts its beneficial effects on cardiovascular outcomes in these patients is by producing favorable left-ventricular remodeling.

One of the two studies involved only patients with heart failure with reduced ejection fraction (HFrEF) with diabetes and examined treatment impact after 36 weeks. The second study focused exclusively on HFrEF patients without diabetes and followed patients for 6 months. Both studies also generated additional significant evidence of favorable left-ventricular effects. 

“The results of these two new trials are incredibly important, as they tell cardiologists one of the mechanisms by which SGLT2 [sodium glucose co-transporter 2] inhibitors reduce heart failure hospitalizations and cardiovascular death,” said Mark C. Petrie,  MBChB, professor at the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, and principal investigator for one of the two studies.

“Many cardiologists want to know mechanisms as well as clinical benefit. These remodeling data showing that these drugs reduce the size of abnormally large hearts [and] are also very important for patients,” Dr. Petrie said in an interview. “There have been more than 50 publications on potential mechanisms of benefit of SGLT2 inhibitors in HFrEF, but these are the first randomized, mechanistic data.”

Mechanistic clues follow large cardiovascular outcome trials

Results from a large randomized trial, EMPEROR-Reduced, recently showed that treatment with empagliflozin (Jardiance) on top of standard HFrEF treatment led to significant benefits in patients with or without type 2 diabetes (T2D), compared with placebo, for major cardiovascular and renal endpoints, including the combination of cardiovascular death or hospitalization for heart failure. And results from a second large randomized trial, DAPA-HF, showed similar results with a different drug from the same class, dapagliflozin (Farxiga), in an earlier report.

But while these reports led to quick uptake of these two drugs for the treatment of patients with HFrEF, the means by which these agents exert their HFrEF benefits have been unclear.

“Our study identifies why this drug [empagliflozin] is effective – because it improves heart function, something that has not been understood until now,” Carlos G. Santos-Gallego, MD, lead investigator for the second new report, said in a written statement. “Many doctors are afraid of prescribing a drug they do not understand, and our findings will help clinicians feel more comfortable giving this to patients once approved.”

On the strength of the DAPA-HF results, dapagliflozin received a revised U.S. label in May 2020 that added the indication for treating patients with HFrEF regardless of the whether patients also have T2D, the original indication for prescribing the drug. Many experts anticipate that a similar addition to the label for empagliflozin will soon occur.

EMPA-TROPISM examines patients with no T2D

The single-center study reported by Dr. Santos-Gallego randomized 84 patients with HFrEF and no diabetes to standard treatment with empagliflozin or placebo and measured several parameters in 80 patients who completed the planned 6 months of treatment. The primary endpoints were the changes in both left ventricular end systolic and diastolic volume from baseline in the empagliflozin-treated patients compared with patients on placebo, measured by cardiac MR.

The results showed an average reduction of end systolic volume of 26.6 mL from baseline compared with a small rise in the placebo patients, and an average drop in end diastolic volume of 25.1 mL from baseline compared again with a small increase in the controls. Both differences were statistically significant, reported the senior author of the study, Juan J. Badimon, PhD, in a talk at the virtual scientific sessions of the American Heart Association. Concurrently, the results were published online in the Journal of the American College of Cardiology.

Results from the EMPA-TROPISM study also showed several other significant benefits from empagliflozin treatment, both to left ventricular shape and function as well as to other measures of patient well being. The drug regimen led to an increase in left ventricular ejection fraction, a decrease in left ventricular mass, reduced myocardial fibrosis and aortic stiffness, increased peak oxygen consumption, an increased distance traveled in a 6-minute walk test, and improved quality of life, said Dr. Badimon, professor of medicine and director of the Atherothrombosis Research Unit at the Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai in New York.

SUGAR-DM-HF enrolled only T2D patients

The second study, SUGAR-DM-HF, randomized 105 patients with HFrEF and T2D to treatment with empagliflozin or placebo at any of 15 centers in Scotland, with 92 patients completing the full 36 weeks on treatment. One of the study’s two primary endpoints was the change in left ventricular end systolic volume index, which dropped by an average of 7.9 mL/m2 in patients who received empagliflozin and by 1.5 mL/m2 in the controls, a significant average between-group difference of 6.0 mL/m2, reported Matthew M.Y. Lee, MBChB, at the same meeting.

However, the second primary endpoint, change in left ventricular global longitudinal strain, showed no significant difference in effect on empagliflozin compared with placebo, said Dr. Lee, a cardiologist at the University of Glasgow. Concurrently with his report the results appeared in an article published online in Circulation.

The results also showed a significant drop in left ventricular end diastolic volume index from baseline compared with the control patients, with an average between-group difference in the reduction from baseline of 8.2 mL/m2.
“Reverse cardiac remodeling is a mechanism by which SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular mortality,” Dr. Lee concluded during his presentation at the meeting.

Although the findings from both studies together provide strong evidence for an effect by empagliflozin on left ventricular shape and function, neither study provides much insight into how this drug exerts these effects. The authors of both studies agreed on several potential explanations, including reductions in cardiac preload and afterload that could reduce left ventricular stretch and volume; a change triggered in myocardial energetics that switches from a metabolism mostly dependent on glucose to one more geared to using fatty acids, ketone bodies, and branched chain amino acids; and a possible drug-induced reduction in oxidative stress and inflammation.

SUGAR-DM-HF was sponsored by a grant from Boehringer Ingelheim, the company that along with Eli Lilly markets empagliflozin (Jardiance). Dr. Lee had no disclosures. Dr. Petrie has been a consultant to Boehringer Ingelheim and Eli Lilly and to several other companies. EMPA-TROPISM was sponsored by a grant from Boehringer Ingelheim. Dr. Badimon and Dr. Santos-Gallego had no disclosures.

[email protected] 

Treatment with the SGLT2 inhibitor empagliflozin led to significant reductions in both left ventricular end systolic and diastolic volumes in two independent randomized studies of patients with heart failure with reduced ejection fraction.

These results provide important new evidence that one way a drug from this class exerts its beneficial effects on cardiovascular outcomes in these patients is by producing favorable left-ventricular remodeling.

One of the two studies involved only patients with heart failure with reduced ejection fraction (HFrEF) with diabetes and examined treatment impact after 36 weeks. The second study focused exclusively on HFrEF patients without diabetes and followed patients for 6 months. Both studies also generated additional significant evidence of favorable left-ventricular effects. 

“The results of these two new trials are incredibly important, as they tell cardiologists one of the mechanisms by which SGLT2 [sodium glucose co-transporter 2] inhibitors reduce heart failure hospitalizations and cardiovascular death,” said Mark C. Petrie,  MBChB, professor at the Institute of Cardiovascular & Medical Sciences at the University of Glasgow, and principal investigator for one of the two studies.

“Many cardiologists want to know mechanisms as well as clinical benefit. These remodeling data showing that these drugs reduce the size of abnormally large hearts [and] are also very important for patients,” Dr. Petrie said in an interview. “There have been more than 50 publications on potential mechanisms of benefit of SGLT2 inhibitors in HFrEF, but these are the first randomized, mechanistic data.”

Mechanistic clues follow large cardiovascular outcome trials

Results from a large randomized trial, EMPEROR-Reduced, recently showed that treatment with empagliflozin (Jardiance) on top of standard HFrEF treatment led to significant benefits in patients with or without type 2 diabetes (T2D), compared with placebo, for major cardiovascular and renal endpoints, including the combination of cardiovascular death or hospitalization for heart failure. And results from a second large randomized trial, DAPA-HF, showed similar results with a different drug from the same class, dapagliflozin (Farxiga), in an earlier report.

But while these reports led to quick uptake of these two drugs for the treatment of patients with HFrEF, the means by which these agents exert their HFrEF benefits have been unclear.

“Our study identifies why this drug [empagliflozin] is effective – because it improves heart function, something that has not been understood until now,” Carlos G. Santos-Gallego, MD, lead investigator for the second new report, said in a written statement. “Many doctors are afraid of prescribing a drug they do not understand, and our findings will help clinicians feel more comfortable giving this to patients once approved.”

On the strength of the DAPA-HF results, dapagliflozin received a revised U.S. label in May 2020 that added the indication for treating patients with HFrEF regardless of the whether patients also have T2D, the original indication for prescribing the drug. Many experts anticipate that a similar addition to the label for empagliflozin will soon occur.

EMPA-TROPISM examines patients with no T2D

The single-center study reported by Dr. Santos-Gallego randomized 84 patients with HFrEF and no diabetes to standard treatment with empagliflozin or placebo and measured several parameters in 80 patients who completed the planned 6 months of treatment. The primary endpoints were the changes in both left ventricular end systolic and diastolic volume from baseline in the empagliflozin-treated patients compared with patients on placebo, measured by cardiac MR.

The results showed an average reduction of end systolic volume of 26.6 mL from baseline compared with a small rise in the placebo patients, and an average drop in end diastolic volume of 25.1 mL from baseline compared again with a small increase in the controls. Both differences were statistically significant, reported the senior author of the study, Juan J. Badimon, PhD, in a talk at the virtual scientific sessions of the American Heart Association. Concurrently, the results were published online in the Journal of the American College of Cardiology.

Results from the EMPA-TROPISM study also showed several other significant benefits from empagliflozin treatment, both to left ventricular shape and function as well as to other measures of patient well being. The drug regimen led to an increase in left ventricular ejection fraction, a decrease in left ventricular mass, reduced myocardial fibrosis and aortic stiffness, increased peak oxygen consumption, an increased distance traveled in a 6-minute walk test, and improved quality of life, said Dr. Badimon, professor of medicine and director of the Atherothrombosis Research Unit at the Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai in New York.

SUGAR-DM-HF enrolled only T2D patients

The second study, SUGAR-DM-HF, randomized 105 patients with HFrEF and T2D to treatment with empagliflozin or placebo at any of 15 centers in Scotland, with 92 patients completing the full 36 weeks on treatment. One of the study’s two primary endpoints was the change in left ventricular end systolic volume index, which dropped by an average of 7.9 mL/m2 in patients who received empagliflozin and by 1.5 mL/m2 in the controls, a significant average between-group difference of 6.0 mL/m2, reported Matthew M.Y. Lee, MBChB, at the same meeting.

However, the second primary endpoint, change in left ventricular global longitudinal strain, showed no significant difference in effect on empagliflozin compared with placebo, said Dr. Lee, a cardiologist at the University of Glasgow. Concurrently with his report the results appeared in an article published online in Circulation.

The results also showed a significant drop in left ventricular end diastolic volume index from baseline compared with the control patients, with an average between-group difference in the reduction from baseline of 8.2 mL/m2.
“Reverse cardiac remodeling is a mechanism by which SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular mortality,” Dr. Lee concluded during his presentation at the meeting.

Although the findings from both studies together provide strong evidence for an effect by empagliflozin on left ventricular shape and function, neither study provides much insight into how this drug exerts these effects. The authors of both studies agreed on several potential explanations, including reductions in cardiac preload and afterload that could reduce left ventricular stretch and volume; a change triggered in myocardial energetics that switches from a metabolism mostly dependent on glucose to one more geared to using fatty acids, ketone bodies, and branched chain amino acids; and a possible drug-induced reduction in oxidative stress and inflammation.

SUGAR-DM-HF was sponsored by a grant from Boehringer Ingelheim, the company that along with Eli Lilly markets empagliflozin (Jardiance). Dr. Lee had no disclosures. Dr. Petrie has been a consultant to Boehringer Ingelheim and Eli Lilly and to several other companies. EMPA-TROPISM was sponsored by a grant from Boehringer Ingelheim. Dr. Badimon and Dr. Santos-Gallego had no disclosures.

[email protected] 

Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.

“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.

American Heart Association

Myonecrosis hypothesis falls flat

The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.

The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.

The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.

“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.

There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.

Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.

American Heart Association

Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
 

Troponin response may vary

A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.

Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.

During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”

American Heart Association

[email protected]

SOURCE: Silvain J. AHA 2020. Session LBS 3.

Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.

“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.

American Heart Association

Myonecrosis hypothesis falls flat

The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.

The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.

The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.

“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.

There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.

Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.

American Heart Association

Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
 

Troponin response may vary

A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.

Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.

During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”

American Heart Association

[email protected]

SOURCE: Silvain J. AHA 2020. Session LBS 3.

Ticagrelor failed to unseat clopidogrel as the guideline-recommended P2Y12 inhibitor of choice in patients undergoing elective percutaneous coronary intervention for stable CAD in the randomized ALPHEUS trial.

“The higher level of platelet inhibition obtained with ticagrelor does not translate into a reduction of periprocedural MI or myocardial injury within 48 hours of high-risk PCI performed in stable coronary patients,” reported Johanne Silvain, MD, PhD, professor of cardiology at the Sorbonne University and director of the ICU at Pitie-Salpetriere Hospital, Paris, at the virtual American Heart Association scientific sessions.

American Heart Association

Myonecrosis hypothesis falls flat

The primary endpoint was the occurrence of major myocardial injury, defined as a periprocedural troponin elevated greater than 5 times the upper limit of normal within 48 hours of PCI; type 4a MI, defined as major myocardial injury plus signs or symptoms of ischemia; or stent thrombosis.

The rates were closely similar: 35.5% with ticagrelor, 36.2% with clopidogrel. The bulk of events consisted of major myocardial injury, with an incidence of 26.7% in the ticagrelor group and 27.7% with clopidogrel. Stent thrombosis occurred in 0.3% of patients in each group. Type 4a MI occurred in 8.5% of the ticagrelor group and 8.2% of patients on clopidogrel.

The study hypothesis was that a substantial portion of periprocedural myonecrosis may be thrombotic in nature, and that a stronger P2Y12 inhibitor could reduce the occurrence of these mini-infarcts and thus provide patient benefit. But the hypothesis was not borne out.

“We don’t know if these events are a risk factor or just a marker of risk,” Dr. Silvain said.

There were no between-group differences in major bleeding events at 48 hours or 30 days. However, the rate of nuisance or minor bleeding at 30 days was 11.2% in the ticagrelor arm, significantly higher than the 7.5% incidence with clopidogrel. Moreover, dyspnea occurred in 11.2% of patients on ticagrelor, compared to 0.2% with clopidogrel. Study drug discontinuation was more frequent in the ticagrelor arm: 2.2%, versus 0.4%.

Dr. Silvain also presented a pooled analysis of the 1,883 patients in ALPHEUS plus 781 from the similarly designed SASSICAIA trial, which compared prasugrel (Effient) to clopidogrel. Neither of the more potent P2Y12 inhibitors showed superiority over clopidogrel.

American Heart Association

Discussant Stephen D. Wiviott, MD, summed things up: “With no evidence for ischemic benefit and higher rates of low-severity bleeding, this trial does not support the use of more potent P2Y12 antagonists for elective PCI. Based on these results, and consistent with SASSICAIA, aspirin with clopidogrel should remain the standard of care in this population.”
 

Troponin response may vary

A striking finding in ALPHEUS was the discrepancy between very high rates of periprocedural troponin elevation and very low rates of clinical events through 30 days of follow-up. “When you look at these modest elevations of troponin it appears that there is a lot of noise here,” said Dr. Wiviott, vice president for clinical trials research and administration at Massachusetts General Hospital and Brigham and Women’s Hospital and a cardiologist at Harvard Medical School, Boston.

Troponin elevations in stable coronary patients undergoing PCI may have a different underlying mechanism than elevated troponins in patients undergoing PCI for an acute coronary syndrome, he added. In stable CAD patients, the phenomenon may be more related to atherosclerosis than to platelet activation and thrombosis.

During a panel discussion, Sunil V. Rao, MD, said cardiologists are “probably going to have to go back to the drawing board and think about what kinds of events are really, really important.”

American Heart Association

[email protected]

SOURCE: Silvain J. AHA 2020. Session LBS 3.