TBD Meeting (3243-21)

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.

A large, multicenter, sham-controlled trial in heart failure showed no benefit at all from stem cell delivery on the primary outcome of recurrent nonfatal decompensated HF events, but the results were still promising, according to the DREAM-HF study’s principal investigator.

When added to guideline-directed medical therapy in patients with HF, a single dose of mesenchymal progenitor cells (MPC) significantly reduced major adverse cardiovascular events (MACE) – a composite of cardiac death, nonfatal MI, and nonfatal stroke – and all-cause death in New York Heart Association (NYHA) class II (but not class III patients), reported Emerson C. Perin, MD, PhD, at the American Heart Association scientific sessions.

The problem is that none of these outcomes were included in the primary endpoint, which was recurrent events because of nonfatal decompensated heart failure. On this endpoint, the hazard ratio for events by the end of follow-up was nonsignificantly but slightly increased among those randomized to MPCs rather than sham control (HR, 1.2; P = .406).

“We learned a lot in this trial,” said Dr. Perin, who is medical director of the Texas Heart Institute in Houston, acknowledging that the expectation of benefit on the primary endpoint now appears to have been misplaced, but the positive result on other outcomes opens a new research direction.

With a negative result on the primary endpoint, a benefit on secondary endpoints is considered hypothesis generating. But Dr. Perin defended his sense of overall optimism about the results, because all of the endpoints on which benefit was demonstrated were prespecified. The positive findings “are not from a post hoc analyses,” he emphasized.
 

DREAM-HF

In the trial, 537 patients with chronic ischemic or nonischemic heart failure with NYHA class II or III symptoms and a left ventricular ejection fraction of 40% or lower were randomized at 51 sites in the United States and Canada. Patients were required to have elevated N-terminal of the prohormone brain natriuretic peptide levels, at least one prior hospitalization for heart failure, and have been on positive inotropic therapy for more than 1 month (but less than 9 months).

The intracardiac administration of MPCs, which are derived from adult human bone marrow, were delivered by injection guided with the NOGA left ventricular electromechanical mapping system. Multiple transendocardial injections were delivered, all in a single session.

There were no differences in baseline characteristics between those receiving MPCs and those who underwent a sham procedure. In both groups, more than half of patients had a previous MI and a coronary revascularization. Nearly 85% had an implanted defibrillator. Roughly two-thirds were in NYHA class III HF and the remaining were in class II.

Over the follow-up, the lines on a graph documenting nonfatal decompensated heart failure events were largely superimposed for the MPC-treated and sham-treated patients, with no significant differences seen over time.

However, the differences on the secondary events were sizable. For the composite outcome of nonfatal MI and nonfatal stroke over a mean follow-up of about 30 months, the rate of events was less than half as great in those randomized to MPCs (4.6% vs. 13.0%). This translated into about 65% reduction in risk (HR, 0.346; P = .001) overall, and the reduction was about the same in class II or III patients.

For a composite endpoint of MACE, events in the group treated with MPCs were about one-third lower than in the sham procedure group (20.3% vs. 30.1%), a difference that also reached significance (HR, 0.667; P = .021).

For this MACE endpoint, response was evaluated by systemic inflammation. For those with a high-sensitivity C-reactive protein (hsCRP) level of less than 2 mg/L, the risk reduction was small and not significant (HR, 0.843; P = .519). Conversely, there was a large risk reduction in those with hsCRP of at least 2 mg/L that did reach statistical significance (HR, 0.551; P = .012).

Inflammation was also found to be a discriminator for time to cardiac death among the patients with NYHA class II HF. Again, there was no benefit among those with hsCRP below 2 mg/L (HR, 1.355; P = .672), but an 80% risk reduction for those with hsCRP of at least 2 mg/L (HR, 0.204; P = .005).

In class II patients with hsCRP at least 2 mg/L, there was also a 60% reduction in all-cause death (HR, 0.401; P = .027). Neither the reduction in cardiac death nor all-cause death was observed in class III HF patients whether or not they had elevated hsCRP.

These signals of benefit provide a direction for a new set of studies, but Dr. Perin said that safety analyses from the DREAM-HF trial are reassuring for further clinical development.

In addition to the fact that “treatment-emergent adverse events and serious adverse events were similar in the MPC-treated and control patients,” Dr. Perin said that MPC administration was not associated with any clinically meaningful immune responses.

MPCs were first injected into a human 15 years ago, according to Dr. Perin. While a phase 2 trial published several years ago did show an association of MPC administration with a reduction in HF-associated events as well as a reduction in adverse ventricular remodeling, the ischemic benefits observed in this trial, particularly in those with elevated hsCRP, provide a new direction for future trials.

“This turns the page in heart failure research. We now have a new mechanism to consider,” Dr. Perin said.
 

Not so fast, expert says

This might be a reasonable conclusion, but the AHA-invited discussant, Larry Allen, MD, believes there is essentially no clinical message from this trial. He reiterated multiple times that this trial was neutral with no trend for benefit on the primary outcome.

“There was benefit on the secondary outcomes of nonfatal MI or stroke, but these are not the outcomes we follow in heart failure patients,” he said, noting that benefit from regenerative therapy on ischemic events has not been a major focus of the trials that preceded DREAM-HF.

Despite these intriguing results, “patients should understand that stem cells remain experimental,” he said. For the patient, it is “more important to double down on the importance of guideline directed medical therapy,” which is still being administered at levels that are suboptimal, according to Dr. Allen, medical director of advanced heart failure at the University of Colorado at Denver, Aurora.

“Keep up the investment” in the promise of stem cell therapy, he said, but he cautioned that some of the secondary benefits observed in DREAM-HF, such as the greater response in patients with elevated hsCRP, appear to be new observations that will require a great deal more study to validate.

Dr. Perin has a financial relationship with Mesoblast, which provided funding for the DREAM-HF trial. Dr. Allen reported no relevant conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

When provided at the bedside of patients hospitalized for heart failure, an electronic health record (EHR) alert with prognostic information did not improve outcomes or appear to have any impact on what treatments were offered.

There was no signal that the EHR prognostic alerts, which identified the 12-month risk of mortality, had any impact on any of a variety of clinical-decision-making metrics or on any of the primary or secondary outcomes, according to Tariq Ahmad, MD, who reported results of the randomized REVEAL-HF trial, presented at the American Heart Association scientific sessions.

“These results call into question the hypothesis that accurate prognostic information alone will lead to better clinical decision-making,” said Dr. Ahmad, medical director of the Heart Transplant and Mechanical Circulatory Support Program at Yale University, New Haven, Conn., and principal investigator of REVEAL-HF.

He acknowledged that the possibility that many clinicians pay little or no attention to EHR alert might have played a role in the negative results.

At four participating Yale-affiliated clinical centers, all patients hospitalized for acute heart failure were randomized as long as they were over the age of 18, had an N-terminal pro-brain natriuretic peptide (NT-proBNP) level above 500 pg/mL, and had been placed on IV diuretics within 24 hours of admission. In the experimental arm, the provider at the time of entering orders received an EHR alert with an estimate of the risk of all-cause mortality at 12 months. There was no such alert for patients managed in the control arm.
 

Twelve-month mortality estimates calculated

The all-cause mortality risk was calculated on a sizeable list of variables that included laboratory results, such as cell counts, and patient characteristics, such as weight and age. The risk estimate was displayed along with a five-category color-coded bar to provide context for the risk in the spectrum of very low, low, medium, high, and very high likelihood of death within 12 months.

The 1,590 patients randomized to the experimental arm and the 1,534 patients randomized to the usual care arm did not differ significantly in any baseline characteristics. The median age was about 77 years, the mean left ventricular ejection fraction (LVEF) was 55%. About 29% had an LVEF below 40%, about 40% had chronic kidney disease, and about 30% had chronic obstructive pulmonary disease (COPD).

The composite primary outcome of all-cause mortality or rehospitalization within 12 months was reached by 38.9% and 39.3% (P = 0.82) of the intervention and control arms, respectively. The components of the primary outcome were also nearly identical, as was inpatient mortality (8.4% vs. 8.8%; P = 0.72).

There were no significant differences in any of the secondary outcomes, which included rates of 30-day rehospitalizations, discharge on guideline-recommended heart failure therapies, implantation of a cardioverter defibrillator, use of a left ventricular assist device, or heart transplant.

The proportion of patients referred for palliative care was almost identical in the very low, low, and medium risk groups. In the high (23.4 vs. 15.6; P = 0.19) and very high (50% vs. 40%; P = 0.92) groups, there were numerically more referrals in the group randomized to usual care, but these rates did not reach significance.
 

No differences seen in discharge meds

There was essentially no difference between groups in the rates at which patients were discharged on beta-blockers, renin-angiotensin system inhibitors, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, or mineralocorticoid antagonists.

When prespecified subgroups, such as those older than age 75 years relative to those younger, males relative to females, Black versus White participants, patients with reduced ejection fraction (HFrEF) relative to preserved ejection fraction (HFpEF), and intensive care unit versus non-ICU patients, were compared, there were no indications that the EHR alert improved outcomes.

Invited discussant Harriette G. C. Van Spall, MD, director of digital health and virtual care and associate professor of cardiology at McMaster University, Hamilton, Ont., did not dispute the conclusions, but she pointed out several potential explanations for the neutral result.

Not least, nearly 75% of those enrolled had low risk or very low risk for adverse outcomes within 1 year, so the opportunity to show a reduction in events, including all-cause mortality, was limited.

“This was largely a HFpEF population, for which there are no treatments for which a risk score would change therapy,” she said.
 

EHR alert efficacy questioned

There is considerable evidence that risk prediction tools “are common but underutilized in HF,” Dr. Van Spall added. She noted that many clinicians find alerts in the EHR more annoying than informative, and it remains unknown what proportion of clinicians pay attention to them, particularly in the absence of evidence that they lead to meaningful improvements in care over their own clinical judgment.

Dr. Ahmad agreed.

“I think that we need to study these alerts in a clinical trial format,” he said. Acknowledging that alerts have been poorly received by many clinicians, Dr. Ahmad said that trials to validate the impact of any specific alert are needed to improve their credibility. If a positive impact cannot be shown, he said the alert should be eliminated, leaving only the alerts with proven clinical value.

Dr. Ahmad reported financial relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Novartis, and Relypsa. Dr. Van Spall reports no potential conflicts of interest.

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

People with paroxysmal atrial fibrillation who explored potential triggers of their arrhythmia, and used them to make lifestyle changes, went on to show a 40% decline in subjectively experienced bouts of AFib in a randomized trial with an unusual design.

American Heart Association

But the study didn’t provide evidence that the drop in self-reported AFib necessarily improved their quality of life, its primary endpoint. Nor was there any apparent relationship between potential triggers and AFib episodes detected less subjectively using a handheld electrocardiography monitor.

Although the study – called I-STOP-AFib – has limitations, its results jibe with alcohol intake’s increasingly appreciated status as a potential AFib trigger. It was alone among many possible triggers tested in showing a consistent association with self-reported AFib.

As a result, the study offers no support for such a link between the arrhythmia and caffeine intake, sleep deprivation, dehydration, exercise, or other conditions sometimes perceived as triggers, observed principal investigator Gregory M. Marcus, MD, MAS, University of California, San Francisco, when presenting results at the American Heart Association scientific sessions. He is also lead author on the study’s simultaneous publication in JAMA Cardiology.

The I-STOP-AFib trial was unusual in part for its virtual design, in which participants followed instructions and tracked AFib episodes – both perceived and detected by the handheld ECG device – through a smartphone application. It also featured an N-of-1 randomized comparisons of different weeks in which individuals were or were not exposed to their self-selected trigger.

Such patients following their own weekly personalized randomization were compared to an entirely separate randomized control arm of the trial, in which patients simply tracked any ECG-monitored and self-perceived AFib episodes.
 

Current use in patients

Although wearable and smartphone-based ECG recorders are increasingly popular for AFib screening, Dr. Marcus said the devices may be especially helpful for validating whether a person’s symptoms are actually caused by AFib.

“I have actually suggested to some of my patients that they run some of these experiments,” he said at a media briefing on I-STOP-AFib before his main presentation of the trial. The demonstration might help patients recognize that some perceived triggers actually do not induce AFib.

Allowing patients to determine on their own whether a substance indeed triggers their AFib “is an efficient use of these devices,” Dr. Marcus said. Such N-of-1 exploration of possible triggers “might help free patients up to enjoy substances – caffeine or coffee is one example – that they otherwise might not, and may help actually reassure them that certain exposures –like certain exercises, which can also be beneficial – might actually not be harmful.”

Dr. Marcus and the other authors on the report noted – as he did at the AHA sessions – that the study has several limitations, such as the subjectivity of self-reported AFib, dropouts from the trial that shrank the randomization arms, and a population that may not be very representative.

There is also the potential for detection bias in the group assigned to track their selected triggers, as Dr. Marcus and some observers have noted.

It follows that conscious avoidance of a potential AFib trigger might well lead to a reduction in AFib subjectively identified by symptoms, proposed David Conen, MD, MPH, Population Health Research Institute, McMaster University, Hamilton, Ont. But perhaps there would have been no reduction in AFib had it been objectively documented with the handheld ECG device, he said in an interview.

“If I were to redesign the study,” he said, “I think the primary endpoint should be confirmed atrial fibrillation, because we would have to show first that the specific trigger actually reduced objective AFib events before we then try to address the question whether reducing that trigger improves quality of life.”
 

Unrepresentative sample

The trial entered 446 overwhelmingly White and college-educated adults known to have symptomatic paroxysmal AFib who were “interested in testing a presumed AFib trigger they could readily introduce or withhold” and who owned a smartphone; the average age was 58 years, and 58% were men. The cohort was randomly assigned to the trigger-testing group or the control group, charged only with tracking their AFib.

Of the total, 320, or about 72%, completed the study; those who did not were mostly from the trigger-testing arm, leaving 136 in that group versus 184 patients in the control group.

Potential triggers that participants selected for tracking included, foremost, caffeine, alcohol, reduced sleep, and exercise, followed by lying on the left side, dehydration, large meals, and cold food or drink, the report noted.

Patients in the control group used the smartphone app and handheld ECG monitor (KardiaMobile, AliveCor) to document the duration and severity of AFib episodes daily and received data summary reports through the app weekly for 10 weeks. They then had the option to follow the trigger-testing protocol at least once.

Those in the trigger-testing group conducted their N-of-1 trials by exposing themselves to their chosen potential trigger during 3 separate weeks and avoiding the trigger during 3 other weeks, alternating each of the 6 weeks of trigger exposure or avoidance. They were instructed through the app to start the 6-week sequence with one or the other strategy randomly and to regularly track their AFib.

At the end of 6 weeks, each participant in the trigger-testing group had the opportunity to review their data for any potential trigger-AFib associations. They were then to use the next 4 weeks to enact lifestyle changes based on what they learned – as described in the report and on clinicaltrials.gov. They had the option of repeating the entire N-of-1 sequence at least one more time.

Participants in both the trigger-tracking and control arms were tested at baseline and at 10 weeks using the validated Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire.

AFEQT scores didn’t change significantly over the 10 weeks in either arm, nor were they significantly different in one arm, compared with the other.

On the other hand, patients in the trigger-tracking arm reported significantly fewer daily AFib episodes during the final 4-week period of lifestyle changes based on their N-of-1 trial results, compared to the monitoring-only control group’s final 4 weeks.

The adjusted relative risk in the trigger-tracking arm was 0.60 (95% confidence interval, 0.43-0.83; P < .001), the difference driven by patients who selected alcohol, dehydration, or exercise for their trigger, Dr. Marcus reported.

Only alcohol intake emerged consistently as a significant predictor of risk for self-reported AFib episodes in a series of meta-analyses conducted using all of the individual N-of-1 trials that provided per-protocol data. The odds ratio was 1.77 (95% CI, 1.20-2.69).

I-STOP-AFib explored an important subject “that has been understudied,” Dr. Conen said. “The trial has some limitations that the authors address themselves, but hopefully it opens the path to future studies that can build upon this experience.”

Dr. Marcus reported receiving personal fees and equity interest from InCarda Therapeutics; personal fees from Johnson & Johnson; and grants from Baylis Medical, Medtronic, the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and the California Tobacco-Related Disease Research Program.

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

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

Higher intake of vegetable fats from foods such as olive oil and nuts is associated with a lower risk for stroke, whereas people who eat more animal fats, especially processed red meats, may have a higher stroke risk, observational findings suggest.

camij/thinkstockphotos.com

In a study of more than 117,000 health professionals who were followed for 27 years, those whose diet was in the highest quintile for intake of vegetable fat had a 12% lower risk for stroke, compared with those who consumed the least amount of vegetable fats.

Conversely, having the highest intake of animal fat from nondairy sources was associated with a 16% increased risk of stroke.

Fenglei Wang, PhD, presented these results at the American Heart Association scientific sessions.

“Our findings support the Dietary Guidelines for Americans and dietary recommendations by AHA,” Dr. Wang, a postdoctoral fellow in the department of nutrition at Harvard University’s T.H. Chan School of Public Health in Boston, told this news organization.

“The main sources of vegetable fat have a large overlap with polyunsaturated fat, such as vegetable oils, nuts, walnuts, and peanut butter,” Dr. Wang noted, adding that fish, especially fatty fish, is a main source of polyunsaturated fat and is recommended for cardiovascular health.

“We would recommend that people reduce consumption of red and processed meat, minimize fatty parts of unprocessed meat if consumed, and replace lard or tallow (beef fat) with nontropical vegetable oils, such as olive oil, corn, or soybean oils in cooking, to lower their stroke risk,” she said.

Moreover, although the results from this study of dietary fat are informative, Dr. Wang continued, “there are other dietary factors (fruits, vegetables, salt, alcohol, et cetera), and lifestyle factors (physical activity, smoking, et cetera), that are associated with stroke risk and worthy of attention as well.”

“Many processed meats are high in salt and saturated fat, and low in vegetable fat,” Alice H. Lichtenstein, DSc, an AHA spokesperson who was not involved with this research, noted in a press release.

“Research shows that replacing processed meat with other protein sources, particularly plant sources, is associated with lower death rates,” added Dr. Lichtenstein, the Stanley N. Gershoff professor of nutrition science and policy at Tufts University in Boston, and lead author of the AHA’s 2021 scientific statement, Dietary Guidance to Improve Cardiovascular Health.

“Key features of a heart-healthy diet pattern,” she summarized, “are to balance calorie intake with calorie needs to achieve and maintain a healthy weight; choose whole grains, lean and plant-based protein, and a variety of fruits and vegetables; limit salt, sugar, animal fat, processed foods, and alcohol; and apply this guidance regardless of where the food is prepared or consumed.”
 

Replace processed meat with plant proteins

The focus on stroke in this study “is important” because, traditionally, studies of diet and cardiovascular health have focused on coronary heart disease, Andrew Mente, PhD, who also was not involved in this research, said in an email to this news organization.

“Overall, the take-home message from the study is that replacing processed meat with plant sources of protein in the diet is probably beneficial,” Dr. Mente, associate professor, health research methods, evidence, and impact, Faculty of Health Sciences, McMaster University, Hamilton, Ont., said.

The finding that people who ate the most vegetable fat had a modest 12% lower risk of stroke than those who ate the least vegetable fat “points to protective effects of foods like seeds, nuts, vegetables, and olive oil, which has been shown previously,” he continued.

The highest quintile of total red meat intake was associated with an 8% higher risk for stroke, but this was driven mainly by processed red meat (which was associated with a 12% higher risk for stroke). These findings are “generally consistent with cohort studies showing that processed meat, as with most highly processed foods for that matter, are associated with an increased risk of cardiovascular events,” Dr. Mente noted.

“Surprisingly, dairy products (such as cheese, butter, or milk) in the study were not connected with the risk of stroke,” he added. This finding differs from results of meta-analyses of multiple cohort studies of dairy intake and stroke and the recent large international PURE study, which showed that dairy intake was associated with a lower risk for stroke.

“What is needed to move the field forward,” according to Dr. Mente, “is to employ new methods that use cutting-edge technology to study nutritional biomarkers and health outcomes.”

“When dealing with modest associations as usually encountered in nutrition, it is a challenge to make causal connections based on dietary questionnaires, which are fraught with measurement error,” he added. “The use of novel methods is where the field is headed.”
 

Total dietary fat, different types, and different food sources

Dr. Wang and colleagues investigated how total dietary fat, different types of fat, and fats from different foods were associated with incident stroke in 73,867 women in the 1984-2016 Nurses’ Health Study and 43,269 men who participated in the 1986-2016 Health Professionals Follow-up Study.

The participants had an average age of 50 years, 63% were women, and 97% were White. They replied to food-frequency questionnaires every 4 years.

Total red meat included beef, pork, or lamb (as a main dish or in sandwiches or mixed dishes) as well as processed red meats (such as bacon, sausage, bologna, hot dogs, and salami).

Animal fat sources included meat, beef tallow, lard, and full-fat dairy products, such as full-fat milk and cheese.

The median percentage of total daily calories from different sources of fat ranged from 10% to 20% for vegetable fat, 3% to 10% for dairy fat, and 7% to 17% for nondairy animal fat (for lowest to highest quintiles).

The median percentage of total daily calories from different types of fat ranged from 5% to 8% for polyunsaturated fat, 4% to 7% for n-6 polyunsaturated fat, 9% to 15% for monounsaturated fat, 8% to 14% for saturated fat, and 1% to 2% for trans fat.

During follow-up, there were 6,189 incident strokes, including 2,967 ischemic strokes and 814 hemorrhagic strokes.

The researchers found that intake in the highest quintile of vegetable fat was associated with a lower risk for total stroke, compared with the lowest quintile (hazard ratio, 0.88; 95% confidence interval, 0.81-0.96; P for trend < .001).

Similarly, the highest intake of polyunsaturated fat was also associated with lower total stroke (HR, 0.88; 95% CI, 0.80-0.96; P for trend = .002). 

Highest intake of nondairy animal fat, however, was associated with an increased risk for total stroke (HR, 1.16; 95% CI, 1.05-1.29; P for trend < .001). They observed “similar associations” for ischemic stroke, but the only positive association for nondairy animal fat was with hemorrhagic stroke, the abstract notes.   

The risk for stroke was lower by 9% per serving per day for vegetable oil but increased by 8% and 12%, respectively, per serving of total red meat or processed red meat.

The association for vegetable oil was attenuated after adjustment for vegetable fat or polyunsaturated fat, whereas adjustment for nondairy animal fat rendered the association for total red meat and processed red meat nonsignificant. 

The study was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Wang has no relevant financial disclosures. Dr. Mente has received research funding from the Dairy Farmers of Canada and the National Dairy Council to analyze data on dairy consumption and health outcomes in the PURE study, which is funded by the Population Health Research Institute, Hamilton Health Sciences Research Institute, and more than 70 other sources (government and pharmaceutical).

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

A novel trial using real-time monitoring found that drinking coffee did not increase atrial arrhythmias but was associated with more premature ventricular contractions.

S_Bachstroem/Getty Images

There was no increase in premature atrial contractions (PACs) or supraventricular tachycardia (SVT) with coffee consumption, and, in fact, there was less SVT in per protocol analyses.

Coffee consumption was also linked to a “clinically meaningful increase in physical activity as well as a clinically meaningful reduction in sleep,” coprincipal investigator Gregory M. Marcus, MD, of the University of California, San Francisco, reported at the American Heart Association scientific sessions.

Although some professional society guidelines warn against caffeine consumption to avoid arrhythmias, he noted that the data have been mixed and that growing evidence suggests coffee consumption may actually lower the risk for arrhythmias, diabetes, and even mortality. The exact relationship has been hard to prove, however, as most coffee studies are observational and rely on self-report.

The Coffee and Real-time Atrial and Ventricular Ectopy (CRAVE) trial took advantage of digital health tools to examine the effect of caffeine consumption on cardiac ectopy burden in 100 healthy volunteers using an N-of-1 design. The primary outcomes were daily PAC and premature ventricular contraction (PVC) counts.

Participants consumed as much coffee as they wanted for 1 day and avoided all caffeine the next, alternating the assignment in 2-day blocks over 2 weeks. They used a smartphone app to receive daily coffee assignments and reminders and wore a continuous recording electrocardiography monitor (ZioPatch, iRhythm Technologies); a continuous glucose monitor (Dexcom); and Fitbit Flex 2, which recorded step counts and sleep duration.

At baseline, 21% of participants drank six to seven cups of coffee per month, 29% drank one cup per day, 21% drank two to three cups per day, and 3% drank four to five cups per day. The U.S. Food and Drug Administration has cited 400 mg per day, or about four or five cups of coffee, as generally safe for healthy adults.

To assess adherence, participants were asked to press the button on the ZioPatch for every coffee drink and were queried daily regarding actual coffee consumption the previous day. Date-stamped receipts for coffee purchases were reimbursed, and smartphone geolocation was used to track coffee shop visits. The great majority of times, participants followed their assignment by all measures, Dr. Marcus said.

ITT and per protocol analyses

ZioPatch data collected over a median of 13.3 days showed a daily median of 12.8 PACs, 7.5 PVCs, 1 nonsustained SVT, and 1 nonsustained ventricular tachycardia.

In intention-to-treat (ITT) analyses, there was no evidence of a relationship between coffee consumption and daily PAC counts (RR, 1.09; 95% confidence interval, 0.98-1.20; P = .10).

In contrast, participants had an average of 54% more PVCs on days randomized to coffee by ITT (RR, 1.54; 95% CI, 1.19-2.00; P = .001), and, per protocol, those consuming more than two cups of coffee per day had a doubling of PVCs (RR, 2.20; 95% CI, 1.24-3.92; P = .007).

No relationship was observed with coffee consumption and SVT episodes in ITT analyses (RR, 0.84; 95% CI, 0.69-1.03; P = .10), but, per protocol, every additional coffee drink consumed in real time was associated with a 12% lower risk for an SVT episode (RR, 0.88; 95% CI, 0.79-0.99; P = .028).

No significant relationships were observed with VT episodes, which were admittedly rare, Dr. Marcus said.

In ITT analyses that adjusted for day of the week, participants took an average of 1,058 more steps on days they drank coffee (95% CI, 441-1,675 steps; P = .001) but slept 36 fewer minutes (95% CI, 22-50 minutes; P < .001).

Per protocol, every additional coffee drink was associated with 587 more steps per day (95% CI, 355-820 steps; P < .001) and 18 fewer minutes of sleep (95% CI, 13-23 minutes; P < .001).

No significant differences in glucose levels were observed. Genetic analyses revealed two significant interactions: fast coffee metabolizers had a heightened risk for PVCs and slow metabolizers experienced more sleep deprivation, Dr. Marcus said.

Typical patients?

Dedicated discussant Sana Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said CRAVE is a “well-conducted and informative trial” that very nicely and effectively used a digital health platform.

She pointed out, however, that the trial enrolled healthy volunteers who not only owned a smartphone but were able to interact with the study team using it. They also had an average age of 38 years, median body mass index of 24 kg/m², and no prior arrhythmias or cardiovascular issues. “These are not representative of the average patient that we see in clinical practice.”

“The other thing to keep in mind is that the primary outcome that they looked at, while relevant, is not adequate in my view to help us derive definitive conclusions about how coffee consumption affects clinically meaningful arrhythmias,” Dr. Al-Khatib said. “Yes, PACs trigger atrial fibrillation, but they don’t do so in every patient. And PVCs have been shown to be associated with increased mortality as well as worsened cardiovascular outcomes, but that’s mostly in patients with structural heart disease.”

She praised the investigators for including genetic data in their analysis. “Whether the results related to physical activity and sleep translate into any major effect on clinical outcomes deserves a study.”

The overall findings need to be replicated by other groups, in other populations, and examine hard outcomes over longer follow-up, concluded Dr. Al-Khatib.

Speaking to this news organization, Dr. Marcus countered that the participants were “pretty run of the mill” coffee drinkers of all ages and that the study highlights the complexity of coffee consumption as well as providing unique data inferring causality regarding increasing physical activity.

“Because coffee is so commonly consumed, highlighting the actual effects is important, and the hope is that understanding those true causal effects and minimizing confounding will help tailor recommendations regarding coffee consumption,” he said. “For those concerned about atrial fibrillation, for example, these data suggest that avoiding coffee does not necessarily make sense to reduce the risk of atrial fibrillation. For those with ventricular arrhythmias, abstinence or minimizing coffee may be a worthwhile experiment.”

Kalyanam Shivkumar, MD, PhD, director of the cardiac arrhythmia center at the University of California, Los Angeles, told this news organization that CRAVE is an important and much-needed study that provides reassuring and objective data for a common clinical question.

“It fits in with the emerging consensus that, in itself, coffee is not problematic,” he said. “And it provides a nice framework for what we’ll be seeing in the future – more studies that use these types of long ECG recordings and interlinking that data with biological readouts.”

Although it is too early to draw any conclusions regarding the genetic analyses, “future studies could use this as a baseline to further explore what happens between fast and slow metabolizers. This is a very useful stepping stone to putting data in context for an individual patient.”

Unless coffee consumption is excessive, such as over five cups per day in young people, all of the evidence points to coffee and caffeine being safe, Chip Lavie, MD, a frequent coffee researcher and medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, New Orleans, told this news organization.

“The benefits of coffee on physical activity/sleep seem to outweigh the risks as this current study suggests,” he said. “This study also supports the safety with regards to atrial arrhythmias, and suggests that those with symptomatic PVCs could try reducing coffee to see if they feel better. In total, however, the benefits of one or several cups of coffee per day on cardiovascular disease outweigh the risks.”

The study was funded by the University of California, San Francisco. Dr. Marcus reports research with the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Tobacco-Related Disease Research Program, Medtronic, Eight Sleep, and Baylis; consulting for InCarda Therapeutics and Johnson & Johnson; and equity in InCarda Therapeutics as cofounder.

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

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

In patients treated for persistent atrial fibrillation (AFib) with pulmonary vein antral isolation (PVAI), there was a numerical but not a statistical advantage for adjunctive left atrial appendage (LAA) ligation in a multicenter randomized trial.

SilkenOne/Thinkstock.com

The study, called aMAZE, was conducted with the LARIAT LAA (AtriCure) ligation system. AtriCure announced in August that the primary efficacy endpoint was not met; the full results were presented Nov. 14 at the American Heart Association scientific sessions.

Exploratory analyses suggested that some subgroups might benefit, but the overall 4.3% advantage provided by adjunctive LAA ligation for freedom from atrial arrhythmias (AA) at 12 months “did not meet predefined criteria for superiority,” according to coprincipal investigator David J. Wilber, MD.

Based on evidence that the LAA contributes substrate for generation of persistent AFib, the hypothesis of the study was that LAA ligation would improve on long-term rhythm control achieved with PVAI alone, which Dr. Wilber noted is currently suboptimal. The LARIAT device is deployed percutaneously into the LAA sac, where it seals off the opening to the left atrium, potentially blocking a pathway for rhythm disturbances.

The study randomized 610 patients at 53 sites in the United States in a 2:1 ratio to LARIAT LAA ligation plus PVAI or to PVAI alone. Enrollment criteria included longstanding persistent and symptomatic AFib and prior failure of ablation therapy. AA was defined as freedom from more than 30 seconds of AFib, atrial flutter, or atrial tachycardia 12 months after treatment without new or increased dosages of antiarrhythmia therapy.

The primary safety endpoint was a composite of serious adverse events within 30 days of placement of the LARIAT device. Technical success was defined as ≤1 mm (+/– 1 mm) residual communication between the LAA and the left atrium.

At 12 months, AA was achieved in 59.9% of those treated with PVAI alone and 64.3% in those who received the LARIAT ligation procedure in addition to PVAI. The P value for superiority was not significant (P = .835).

At 3.4%, the incidence of serious events at 30 days was considered reasonable, leading Dr. Wilber, director of electrophysiology at Loyola University in Chicago, to conclude that the LARIAT system “appears safe.” Overall, bleeding events requiring intervention occurred in 2.2%, cardiac structural injuries requiring surgery occurred in 0.8%, and vascular injuries requiring surgery occurred in 0.3%.

Technical success at 30 days was achieved by the study definition in 81%. If defined as a residual communication of 5 mm or less, the technical success rate was 99%.

Two groups appeared to potentially benefit in exploratory analyses. When stratified by AFib duration, there was a relative 7.5% reduction in AA for those who received LARIAT plus PVAI relative to PVAI alone. This trended towards statistical significance (P = .084), but no advantage was seen for those with longer duration of AFib.

For those with a median volume of at least133 cm³, the advantage of LARIAT for the primary endpoint was 12.4%. This also trended toward significance (P = .093). Conversely, there was a numerical disadvantage for LARIAT plus PVAI relative to PVAI alone for AA at 12 months.

While Dr. Wilber stressed that these analyses were not prespecified and require further exploration, he did conclude that strategies to build on the current success of PVAI with adjunctive strategies “may require some individualization,” taking into account patient or disease characteristics that exert an impact on risk of recurrent AA.

As an AHA-invited discussant on this trial, Usha B. Tedrow, MD, director of the clinical cardiac electrophysiology fellowship at Brigham and Women’s Hospital, Boston, reiterated that this study failed to meet its primary endpoint, but she agreed with the premise that “some subgroups may benefit.”

She identified several aspects of AFib pathophysiology involving the pulmonary vein and the LAA as well as prior studies that suggest the LAA might be a target for adjunctive therapy in patients treated with PVAI for persistent AFib. On this basis, she suggested that there might be other directions to explore before ruling out a role of the LARIAT device in all patients. For example, PVAI plus LARIAT ligation plus another adjunctive ablation intervention might be considered to add durable rhythm control.

She also said that the rigorous conduct of the aMAZE trial might have been a relative obstacle to its own success. Although she praised the meticulous design and conduct of the trial, it might have resulted in an uncommon benefit in controls that diluted the results.

“The success rate in the PVAI group in aMAZE was higher than standard ablation in previous studies looking at LAA exclusion. Could the strict protocol have played a role?” she asked.

Dr. Wilbur reports financial relationships with Abbott, Biosense Webster, Boston Scientific, and AtriCure, which provided funding for this study. Dr. Tedrow reports financial relationships with Abbott, Baylis Medical, Boston Scientific, Biosense Webster, and Thermedical.

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Sam Rogers; Courtesy American Heart Association

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death “across the spectrum” of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m² and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m², Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m² in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, “don’t wait for patients to develop heart failure” to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. “It’s time to start using these drugs upstream to have fewer patients with heart failure downstream,” she said in an interview.

Finerenone works differently than spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Dr. Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m². Statistical analysis showed no hint of an interaction between finerenone’s effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m² or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Dr. Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

“We use MRAs [such as spironolactone] in heart failure patients, but it’s difficult to use because of the risk of patients developing hyperkalemia,” noted Dr. Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin uniquely inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Dr. Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

A prespecified analysis for the combined data from both studies looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m² as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment “was consistent across the full range of eGFR,” said Dr. Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Dr. Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that’s independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Dr. Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Dr. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

mzoler@mdedge.com
 

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

The proportion of hypertensive patients with blood pressure control fell substantially in the United States during the COVID-19 pandemic, if the data from 24 health systems is representative of national trends.

GlobalStock/Getty Images

The decline in blood pressure control corresponded with – and might be explained by – a parallel decline in follow-up visits for uncontrolled hypertension from the same data source, according to Alanna M. Chamberlain, PhD, associate professor of epidemiology in the division of quantitative health sciences, Mayo Clinic, Rochester, Minn.

If the data are representative, a wave of cardiovascular (CV) events might be coming.

The study, called BP Track, collated electronic medical data on almost 1.8 million patients with hypertension from 2017 through 2020. Up until the end of 2019 and prior to the pandemic, slightly less than 60% of these patients had blood pressure control, defined as less than 140/90 mm Hg.

While the pre-COVID control rates were already “suboptimal,” a decline began almost immediately when the full force of the COVID-19 pandemic began in March of 2020, said Dr. Chamberlain in reporting the BP Track results at the American Heart Association scientific sessions.

When graphed from the start of the pandemic until the end of 2020, the proportion under control fell 7.2% to a level just above 50%. For the more rigorous target of less than 130/80 mm Hg, the proportion fell 4.6% over the same period of time, leaving only about 25% at that level of control.

Repeat visits for BP control rebounded

The proportion of patients with a repeat office visit within 4 weeks of a diagnosis of uncontrolled hypertension fell even more steeply, reaching a nadir at about the middle of 2020, but it was followed by a partial recovery. The rate was 5% lower by the end of 2020, relative to the prepandemic rate (31.7% vs. 36.7%), but that was 5% higher than the nadir.

A similar phenomenon was observed with several other metrics. For example, there was a steep, immediate fall correlating with the onset of the pandemic in the proportion of patients who achieved at least a 10–mm Hg reduction or a BP under 140/90 mm Hg when treated for hypertension. Again, the nadir in this proportion was reached in about mid-2020 followed by a partial recovery. By the end of 2020, 5.9% fewer patients were achieving 10–mm Hg or better improvement in BP control when treated relative to the prepandemic level (23.8% vs. 29.7%), but this level was almost 10% higher than the nadir.

Data based on electronic medical records

The nearly 1.8 million patient records evaluated in the BP Track study were drawn from the 24 centers participating in the PCORnet Blood Pressure Control Laboratory Surveillance System. Nationally distributed, 18 of the 24 systems were academically affiliated.

When stratified by race, the proportion of Asians meeting the definition of BP control prior to the pandemic was about 5% higher than the overall average, and the proportion in Blacks was more than 5% lower. Whites had rates of blood pressure control very near the average. The relative declines in BP and the proportion of patients with uncontrolled blood pressure who had a repeat visit within 4 weeks during the pandemic were generally parallel across racial groups.

The implications of these data and the role of the COVID-19 pandemic on blood pressure control are “concerning,” according to Adam Bress, PharmD, department of population health sciences, University of Utah, Salt Lake City.

Citing a study published in 2020 that suggested blood pressure control rates in the United States were already declining before the COVID-19 pandemic, he said the COVID-19 epidemic appears to be exacerbating an existing problem. He expressed particular concern for populations who already have low rates of control, such as African Americans.

“The impact of COVID-19 is likely to be disproportionately greater for underserved and minoritized patients,” said Dr. Bress, who was the lead author of a recent article on this specific topic.

The implication of BP Track is that a wave of cardiovascular events will be coming if the data are nationally representative.

“A recent meta-analysis shows that each 5–mm Hg reduction in blood pressure is associated with age-related reductions in CV events,” Dr. Bress said. For those 55 years of age or older, he said the risk reduction is about 10%. Given that the inverse is almost certainly true, he expects diminishing blood pressure control, whether COVID-19-related or not, to translate into increased CV events.

However, there is no guarantee that the BP Track data are representative of the U.S. population, cautioned Eugene Yang, MD, professor in the division of cardiology, University of Washington, Seattle. Even though a large group of patients was included, they were largely drawn from academic centers.

Nevertheless, Dr. Yang, who chairs the Hypertension Working Group of the American College of Cardiology’s Prevention of Cardiovascular Disease Council, acknowledged that the implications are “scary.”

If the data are representative, “this type of reduction in blood pressure control would be expected to have a significant impact on morbidity and mortality, but we also have to think of all the variables that were not tracked and might add to risk,” he said. He named such risk factors as weight gain, diminished exercise, and increased alcohol consumption, which have been cited by others as being exacerbated by the pandemic.

If these lead to more cardiovascular events on a population basis, the timing of these events would be expected to be age dependent.

“If you look at the patients included in this study, about 50% were 65 years of age or older. In a population like this you would expect to see an increase in events sooner rather than later,” said Dr. Wang.

In other words, if the trial is representative, a wave of cardiovascular events might be seen in the most vulnerable patients “within the next few years,” Dr. Yang speculated.

Dr. Chamberlain reports a research grant from EpidStrategies. Dr. Bress and Dr. Yang report no potential financial conflicts of interest.

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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

Better to intervene early with a new valve in patients with severe aortic stenosis (AS) who are asymptomatic, even during exercise, than to wait for the disease to progress and symptoms to emerge before operating, suggests a small, randomized trial that challenges the guidelines.

Of the trial’s 157 patients, all with negative results on stress tests and normal left ventricular (LV) function despite severe AS, those assigned to early surgical aortic valve replacement (SAVR), compared with standard watchful waiting, showed a better-than-50% drop in risk for death or major adverse cardiac events (MACE) over 2-3 years. The benefit appeared driven by fewer hospitalizations for heart failure (HF) and deaths in the early-surgery group.

The findings “advocate for early surgery once aortic stenosis becomes significant and regardless of symptom status,” Marko Banovic, MD, PhD, said during his presentation at the American Heart Association scientific sessions.

Dr. Banovic, from the University of Belgrade Medical School in Serbia, is coprincipal investigator on the trial, called AVATAR (Aortic Valve Replacement vs. Conservative Treatment in Asymptomatic Severe Aortic Stenosis). He is also lead author on the study’s publication in Circulation, timed to coincide with his AHA presentation.

“The AVATAR findings provide additional evidence to help clinicians in guiding their decision when seeing a patient with significant aortic stenosis, normal left ventricular function, overall low surgical risk, and without significant comorbidities,” Dr. Banovic told this news organization.

European and North American Guidelines favor watchful waiting for asymptomatic patients with severe aortic stenosis, with surgery upon development of symptoms or LV dysfunction, observed Victoria Delgado, MD, PhD, Leiden (the Netherlands) University Medical Center, an invited discussant for the AVATAR presentation.

AVATAR does suggest that “early surgery in truly asymptomatic patients with severe aortic stenosis and preserved ejection fraction seems to provide better outcomes as compared to the conservative treatment,” she said. “But I think that the long-term follow-up for potential events, such as valve durability or endocarditis, is still needed.”

The trial has strengths, compared with the recent RECOVERY trial, which also concluded in favor of early SAVR over watchful waiting in patients described as asymptomatic with severe aortic stenosis. Dr. Delgado and other observers, however, have pointed out limitations of that trial, including questions about whether the patients were truly asymptomatic – stress testing wasn›t routinely performed.

In AVATAR, all patients were negative at stress testing, which required them to reach their estimated maximum heart rate, Dr. Banovic noted. As he and his colleagues write, the trial expands on RECOVERY “by providing evidence of the benefit of early surgery in a setting representative of a dilemma in decision making, in truly asymptomatic patients with severe but not critical aortic stenosis and normal LV function.”

A role for TAVR?

Guidelines in general “can be very conservative and lag behind evidence a bit,” Patricia A. Pellikka, MD, Mayo Clinic, Rochester, Minn., who is not associated with AVATAR, said in an interview.

“I think when we see patients clinically, we can advise them that if they don’t have symptoms and they do have severe aortic stenosis,” she said, “they’re likely going to get symptoms within a reasonably short period of time, according to our retrospective databases, and that doing the intervention early may yield better long-term outcomes.”

The results of AVATAR, in which valve replacement consisted only of SAVR, “probably could be extrapolated” to transcatheter aortic valve replacement (TAVR), Dr. Pellikka observed. “Certainly, TAVR is the procedure that patients come asking for. It’s attractive to avoid a major surgery, and it seems very plausible that TAVR would have yielded similar results if that had been a therapy in this trial.”

In practice, patient age and functional status would figure heavily in deciding whether early valve replacement, and which procedure, is appropriate, Dr. Banovic said in an interview. Importantly, the trial’s patients were at low surgical risk and free of major chronic diseases or other important health concerns.

“Frailty and older age are known risk factors for suboptimal recovery” after SAVR, Dr. Banovic said when interviewed. Therefore, frail patients, who were not many in AVATAR, might be “more suitable for TAVR than SAVR, based on the TAVR-vs.-SAVR results in symptomatic AS patients,” he said.

“One might extrapolate experience from AVATAR trial to TAVR, which may lower the bar for TAVR indications,” but that would require more supporting evidence, Dr. Banovic said.

Confirmed asymptomatic

AVATAR, conducted at nine centers in seven countries in the European Union, randomly assigned 157 adults with severe AS by echocardiography and a LV ejection fraction (LVEF) greater than 50% to early SAVR or conservative management. They averaged 67 years in age, and 43% were women.

The trial excluded anyone with dyspnea, syncope, presyncope, angina, or LV dysfunction and anyone with a history of atrial fibrillation or significant cardiac, renal, or lung disease. The cohort’s average Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 1.7%.

The 78 patients in the early-surgery group “were expected” to have the procedure within 8 weeks of randomization, the published report states; the median time was 55 days. Six of them ultimately did not have the surgery. There was only one periprocedural death, for an operative mortality of 1.4%.

The 79 patients assigned to conservative care were later referred for surgery if they developed symptoms, their LVEF dropped below 50%, or they showed a 0.3-m/sec jump in peak aortic jet velocity at follow-up echocardiography. That occurred with 25 patients a median of 400 days after randomization.

The rate of the primary endpoint – death from any cause, acute myocardial infarction, stroke, or unplanned HF hospitalization – was 16.6% in the early-surgery group and 32.9% for those managed conservatively over a median of 32 months. The hazard ratio by intention-to-treat analysis was 0.46 (95% confidence interval, 0.23-0.90; P = .02). The HR for death from any cause or HF hospitalization was 0.40 (95% CI, 0.19-0.84; P = .013). Any differences in the individual endpoints of death, first HF hospitalizations, thromboembolic complications, or major bleeding were not significant.

If early aortic valve replacement is better for patients like those in AVATAR, some sort of screening for previously unknown severe aortic stenosis may seem attractive for selected populations. “Echocardiography would be the screening test for aortic stenosis, but it’s fairly expensive and therefore has never been advocated as a test to screen everyone,” Dr. Pellikka observed.

“But things are changing,” given innovations such as point-of-care ultrasonography and machine learning, she noted. “Artificial intelligence is progressing in its application to echocardiography, and it’s conceivable that in the future, there might be some abbreviated or screening type of test. But I don’t think we’re quite there yet.”

Dr. Banovic had no conflicts; disclosures for the other authors are in the report. Dr. Delgado disclosed speaker fees from Edwards Lifesciences, Abbott Vascular, Medtronic, Merck, Novartis, and GE Healthcare and unrestricted research grants to her institution from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis, and Medtronic. Dr. Pellikka disclosed receiving a research grant from Ultromics and having unspecified modest relationships with GE Healthcare, Lantheus, and OxThera.

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