Lipid Disorders

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Translating the benefits

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Translating the benefits

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Translating the benefits

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

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

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

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

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

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

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

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

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

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

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

New research is suggesting that there are “meaningful” associations between higher dietary intake of omega-3 fatty acids and lower risk for depressive episodes.

In a longitudinal study of more than 13,000 participants, consumption of omega-3 fatty acids (total and subtypes) was associated with a 2%-65% reduction in the risk for depressive episodes in patients with depressive episodes at baseline.

In addition, consumption of total fatty acids and alpha-linolenic acid was associated with a reduced risk for incident depressive episodes (9% and 29%, respectively).

“Our results showed an important protective effect from the consumption of omega-3,” Maria de Jesus Mendes da Fonseca, University of the State of Rio de Janeiro, and colleagues write.

The findings were published online in Nutrients.
 

Mixed bag of studies

Epidemiologic evidence suggests that deficient dietary omega-3 intake is a modifiable risk factor for depression and that individuals with low consumption of omega-3 food sources have more depressive symptoms.

However, the results are inconsistent, and few longitudinal studies have addressed this association, the investigators note.

The new analysis included 13,879 adults (aged 39-65 years or older) participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) from 2008 to 2014.

Data on depressive episodes were obtained with the Clinical Interview Schedule Revised (CIS-R), and food consumption was measured with the Food Frequency Questionnaire (FFQ).

The target dietary components were total polyunsaturated fatty acids (PUFA) and the omega-3 fatty acids: alpha-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

The majority of participants had adequate dietary intake of omega-3 fatty acids, and none was taking omega-3 supplements.

In the fully adjusted model, consumption of fatty acids from the omega-3 family had a protective effect against maintenance of depressive episodes, showing “important associations, although the significance levels are borderline, possibly due to the sample size,” the researchers report.

In regard to onset of depressive episodes, estimates from the fully adjusted model suggest that a higher consumption of omega-3 acids (total and subtypes) is associated with lower risk for depressive episodes – with significant associations for omega-3 and alpha-linolenic acid.

The investigators note that strengths of the study include “its originality, as it is the first to assess associations between maintenance and incidence of depressive episodes and consumption of omega-3, besides the use of data from the ELSA-Brasil Study, with rigorous data collection protocols and reliable and validated instruments, thus guaranteeing the quality of the sample and the data.”

A study limitation, however, was that the ELSA-Brasil sample consists only of public employees, with the potential for a selection bias such as healthy worker phenomenon, the researchers note. Another was the use of the FFQ, which may underestimate daily intake of foods and depends on individual participant recall – all of which could possibly lead to a differential classification bias.
 

Interpret cautiously

Commenting on the study, David Mischoulon, MD, PhD, professor of psychiatry, Harvard Medical School, and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said that data on omega-3s in depression are “very mixed.”

“A lot of the studies don’t necessarily agree with each other. Certainly, in studies that try to seek an association between omega-3 use and depression, it’s always complicated because it can be difficult to control for all variables that could be contributing to the result that you get,” said Dr. Mischoulon, who is also a member of the Anxiety and Depression Association of America and was not involved in the research.

A caveat to the current study was that diet was assessed only at baseline, “so we don’t really know whether there were any substantial dietary changes over time, he noted.

He also cautioned that it is hard to draw any firm conclusions from this type of study.

“In general, in studies with a large sample, which this study has, it’s easier to find statistically significant differences. But you need to ask yourself: Does it really matter? Is it enough to have a clinical impact and make a difference?” Dr. Mischoulon said.

The ELSA-Brasil study was funded by the Brazilian Ministry of Science, Technology, and Innovation and by the Ministry of Health. The investigators have reported no relevant financial relationships. Dr. Mischoulon has received research support from Nordic Naturals and heckel medizintechnik GmbH and honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy. He also works with the MGH Clinical Trials Network and Institute, which has received research funding from multiple pharmaceutical companies and the National Institute of Mental Health.

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

New research is suggesting that there are “meaningful” associations between higher dietary intake of omega-3 fatty acids and lower risk for depressive episodes.

In a longitudinal study of more than 13,000 participants, consumption of omega-3 fatty acids (total and subtypes) was associated with a 2%-65% reduction in the risk for depressive episodes in patients with depressive episodes at baseline.

In addition, consumption of total fatty acids and alpha-linolenic acid was associated with a reduced risk for incident depressive episodes (9% and 29%, respectively).

“Our results showed an important protective effect from the consumption of omega-3,” Maria de Jesus Mendes da Fonseca, University of the State of Rio de Janeiro, and colleagues write.

The findings were published online in Nutrients.
 

Mixed bag of studies

Epidemiologic evidence suggests that deficient dietary omega-3 intake is a modifiable risk factor for depression and that individuals with low consumption of omega-3 food sources have more depressive symptoms.

However, the results are inconsistent, and few longitudinal studies have addressed this association, the investigators note.

The new analysis included 13,879 adults (aged 39-65 years or older) participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) from 2008 to 2014.

Data on depressive episodes were obtained with the Clinical Interview Schedule Revised (CIS-R), and food consumption was measured with the Food Frequency Questionnaire (FFQ).

The target dietary components were total polyunsaturated fatty acids (PUFA) and the omega-3 fatty acids: alpha-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

The majority of participants had adequate dietary intake of omega-3 fatty acids, and none was taking omega-3 supplements.

In the fully adjusted model, consumption of fatty acids from the omega-3 family had a protective effect against maintenance of depressive episodes, showing “important associations, although the significance levels are borderline, possibly due to the sample size,” the researchers report.

In regard to onset of depressive episodes, estimates from the fully adjusted model suggest that a higher consumption of omega-3 acids (total and subtypes) is associated with lower risk for depressive episodes – with significant associations for omega-3 and alpha-linolenic acid.

The investigators note that strengths of the study include “its originality, as it is the first to assess associations between maintenance and incidence of depressive episodes and consumption of omega-3, besides the use of data from the ELSA-Brasil Study, with rigorous data collection protocols and reliable and validated instruments, thus guaranteeing the quality of the sample and the data.”

A study limitation, however, was that the ELSA-Brasil sample consists only of public employees, with the potential for a selection bias such as healthy worker phenomenon, the researchers note. Another was the use of the FFQ, which may underestimate daily intake of foods and depends on individual participant recall – all of which could possibly lead to a differential classification bias.
 

Interpret cautiously

Commenting on the study, David Mischoulon, MD, PhD, professor of psychiatry, Harvard Medical School, and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said that data on omega-3s in depression are “very mixed.”

“A lot of the studies don’t necessarily agree with each other. Certainly, in studies that try to seek an association between omega-3 use and depression, it’s always complicated because it can be difficult to control for all variables that could be contributing to the result that you get,” said Dr. Mischoulon, who is also a member of the Anxiety and Depression Association of America and was not involved in the research.

A caveat to the current study was that diet was assessed only at baseline, “so we don’t really know whether there were any substantial dietary changes over time, he noted.

He also cautioned that it is hard to draw any firm conclusions from this type of study.

“In general, in studies with a large sample, which this study has, it’s easier to find statistically significant differences. But you need to ask yourself: Does it really matter? Is it enough to have a clinical impact and make a difference?” Dr. Mischoulon said.

The ELSA-Brasil study was funded by the Brazilian Ministry of Science, Technology, and Innovation and by the Ministry of Health. The investigators have reported no relevant financial relationships. Dr. Mischoulon has received research support from Nordic Naturals and heckel medizintechnik GmbH and honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy. He also works with the MGH Clinical Trials Network and Institute, which has received research funding from multiple pharmaceutical companies and the National Institute of Mental Health.

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

New research is suggesting that there are “meaningful” associations between higher dietary intake of omega-3 fatty acids and lower risk for depressive episodes.

In a longitudinal study of more than 13,000 participants, consumption of omega-3 fatty acids (total and subtypes) was associated with a 2%-65% reduction in the risk for depressive episodes in patients with depressive episodes at baseline.

In addition, consumption of total fatty acids and alpha-linolenic acid was associated with a reduced risk for incident depressive episodes (9% and 29%, respectively).

“Our results showed an important protective effect from the consumption of omega-3,” Maria de Jesus Mendes da Fonseca, University of the State of Rio de Janeiro, and colleagues write.

The findings were published online in Nutrients.
 

Mixed bag of studies

Epidemiologic evidence suggests that deficient dietary omega-3 intake is a modifiable risk factor for depression and that individuals with low consumption of omega-3 food sources have more depressive symptoms.

However, the results are inconsistent, and few longitudinal studies have addressed this association, the investigators note.

The new analysis included 13,879 adults (aged 39-65 years or older) participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) from 2008 to 2014.

Data on depressive episodes were obtained with the Clinical Interview Schedule Revised (CIS-R), and food consumption was measured with the Food Frequency Questionnaire (FFQ).

The target dietary components were total polyunsaturated fatty acids (PUFA) and the omega-3 fatty acids: alpha-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA).

The majority of participants had adequate dietary intake of omega-3 fatty acids, and none was taking omega-3 supplements.

In the fully adjusted model, consumption of fatty acids from the omega-3 family had a protective effect against maintenance of depressive episodes, showing “important associations, although the significance levels are borderline, possibly due to the sample size,” the researchers report.

In regard to onset of depressive episodes, estimates from the fully adjusted model suggest that a higher consumption of omega-3 acids (total and subtypes) is associated with lower risk for depressive episodes – with significant associations for omega-3 and alpha-linolenic acid.

The investigators note that strengths of the study include “its originality, as it is the first to assess associations between maintenance and incidence of depressive episodes and consumption of omega-3, besides the use of data from the ELSA-Brasil Study, with rigorous data collection protocols and reliable and validated instruments, thus guaranteeing the quality of the sample and the data.”

A study limitation, however, was that the ELSA-Brasil sample consists only of public employees, with the potential for a selection bias such as healthy worker phenomenon, the researchers note. Another was the use of the FFQ, which may underestimate daily intake of foods and depends on individual participant recall – all of which could possibly lead to a differential classification bias.
 

Interpret cautiously

Commenting on the study, David Mischoulon, MD, PhD, professor of psychiatry, Harvard Medical School, and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said that data on omega-3s in depression are “very mixed.”

“A lot of the studies don’t necessarily agree with each other. Certainly, in studies that try to seek an association between omega-3 use and depression, it’s always complicated because it can be difficult to control for all variables that could be contributing to the result that you get,” said Dr. Mischoulon, who is also a member of the Anxiety and Depression Association of America and was not involved in the research.

A caveat to the current study was that diet was assessed only at baseline, “so we don’t really know whether there were any substantial dietary changes over time, he noted.

He also cautioned that it is hard to draw any firm conclusions from this type of study.

“In general, in studies with a large sample, which this study has, it’s easier to find statistically significant differences. But you need to ask yourself: Does it really matter? Is it enough to have a clinical impact and make a difference?” Dr. Mischoulon said.

The ELSA-Brasil study was funded by the Brazilian Ministry of Science, Technology, and Innovation and by the Ministry of Health. The investigators have reported no relevant financial relationships. Dr. Mischoulon has received research support from Nordic Naturals and heckel medizintechnik GmbH and honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy. He also works with the MGH Clinical Trials Network and Institute, which has received research funding from multiple pharmaceutical companies and the National Institute of Mental Health.

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

Drinking tea has several reported health benefits, but most studies have been conducted in regions where green tea predominates. New data from Britain – where there is a strong tradition of ‘afternoon tea’ – now shows that black tea is also associated with health benefits.

The findings come from a prospective study of nearly 500,000 participants in the UK Biobank cohort, among whom drinking black tea was common. They suggest that drinking black tea may be associated with a moderately lower all-cause mortality risk, and the risk was lowest among those drinking two or more cups of tea per day.

The study was published online in Annals of Internal Medicine.

During a median follow-up of 11.2 years, those who drank at least two cups of tea each day had a lower all-cause mortality risk, reported Maki Inoue-Choi, PhD, and colleagues from the National Cancer Institute in Bethesda, Md.  

After multivariate adjustment, the hazard ratios for death among tea drinkers, compared with no tea intake, were similar across intake levels: 0.95 for daily intake of up to 1 cup, 0.87 for 2-3 cups, 0.88 for 4-5 cups, 0.88 for 6-7 cups, 0.91 for 8-9 cups, and 0.89 for 10 or more cups.

Drinking tea also showed an inverse association with mortality from cardiovascular disease (adjusted HRs ranging from 0.98 to 0.76), ischemic heart disease (aHRs ranging from 1.03 to 0.74), and stroke (aHRs ranging from 0.92 to 0.48 ), However, the researchers added that “no clear trend was seen for cancer or respiratory disease mortality, with associations among higher intake categories tending toward the null.”

There is “no clear answer” as to why no association was observed between tea consumption and cancer mortality in the current study, Dr. Inoue-Choi said at a press briefing. Notably, the effects were apparent regardless of whether milk or sugar was added to tea, tea temperature, or genetic variations in caffeine metabolism among participants.

She and her colleagues controlled for these factors, as well as numerous others that could confound the results, including coffee consumption and baseline health and demographic characteristics..

The study subjects were 498,043 adults with a mean baseline age of 56.5 years. About 85% reported drinking tea, 90% reported drinking black tea, and most drank two to three cups (29%), four to five cups (26%), or six to seven cups (12%) per day.

A limitation of the study is the lack of information on certain aspects of tea intake, such as portion size and tea strength, the authors noted.

Tea is among the most frequently consumed beverages worldwide, and studies from places where green tea is popular, like China and Japan, have demonstrated health benefits. Data from places where black tea is more commonly consumed have been lacking and have provided conflicting results, Dr. Inoue-Choi said.

 A presumed mechanism of action related to tea consumption is reduced oxidative stress and inflammation thanks to "polyphenols and flavonoids, namely catechins and their oxidated products," the authors explained. Oxidative stress and inflammation may promote carcinogenesis; therefore, reducing oxidative stress and inflammation may improve endothelial function, they added.

“While these findings may offer reassurance to tea drinkers, they do not indicate that people should start drinking tea or change their tea consumption for health benefits,” Dr. Inoue-Choi said, explaining that “the results need to be replicated in future studies and extended in other diverse populations.”

This study was funded by the National Cancer Institute Intramural Research Program and the NCI division of cancer epidemiology & genetics. The authors reported no relevant financial relationships.

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

This article was updated 8/31/22.

Drinking tea has several reported health benefits, but most studies have been conducted in regions where green tea predominates. New data from Britain – where there is a strong tradition of ‘afternoon tea’ – now shows that black tea is also associated with health benefits.

The findings come from a prospective study of nearly 500,000 participants in the UK Biobank cohort, among whom drinking black tea was common. They suggest that drinking black tea may be associated with a moderately lower all-cause mortality risk, and the risk was lowest among those drinking two or more cups of tea per day.

The study was published online in Annals of Internal Medicine.

During a median follow-up of 11.2 years, those who drank at least two cups of tea each day had a lower all-cause mortality risk, reported Maki Inoue-Choi, PhD, and colleagues from the National Cancer Institute in Bethesda, Md.  

After multivariate adjustment, the hazard ratios for death among tea drinkers, compared with no tea intake, were similar across intake levels: 0.95 for daily intake of up to 1 cup, 0.87 for 2-3 cups, 0.88 for 4-5 cups, 0.88 for 6-7 cups, 0.91 for 8-9 cups, and 0.89 for 10 or more cups.

Drinking tea also showed an inverse association with mortality from cardiovascular disease (adjusted HRs ranging from 0.98 to 0.76), ischemic heart disease (aHRs ranging from 1.03 to 0.74), and stroke (aHRs ranging from 0.92 to 0.48 ), However, the researchers added that “no clear trend was seen for cancer or respiratory disease mortality, with associations among higher intake categories tending toward the null.”

There is “no clear answer” as to why no association was observed between tea consumption and cancer mortality in the current study, Dr. Inoue-Choi said at a press briefing. Notably, the effects were apparent regardless of whether milk or sugar was added to tea, tea temperature, or genetic variations in caffeine metabolism among participants.

She and her colleagues controlled for these factors, as well as numerous others that could confound the results, including coffee consumption and baseline health and demographic characteristics..

The study subjects were 498,043 adults with a mean baseline age of 56.5 years. About 85% reported drinking tea, 90% reported drinking black tea, and most drank two to three cups (29%), four to five cups (26%), or six to seven cups (12%) per day.

A limitation of the study is the lack of information on certain aspects of tea intake, such as portion size and tea strength, the authors noted.

Tea is among the most frequently consumed beverages worldwide, and studies from places where green tea is popular, like China and Japan, have demonstrated health benefits. Data from places where black tea is more commonly consumed have been lacking and have provided conflicting results, Dr. Inoue-Choi said.

 A presumed mechanism of action related to tea consumption is reduced oxidative stress and inflammation thanks to "polyphenols and flavonoids, namely catechins and their oxidated products," the authors explained. Oxidative stress and inflammation may promote carcinogenesis; therefore, reducing oxidative stress and inflammation may improve endothelial function, they added.

“While these findings may offer reassurance to tea drinkers, they do not indicate that people should start drinking tea or change their tea consumption for health benefits,” Dr. Inoue-Choi said, explaining that “the results need to be replicated in future studies and extended in other diverse populations.”

This study was funded by the National Cancer Institute Intramural Research Program and the NCI division of cancer epidemiology & genetics. The authors reported no relevant financial relationships.

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

This article was updated 8/31/22.

Drinking tea has several reported health benefits, but most studies have been conducted in regions where green tea predominates. New data from Britain – where there is a strong tradition of ‘afternoon tea’ – now shows that black tea is also associated with health benefits.

The findings come from a prospective study of nearly 500,000 participants in the UK Biobank cohort, among whom drinking black tea was common. They suggest that drinking black tea may be associated with a moderately lower all-cause mortality risk, and the risk was lowest among those drinking two or more cups of tea per day.

The study was published online in Annals of Internal Medicine.

During a median follow-up of 11.2 years, those who drank at least two cups of tea each day had a lower all-cause mortality risk, reported Maki Inoue-Choi, PhD, and colleagues from the National Cancer Institute in Bethesda, Md.  

After multivariate adjustment, the hazard ratios for death among tea drinkers, compared with no tea intake, were similar across intake levels: 0.95 for daily intake of up to 1 cup, 0.87 for 2-3 cups, 0.88 for 4-5 cups, 0.88 for 6-7 cups, 0.91 for 8-9 cups, and 0.89 for 10 or more cups.

Drinking tea also showed an inverse association with mortality from cardiovascular disease (adjusted HRs ranging from 0.98 to 0.76), ischemic heart disease (aHRs ranging from 1.03 to 0.74), and stroke (aHRs ranging from 0.92 to 0.48 ), However, the researchers added that “no clear trend was seen for cancer or respiratory disease mortality, with associations among higher intake categories tending toward the null.”

There is “no clear answer” as to why no association was observed between tea consumption and cancer mortality in the current study, Dr. Inoue-Choi said at a press briefing. Notably, the effects were apparent regardless of whether milk or sugar was added to tea, tea temperature, or genetic variations in caffeine metabolism among participants.

She and her colleagues controlled for these factors, as well as numerous others that could confound the results, including coffee consumption and baseline health and demographic characteristics..

The study subjects were 498,043 adults with a mean baseline age of 56.5 years. About 85% reported drinking tea, 90% reported drinking black tea, and most drank two to three cups (29%), four to five cups (26%), or six to seven cups (12%) per day.

A limitation of the study is the lack of information on certain aspects of tea intake, such as portion size and tea strength, the authors noted.

Tea is among the most frequently consumed beverages worldwide, and studies from places where green tea is popular, like China and Japan, have demonstrated health benefits. Data from places where black tea is more commonly consumed have been lacking and have provided conflicting results, Dr. Inoue-Choi said.

 A presumed mechanism of action related to tea consumption is reduced oxidative stress and inflammation thanks to "polyphenols and flavonoids, namely catechins and their oxidated products," the authors explained. Oxidative stress and inflammation may promote carcinogenesis; therefore, reducing oxidative stress and inflammation may improve endothelial function, they added.

“While these findings may offer reassurance to tea drinkers, they do not indicate that people should start drinking tea or change their tea consumption for health benefits,” Dr. Inoue-Choi said, explaining that “the results need to be replicated in future studies and extended in other diverse populations.”

This study was funded by the National Cancer Institute Intramural Research Program and the NCI division of cancer epidemiology & genetics. The authors reported no relevant financial relationships.

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

This article was updated 8/31/22.

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

To address current gaps in expert guidance on newer nonstatin agents, the American College of Cardiology has issued an expert consensus decision pathway on the role of nonstatin therapies in LDL cholesterol lowering for risk reduction in atherosclerotic cardiovascular disease (ASCVD).

Since the publication of the most recent AHA/ACC cholesterol guidelines in 2018, a number of newer nonstatin medications have become available for management of lipid-associated risk, including bempedoic acid, inclisiran, evinacumab, and icosapent ethyl.

These medications were not addressed in the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.

The 53-page document – 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk – was published online in the Journal of the American College of Cardiology.

The new expert consensus document provides guidance for clinicians until the next formal guidelines are produced, Donald Lloyd-Jones, MD, chair of the writing committee, told this news organization.

• In what patient populations should newer nonstatin therapies be considered?
• In what situations should newer nonstatin therapies be considered?
• If newer nonstatin therapies are to be added, which therapies should be considered and in what order to maximize patient benefit and preference?

The document provides algorithms that endorse the four evidence-based patient groups identified in the 2018 guidelines and assumes that the patient is currently taking or has attempted to take a statin, given that that is the most effective initial therapy, the writing group says.

“The algorithms have been streamlined for ease of use by clinicians to help them identify who may need adjunctive nonstatin medications, to provide thresholds for consideration of those medications, and to provide a prioritization of those medications based on the strength of available evidence of efficacy,” said Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University’s Feinberg School of Medicine, Chicago.

“We hope that these pathways will assist the decision-making process for clinicians and patients,” he added.

He also noted that statins remain the “most important first-line therapy for reducing ASCVD risk, because of their efficacy, safety, and low cost. However, for some patients, there are now options if statins do not fully achieve the goals for reducing ASCVD risk or if statins are not tolerated at effective doses.”

“The new expert consensus document highlights that higher-risk patients should be considered more often for adjunctive therapy and provides user-friendly decision pathways to assist in considering the reasonable choices available under different clinical scenarios,” Dr. Lloyd-Jones said.

The document has been endorsed by the National Lipid Association.

This research had no commercial funding. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Allopurinol, a drug commonly used to treat gout, provided no benefit in terms of reducing cardiovascular (CV) events in patients with ischemic heart disease, new randomized trial results show.

Treatment of these patients without gout with 600 mg of allopurinol daily had no effect on composite primary endpoint outcomes, including nonfatal MI, nonfatal stroke, or CV death.

“ALL-HEART is the first large, prospective, randomized trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease and provides robust evidence on the role of allopurinol in these patients,” principal investigator Isla Shelagh Mackenzie, MBChB (Honors), PhD, University of Dundee (Scotland), concluded at a press conference.

Their results suggest allopurinol should not be recommended for secondary prevention of events in this group, Dr. Mackenzie said. Although it remains an important treatment for gout, she added, “other avenues for treatment of ischemic heart disease should be explored in future.”

Results of the ALL-HEART (Allopurinol and Cardiovascular Outcomes in Ischemic Heart Disease) trial were presented at the annual congress of the European Society of Cardiology.
 

Gout treatment

Allopurinol is a xanthine oxidase inhibitor and acts by reducing serum uric acid levels and oxidative stress. Treatment is generally well tolerated, Dr. Mackenzie noted in her presentation, but some patients develop a rash, which can in some cases be serious or even fatal, progressing to Stevens-Johnson syndrome or toxic epidermal necrolysis, “particularly in certain ethnicities.” If rash develops, the advice is to stop treatment immediately.

“The importance of serum uric acid levels in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Dr. Mackenzie explained.

Observational studies have shown variable results, whereas intervention trials, most with fewer than 100 participants, have suggested potential improvements in factors such as blood pressure, endothelial function, left ventricular hypertrophy, or carotid intima-media thickness. Some have reported benefits in acute coronary syndrome and coronary artery bypass grafting, but others have not, she said. A previous study by their own group suggested an improvement in chest pain and exercise time in patients with chronic stable angina and documented coronary artery disease (CAD).

“So, until now, there have been no large prospective randomized trials of the effects of allopurinol on major cardiovascular outcomes in patients with ischemic heart disease,” Dr. Mackenzie said, and this was the aim of ALL-HEART.

ALL-HEART was a prospective, randomized, open-label, blinded-endpoint, multicenter trial. Patients with ischemia heart disease but no history of gout were recruited from 424 general practices across the United Kingdom, starting in February 2014 and with follow-up ending in September 2021. Participants were randomly assigned 1:1 to receive 600 mg of allopurinol daily or usual care.

“It was a decentralized trial, so the follow-up was largely remote after the first 6 weeks, and that included using record linkage data collected from centralized NHS [National Health Service] databases for hospitalizations and deaths in Scotland and England,” she said. The average follow-up was 4.8 years.

During that time, 258 (9.0%) participants in the allopurinol group and 76 (2.6%) in usual care withdrew from follow-up. By the end of the trial, 57.4% of patients in the allopurinol arm withdrew from randomized treatment.

Mean serum uric acid levels dropped from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” she noted.

In total, there were 5,721 patients in the final intention-to-treat analysis, and 639 patients had a first primary event.

For the primary outcome of nonfatal MI, nonfatal stroke, and cardiovascular death, there was no difference between the groups, the researchers reported, with a hazard ratio of 1.04 (95% confidence interval, 0.89-1.21; P = .65). Similarly, in secondary analyses, there were no differences in any of the component endpoints making up the primary outcome (nonfatal MI: HR, 0.97; 95% CI, 0.78-1.21; P = .81; nonfatal stroke: HR, 1.20; 95% CI, 0.89-1.60; P = .23; cardiovascular death: HR, 1.10; 95% CI, 0.85-1.43; P = .48), or in all-cause mortality (HR, 1.02; 95% CI, 0.87-1.20; P = .77), between the two groups, Dr. Mackenzie noted, “so a definitively neutral trial all round.”

In addition, no differences were seen in prespecified subgroups, including age, sex, estimated glomerular filtration rate, or diabetes, MI, heart failure, peripheral arterial disease, stroke, and stroke or transient ischemic attack at baseline.

There were also no significant effects on quality of life outcomes. Cost-effectiveness analyses are ongoing, although no differences are expected there, Dr. Mackenzie noted.

In terms of safety, incident cancers and all-cause mortality did not differ between groups. Serious adverse events were also similar between groups, Dr. Mackenzie said, “and there were no fatal treatment-related SAEs [serious adverse events] in the study.”

Another negative antioxidant trial

Invited discussant for the presentation, Leslie Cho, MD, of the Cleveland Clinic said that ALL-HEART, while an excellent trial with a pragmatic design, constitutes yet another negative antioxidant trial.

She pointed to three problems with this study and antioxidant trials in general. “First, the problem is with the antioxidant,” a xanthine oxidase inhibitor. “Xanthine oxidase is not a major trigger of oxidative stress. In a field of major players,” including nitric oxide, uncoupled endothelial nitric oxide synthase, and mitochondria myeloperoxidase, Dr. Cho said, “xanthine oxidase is a minor player.”

“Moreover, 57% of the patients stopped taking allopurinol, and rightfully so,” she said. Patients were receiving optimal medical therapies, many of which are also antioxidants, including statins, ACE inhibitors, angiotensin receptor blockers, and beta-blockers.

Second, the patient population was older, with an average age of 72 years. “This makes the ALL-HEART study a chronic angina study, chronic CAD study, one of the oldest modern day CAD trials. If you look at LoDoCo or ISCHEMIA trials, the average age is 63.” Patients also had established disease, many with previous revascularization.

The final issue seen with this trial, and all antioxidant trials, is that patient selection is not based on oxidative stress or antioxidant level. “The antioxidant trials have been disappointing at best. There is clear and convincing evidence that oxidative stress is involved in the pathogenesis of atherosclerosis, and yet study after study of antioxidant trials have been negative,” she said.

“Currently, there is no reliable measurement of global level of oxidative stress,” Dr. Cho noted. “Moreover, dose response was not tested, and if we cannot test the baseline antioxidant stress level of patients, we also cannot measure the effect of treatment on the global oxidative stress.”

So, “is there no hope for antioxidant trials?” she asked. Three factors will be required for future success, she said. “No. 1, selecting the right patient at the right time. No. 2, a reliable biomarker to measure oxidative stress to guide who should get therapy, and if the therapy is working. And lastly, targeted therapies that work on major triggers of oxidative stress.”

Also commenting on the results, B. Hadley Wilson, MD, executive vice chair of the Sanger Heart & Vascular Institute/Atrium Health, clinical professor of medicine at the University of North Carolina at Chapel Hill, and vice president of the American College of Cardiology, called ALL-HEART “an important and interesting study.”

“For years, cardiologists and others have been interested in allopurinol as an anti-inflammatory, xanthine oxidase inhibitor ... to prevent coronary ischemic events,” he said in an interview.

But this was a well-designed, well-conducted study, and “unfortunately there was no improvement in the primary outcome, no reduction in major cardiovascular events like myocardial infarction or stroke or cardiovascular death,” Dr. Wilson said. “So, it’s a bit of a disappointment that it’s not there as an important medication to help us with these patients with ischemic heart disease, but it’s also an important question answered — that we need to look at treatments for ischemic heart disease other than allopurinol.”

The trial was supported by the National Institute for Health and Care Research Health Technology Assessment Program in the United Kingdom. Dr. Mackenzie reported research contracts to her institution from NIHR HTA for this work, and other disclosures related to other work. Dr. Cho and Dr. Wilson reported no relevant disclosures.

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

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

Typically, artificial intelligence (AI) is applied to analyze a complex set of variables to make correlations not readily made by unassisted observation. But an AI offshoot, sometimes referred to as causal AI, incorporates causation not just association, and it appears capable of changing the paradigm for preventing cardiovascular (CV) events.

“Causal AI is a new generation of AI algorithms that empowers AI to move beyond prediction to help guide clinical decision-making for each individual,” reported Brian A. Ference, MD, director of research in translational therapeutics, University of Cambridge (England).

In a novel study testing this premise, called CAUSAL AI, this approach was explored with two major risk factors, elevated LDL cholesterol (LDL-C) and elevated systolic BP (SBP). Based on a deep learning algorithm that studied the impact of these risk factors on the biology of atherosclerosis, causal effects of these risk factors were assessed and then embedded in risk estimation.
 

Causal AI can predict treatment effect

The study showed that the accuracy of risk prediction can be improved markedly with causal AI, but, more importantly, it suggests that causal AI can predict the impact of specific actions to reduce this risk in the context of the patient’s trajectory toward CV events.

“Risk-estimating algorithms are used to select patients at high risk who may benefit from interventions to reduce risk, but they do not include the causal effects of changes in LDL-C and SBP,” Dr. Ference explained.

As a result, they “may not accurately estimate the baseline risk of cardiovascular events caused by a person’s LDL-C or SBP level or the benefit of treating these risk factors,” he added.

In the CAUSAL AI study, presented at the annual congress of the European Society of Cardiology, risk prediction embedded with causal AI demonstrated the ability to match predicted events with actual events in several large sets of patient data.

“Embedding causal effects into risk-estimating algorithms accurately estimates baseline cardiovascular risk caused by LDL and SBP and the benefit of lowering LDL, SBP, or both beginning at any age and extending for any duration,” Dr. Ference said.

Deep-learning AI evaluated more than 300 gene variants

The deep-learning AI was based on Mendelian randomization studies evaluating 140 gene variants associated with LDL-C and 202 variants associated with SBP.

In one test of the predictive impact of causal AI, risk prediction was first conducted in 445,771 participants in the UK Biobank with the Joint British Societies (JBS3) risk calculator. Relative to actual events in this population, the JBS3 alone “consistently underestimated the increased risk caused by elevated LDL, blood pressure, or both” over the lifetime of the patient, according to Dr. Ference.

It also systematically overestimated the risk of cardiovascular events among participants with lower LDL-C, blood pressure, or both.

However, after embedding the causal effect of LDL and blood pressure, “the same algorithm was able to precisely predict the risk of cardiovascular events,” Dr. Ference said. The improved accuracy resulted in “nearly superimposable observed and predicted event curves over time.”
 

Embedded causal effects precisely predicts outcomes

Causal AI, embedded into risk analyses, was also able to correct for inaccurate risk benefit derived from short-term clinical trials. These also “systematically underestimate the benefit of lowering LDL, blood pressure, or both,” according to Dr. Ference.

“By contrast, after embedding causal effects of LDL and blood pressure into the algorithm, the same algorithm precisely predicted the benefit of lowering LDL, blood pressure, or both at every age, once again producing superimposable observed and predicted event curves.

In another evaluation conducted by Dr. Ference and coinvestigators, the JBS3 algorithm was applied to several major trials, such as the Heart Protection Trial and HOPE-3. By itself, the JBS3 algorithm predicted less benefit than actually observed.

“After embedding causal effects of LDL and blood pressure, the same algorithm was able to precisely predict the benefit of lowering LDL, blood pressure, or both observed in the trials after 3-5 years,” Dr. Ference reported.

In a sensitivity analysis, the accuracy of the prediction remained largely similar across stratifications by risk factors, such as male sex, presence of diabetes, family history of cardiovascular disease, and other variables. It was also similar across participant age prior to a cardiovascular event and all durations of follow-up.

The data presented by Dr. Ference provides compelling evidence that JBS3, which is widely used in the United Kingdom for risk estimates, does not accurately estimate the risk of cardiovascular disease caused by elevated LDL or SBP. It also fails to estimate the benefit of treating these risk factors.

“Therefore, they cannot be used to determine the optimal timing, intensity, and duration of therapies to prevent cardiovascular events,” Dr. Ference said.

By embedding the causal effects of LDL-C and blood pressure through an AI-based algorithm, the benefit of treatment can be estimated accurately “beginning at any age and lasting for any duration, thus providing the essential information to inform individual treatment decisions about ultimate timing, intensity, and duration,” according to Dr. Ference.
 

Routine application awaits further steps

Despite the promise of this concept, there are many steps to be taken before it is introduced into the clinic, asserted designated discussant Folkert Asselbergs, MD, PhD. In addition to testing the accuracy in multiple populations, “we have to do the trials as well,” meaning prospective evaluations to validate the concept is meaningful for improving outcomes.

However, he does not doubt that the concept of causal AI is promising and likely to have a meaningful impact on cardiology after further validation.

“Causal AI is a crucial step that we need to take for more efficient health care,” he said. One reason he expressed caution is that several risk scores enhanced by AI, although not necessarily causal AI, have shown only “modest predictive value” in several studies that he cited.

“Hopefully the data presented from the CAUSAL AI study will really help us take a step up in the discussion to see how we can really benefit by including genetic information in an AI framework to include causality in predicting risk and predicting benefit of treatment,” said Dr. Asselbergs, professor of precision medicine, University of Utrecht (the Netherlands) Medical Center.

Dr. Ference reported financial relationships with more than 15 pharmaceutical companies. Dr. Asselbergs reported no potential conflicts of interest.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

BARCELONA – Fewer than half the adults in Denmark with type 2 diabetes in 2015 had a recent assessment for albuminuria, and those who underwent testing and had albuminuria had a greater than 50% increased rate of incident heart failure, MI, stroke, or all-cause death during 4-year follow-up, in a study of more than 74,000 Danish residents.

Even those in this study with type 2 diabetes but without albuminuria had a 19% rate of these adverse outcomes, highlighting the “substantial” cardiovascular disease risk faced by people with type 2 diabetes even without a clear indication of nephropathy, Saaima Parveen, MD, a cardiology researcher at Herlev and Gentofte University Hospital in Copenhagen, said at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

This high rate of heart failure, MI, stroke, or death even in the absence of what is conventionally defined as albuminuria – a urinary albumin-to-creatinine ratio (UACR) of at least 30 mg/g – suggests that this threshold for albuminuria may be too high, commented Luis M. Ruilope, MD, professor of public health and preventive medicine at Autonoma University, Madrid, who was not involved with the Danish study.

The study reported by Dr. Parveen “is very important because it shows that the risk of events is high not only in people with diabetes with albuminuria, but also in those without albuminuria,” Dr. Ruilope said in an interview.

The profile of albuminuria as a risk marker for people with type 2 diabetes spiked following the 2021 U.S. approval of finerenone (Kerendia) as an agent specifically targeted to adults with type 2 diabetes and albuminuria. (Finerenone gained marketing approval by in Europe in February 2022 under the same brand name.)
 

A lower threshold for albuminuria?

“Even patients with a UACR of 10-29 mg/g have risk and should be considered for finerenone treatment, said Dr. Ruilope. “People with type 2 diabetes with a UACR of 10-29 mg/g could explain” the high background risk shown by Dr. Parveen in her reported data. “In people with type 2 diabetes and a UACR of 10-29 mg/g we also see progression of kidney disease, but it’s slower” than in those who meet the current, standard threshold for albuminuria.

MDedge News/Mitchel L. Zoler

Dr. Ruilope was a coinvestigator for both of the finerenone pivotal trials, FIDELIO-DKD and FIGARO-DKD. Although the design of both these studies specified enrollment of people with type 2 diabetes and a UACR of at least 30 mg/g, a few hundred of the total combined enrollment of more than 13,000 patients had UACR values below this level, and analysis of this subgroup could provide some important insights into the value of finerenone for people with “high normal” albuminuria, he said.

The study led by Dr. Parveen used data routinely collected in Danish national records and focused on all Danish adults diagnosed with type 2 diabetes as of Jan. 1, 2015, who also had information in their records for a UACR and an estimated glomerular filtration rate (eGFR) within the preceding year.

The records showed that only 47% of these people had a UACR value during this time frame, and that 57% had a recent measure of their eGFR, despite prevailing recommendations for routine and regular measurements of these parameters for all people with type 2 diabetes.

Dr. Parveen hypothesized that UACR measurement may lag for several reasons, such as reliance by primary care physicians on urine dipstick assessments, which preclude calculation of a UACR, poor adherence to regular medical assessment by people in low socioeconomic groups, and medical examination done outside of morning time periods, which is the best time of day for assessing UACR.

More albuminuria measurement needed in primary care

“Measurement of albuminuria in people with type 2 diabetes is improving in Europe, but is not yet at the level that’s needed,” commented Dr. Ruilope. “We are pushing to have it done more often in primary care practices,” he said.

Among the 74,014 people with type 2 diabetes who had the measurement records that allowed for their inclusion in the study, 40% had albuminuria and 60% did not.

During 4 years of follow-up, the incidence of heart failure, MI, stroke, or all-cause death was 28.6% in those with albuminuria and 18.7% among those without albuminuria, reported Dr. Parveen.

The rates for each event type in those with albuminuria were 7.0% for heart failure, 4.4% for MI, 7.6% for stroke, and 16.6% for all-cause death (each patient could tally more than one type of event). Among those without albuminuria, the rates were 4.0%, 3.2%, 5.5%, and 9.3%, respectively.

The study received no commercial funding. Dr. Parveen and Dr. Ruilope had no disclosures.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Increased medical therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Increased medical therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Increased medical therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.

BARCELONA – The SGLT2 inhibitor dapagliflozin (Farxiga) became the third agent from the class to show evidence for efficacy in patients with heart failure with preserved ejection fraction (HFpEF) in results from more than 6,200 randomized patients in the DELIVER trial.

These results proved that dapagliflozin treatment benefits patients with heart failure regardless of their left ventricular function, when considered in tandem with previously reported findings in the DAPA-HF trial that tested the same drug in patients with heart failure with reduced ejection fraction (HFrEF). The DELIVER results for dapagliflozin also highlighted an apparent class effect for heart failure from agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, because of similar, prior findings for two other drugs in the class: empagliflozin (Jardiance) and sotagliflozin (approved in Europe and sold under the name Zynquista).

The upshot, said experts, is that the DELIVER results have further solidified a new paradigm for treating patients with heart failure that is much more agnostic when it comes to left ventricular function and underscores the need to quickly start SGLT2 inhibitor treatment in patients as soon as they receive a heart failure diagnosis, without the need to first measure and consider a patient’s left ventricular ejection fraction.

The new data support the use of SGLT2 inhibitors as “foundational agents for virtually all patients with heart failure” regardless of their ejection fraction or whether or not they have type 2 diabetes, said Scott D. Solomon, MD, who presented the primary results from the DELIVER trial at the annual congress of the European Society of Cardiology. Simultaneous publication of the findings occurred online in The New England Journal of Medicine.

MDedge News/Mitchel L. Zoler

Combined analyses document consistency

Combined analysis of the DELIVER results with the findings from DAPA-HF in a prespecified analysis that included a total of 11,007 patients with heart failure across the full spectrum of ejection fraction values (with individual patients having values as low as less than 20% or as high as more than 70%) showed a consistent benefit from dapagliflozin treatment for significantly reducing the combined endpoint of cardiovascular death or hospitalization for heart failure by about 22%, compared with placebo, across the complete range of this ejection fraction continuum.

The consistency of the benefit, regardless of left ventricular function, “is important clinically, as patients often have to wait for a heart scan to measure ejection fraction and decide on which therapies are indicated,” said Pardeep S. Jhund, MBChB, PhD, who reported this analysis in a separate talk at the congress and in a simultaneous publicationonline in Nature Medicine. Provided patients have no contraindications to treatment with dapagliflozin or another evidence-based SGLT2 inhibitor, prescribing this class prior to imaging to assess ejection fraction “speeds access to this life-saving medication,” said Dr. Jhund, a professor of cardiology and epidemiology at the University of Glasgow.

MDedge News/Mitchel L. Zoler

MDedge News/Mitchel L. Zoler

A ‘swan song’ for ejection fraction

“The striking consistency of effect across the entire ejection fraction range” from SGLT2 inhibitors heralds a “swan song for ejection fraction,” commented Frank Ruschitzka, MD, director of the Heart Center of the University Hospital of Zürich and designated discussant for Dr. Vaduganathan’s report. He also predicted that the medical societies that produce recommendations for managing patient with heart failure will soon, based on the accumulated data, give SGLT2 inhibitors a strong recommendation for use on most heart failure patients, sentiments echoed by several other discussants at the meeting and by editorialists who wrote about the newly published studies.

“SGLT2 inhibitors are the bedrock of therapy for heart failure regardless of ejection fraction or care setting,” wrote Katherine R. Tuttle, MD, and Janani Rangaswami, MD, in an editorial that accompanied the combined analysis published by Dr. Vaduganathan.

DELIVER was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Solomon has been a consultant to and received research funding from AstraZeneca and numerous other companies. Dr. Jhund has received research funding from AstraZeneca. Dr. Vaduganathan has been an advisor to and received research funding from AstraZeneca and numerous other companies. Dr. Tuttle has been a consultant to AstraZeneca as well as Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere. Dr. Rangaswami has been a consultant to AstraZeneca as well as Boehringer Ingelheim, Edwards, and Eli Lilly, and she has been an advisor to Procyrion.