CAD & Atherosclerosis

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

In the placebo-controlled REDUCE-IT trial, icosapent ethyl (IPE) was linked to a significant reduction in major adverse cardiovascular events (MACE) when administered on top of LDL cholesterol control, but a new substudy suggests a greater relative advantage in those with a prior myocardial infarction.

In the study as a whole, IPE (Vascepa, Amarin) was tied to a 20% reduction in CV death (hazard ratio, 0.80; P = .03), but it climbed to a 30% reduction (HR, 0.70; P = .01) in the subgroup with a prior MI, reported a multinational team of investigators led by Prakriti Gaba, MD, a cardiologist at Brigham and Women’s Hospital, Boston.

On the basis of these data, “the imperative to treat patients who have a history of prior MI is even stronger,” said Deepak L. Bhatt, MD, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital.

The principal investigator of REDUCE-IT and a coauthor of this subanalysis, Dr. Bhatt said in an interview, “The significant reduction in cardiovascular mortality, as well as sudden cardiac death and cardiac arrest, really should make physicians strongly consider this therapy in eligible patients.”

The main results of the REDUCE-IT trial were published more than 3 years ago. It enrolled patients with established CV disease or diabetes with additional risk factors who were on a statin and had elevated triglyceride (TG) levels.

A 25% reduction in MACE reported

In those randomized to IPE, there was about a 25% reduction in the primary composite MACE outcome of cardiovascular death, nonfatal MI, nonfatal stroke, revascularization, and unstable angina relative to placebo. About the same relative reduction was achieved in the key secondary endpoint of CV death, nonfatal MI, and nonfatal stroke.

Some guidelines have been changed on the basis of these data. The National Lipid Association, for example, conferred a class 1 recommendation for adding IPE to other appropriate lipid-reducing therapies in any individual 45 years of age or older with atherosclerotic cardiovascular disease.

This new substudy (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.02.035), is likely to be influential for those guidelines not yet revised. In the substudy of the prior MI patients, the relative benefit of IPE for the primary and secondary MACE endpoints were of similar magnitude to the overall study population, but events occurred more frequently in the prior-MI subgroup, greatly increasing the statistical power of the advantage.


 

More MACE in prior MI patients

For example, the primary outcome was observed in 22% of the placebo patients in the overall REDUCE-IT analysis but in 26.1% of those with prior MI, so even though the relative risk reduction remained at about 25%, the statistical strength was a hundred-fold greater (P = .00001 vs. P < .001).

For the key secondary composite MACE endpoint, the relative reduction for those with a prior MI was modestly greater than the study as a whole (HR 0.71 vs. HR. 075) but the statistical strength was again magnified in those with a prior MI (P = .00006 vs. P < .001). In those with a prior MI , the advantage of receiving IPE was similar whether or not there had been a prior revascularization.

The 20% lower rate of all-cause mortality among prior MI patients receiving IPE rather than placebo fell just short of statistical significance (HR, 0.80; P = .054). Ischemic events on IPE were reduced by 35% (P = .0000001) and recurrent MI was reduced by 34% (P = .00009).

In the substudy as well as in the REDUCE-IT trial overall, IPE was well tolerated. A slightly higher rate of atrial fibrillation was reported in both.

The REDUCE-IT substudy evaluated 3,693 patients with a history of MI, representing 45% of the 8,179 patients randomized.

IPE, an ethyl ester of the omega-3 polyunsaturated fatty acid, initially attracted attention for its ability to reduce elevated TG. It was hoped this would address reduce residual risk in patients on maximally reduced LDL cholesterol. However, it is suspected that IPE exerts benefits additive to or independent of TG lowering, according to the authors of the REDUCE-IT substudy. These include attenuation of the inflammatory response, release of nitric oxide, and effects that support stabilization of atherosclerotic plaque.

The investigators reported that the pattern of response supports this theory. In the newly reported substudy, the primary event curves that included nonthrombotic events separated at about 1 year, but even curves for CV death and sudden cardiac death were more delayed.

This delay might be explained “by the slow but steady reduction in plaque volume, mitigation of inflammation, improvements in endothelial function, and membrane stabilization,” according to the authors, who cited studies suggesting each of these effects might not be wholly dependent on TG reductions alone.
 

Prior TG-lowering studies disappointing

In fact, several studies evaluating other strategies for TG reductions have been disappointing, according to an accompanying editorial (J Am Coll Cardiol. 2022 Apr 25; doi: 10.1016/j.jacc.2022.03.001). For example, the STRENGTH trial did not show clinical benefits despite a slightly greater reduction in TGs than that shown in REDUCE-IT (19% reduction vs. 18.3%).

Overall, the REDUCE-IT trial and the prior-MI REDUCE-IT substudy show that there is targetable residual risk in high risk patients on statin therapy. One of the authors of the editorial that accompanied the prior-MI substudy of REDUCE-IT, William E. Boden, MD, professor of medicine, Boston University, emphasized this point. On the basis of REDUCE-IT, he said he believes that IPE should be considered to have broad indications as an adjunctive treatment to other lipid-lowering strategies.

“My practice centers on optimizing secondary prevention in high-risk patients who have elevated TG levels despite well-controlled LDL levels on statins, ezetimibe, or even PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitors,” Dr. Boden said in an interview. Patients with diabetes are notorious for presenting with this profile of dyslipidemia, but he added that “even nondiabetics with prior MI, acute coronary syndrome, or revascularization will benefit from the addition of IPE to high-potency statins.”

Although the American Heart Association and the American College of Cardiology have not yet updated their guidelines to include IPE, Dr. Boden pointed out that the European Society of Cardiology, the Canadian Cardiovascular Society, and the American Diabetes Society have.

Dr. Bhatt added that there is a clear message from REDUCE-IT that IPE addresses residual risk.

Targeting the subgroup of high-risk patients with elevated TGs “is easy” because they are so readily identifiable, according to Dr. Bhatt, but he said it should be used for any patient that meet the entry criteria used for REDUCE-IT.

“The overall results of REDUCE-IT were robustly positive, so I wouldn’t just use it in patients with prior MI,” Dr. Bhatt said.

Dr. Bhatt reports financial relationships with more than 20 pharmaceutical companies, including Amarin, which provided funding for this trial. Dr. Boden reports no potential conflicts of interest.

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Although lipoprotein(a) is causally related to coronary artery disease and aortic valve stenosis – two known risk factors for atrial fibrillation (AFib) – evidence linking Lp(a) to a causal role in the development of AFib has been lukewarm at best.

A recent Mendelian randomization study showed only a nominally significant effect of Lp(a) on AFib, whereas an ARIC substudy showed high levels of Lp(a) to be associated with elevated ischemic stroke risk but not incident AFib.

A new study that adds the heft of Mendelian randomization to large observational and genetic analyses, however, implicates Lp(a) as a potential causal mediator of AFib, independent of its known effects on atherosclerotic cardiovascular disease (ASCVD).

“Why this is exciting is because it shows that Lp(a) has effects beyond the arteries and beyond the aortic valve, and that provides two things,” senior author Guillaume Paré, MD, MSc, Population Health Research Institute, Hamilton, Ontario, told this news organization.

“First, it provides a potential means to decrease the risk, because there are all these Lp(a) inhibitors in development,” he said. “But I think the other thing is that it just points to a new pathway that leads to atrial fibrillation development that could potentially be targeted with other drugs when it’s better understood. We don’t pretend that we understand the biology there, but it opens this possibility.”

The results were published in the Journal of the American College of Cardiology.

Using data from 435,579 participants in the UK Biobank, the researchers identified 20,432 cases of incident AFib over a median of 11 years of follow-up. They also constructed a genetic risk score for Lp(a) using genetic variants within 500 kb of the LPA gene.

After common AFib risk factors were controlled for, results showed a 3% increased risk for incident AFib per 50 nmol/L increase in Lp(a) at enrollment (hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

A Mendelian randomization analysis showed a similar association between genetically predicted Lp(a) and AFib (odds ratio, 1.03; 95% CI, 1.02-1.05).

To replicate the results, the investigators performed separate Mendelian randomization analyses using publicly available genome-wide association study (GWAS) statistics from the largest GWAS of AFib involving more than 1 million participants and from the FinnGen cohort involving more than 114,000 Finnish residents.

The analyses showed a 3% increase in risk for AFib in the genome-wide study (OR, 1.03; 95% CI, 1.02-1.05) and an 8% increase in risk in the Finnish study (OR, 1.08; 95% CI, 1.04-1.12) per 50 nmol/L increase in Lp(a).

There was no evidence that the effect of observed or genetically predicted Lp(a) was modified by prevalent ischemic heart disease or aortic stenosis.

Further, MR analyses revealed no risk effect of low-density-lipoprotein cholesterol or triglycerides on AFib.

Notably, only 39% of Lp(a) was mediated through ASCVD, suggesting that Lp(a) partly influences AFib independent of its known effect on ASCVD.

“To me, the eureka moment is when we repeated the same analysis for LDL cholesterol and it had absolutely no association with AFib,” Dr. Paré said. “Because up to that point, there was always this lingering doubt that, well, it’s because of coronary artery disease, and that’s logical. But the signal is completely flat with LDL, and we see this strong signal with Lp(a).”

Another ‘red flag’

Erin D. Michos, MD, MHS, senior author of the ARIC substudy and associate director of preventive cardiology at Johns Hopkins School of Medicine, Baltimore, said the findings are “another red flag that lipoprotein(a) is a marker we need to pay attention to and potentially needs treatment.”

“The fact that it was Mendelian randomization does suggest that there’s a causal role,” she said. “I think the relationship is relatively modest compared to its known risk for stroke, ASCVD, coronary disease, and aortic stenosis, ... which may be why we didn’t see it in the ARIC cohort with 12,000 participants. You needed to have a million participants and 60,000 cases to see an effect here.”

Dr. Michos said she hopes the findings encourage increased testing, particularly with multiple potential treatments currently in the pipeline. She pointed out that the researchers estimated that the experimental antisense agent pelacarsen, which lowers Lp(a) by about 80%, would translate into about an 8% reduction in AFib risk, or “the same effect as 2 kg of weight loss or a 5 mm Hg reduction in blood pressure, which we do think are meaningful.”

Adding to this point in an accompanying editorial, Daniel Seung Kim, MD, PhD, and Abha Khandelwal, MD, MS, Stanford University School of Medicine, California, say that “moreover, reduction of Lp(a) levels would have multifactorial effects on CAD, cerebrovascular/peripheral artery disease, and AS risk.

“Therefore, approaches to reduce Lp(a) should be prioritized to further reduce the morbidity and mortality of a rapidly aging population,” they write.

The editorialists also join the researchers in calling for inclusion of AFib as a secondary outcome in ongoing Lp(a) trials, in addition to cerebrovascular disease and peripheral vascular disease.
 

Unanswered questions

As to what’s driving the risk effect of Lp(a), first author Pedrum Mohammadi-Shemirani, PhD, also from the Population Health Research Institute, explained that in aortic stenosis, “mechanical stress increases endothelial permeability, allowing Lp(a) to infiltrate valvular tissue and induce gene expression that results in microcalcifications and cell death.”

“So, in theory, a similar sort of mechanism could be at play in atrial tissue that may lead to damage and the electrical remodeling that causes atrial fibrillation,” he told this news organization.

Dr. Mohammadi-Shemirani also noted that Lp(a) has proinflammatory properties, but added that any potential mechanisms are “speculative and require further research to disentangle.”

Dr. Paré and colleagues say follow-up studies are also warranted, noting that generalizability of the results may be limited because AFib cases were found using electronic health records in the population-scale cohorts and because few UK Biobank participants were of non-European ancestry and Lp(a) levels vary among ethnic groups.

Another limitation is that the number of kringle IV type 2 domain repeats within the LPA gene, the largest contributor to genetic variation in Lp(a), could not be directly measured. Still, 71.4% of the variation in Lp(a) was explained using the genetic risk score alone, they say.

Dr. Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. Dr. Mohammadi-Shemirani is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr. Michos reports consulting for Novartis and serving on advisory boards for Novartis, AstraZeneca, Bayer, and Boehringer Ingelheim. Dr. Kim reports grant support from the National Institutes of Health and the American Heart Association. Dr. Khandelwal serves on the advisory board of Amgen and has received funding from Novartis CTQJ and Akcea.

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

Bariatric surgery can reduce the risk of long-term cardiovascular outcomes in older Medicare beneficiaries with obesity, a large new observational study in which a third of the patients were over age 65 years suggests.

Overall, patients who underwent bariatric surgery had 37% lower all-cause mortality and were significantly less likely to have admissions for new-onset heart failure (64% risk reduction), myocardial infarction (37% risk reduction), and ischemic stroke (29% risk reduction), compared with similar patients who received more conservative treatment, after a median of 4 years of follow-up, report Amgad Mentias, MD, MS, a clinical cardiologist at the Cleveland Clinic Foundation, Ohio, and colleagues.

The results were published in the Journal of the American College of Cardiology.

Previous studies on bariatric surgery outcomes have primarily focused on individuals from select health care networks or medical facilities with restricted coverage in the United States or on patients with diabetes, noted Tiffany M. Powell-Wiley, MD, MPH, of the National Institutes of Health’s National Heart, Lung, and Blood Institute, Bethesda, Maryland, and colleagues in an accompanying editorial.

Contemporary cohort of patients

“A lot of the studies showed long-term outcomes outside of the U.S., specifically in Europe,” Dr. Mentias added.

The aim of this study was to evaluate the long-term association between bariatric surgery and risk of adverse cardiovascular outcomes in a contemporary large cohort from the United States.

Older patients (> 65 years) and those without diabetes were looked at as specific subgroups.

The researchers assessed 189,770 patients. There were 94,885 matched patients in each cohort. Mean age was 62.33 years. Female patients comprised 70% of the cohort. The study group had an average BMI of 44.7 kg/m2.

The study cohort was matched 1:1. Participants were either part of a control group with obesity or a group of Medicare beneficiaries who had bariatric surgery between 2013 and 2019. Sex, propensity score matching on 87 clinical variables, age, and BMI were used to match patients.

Myocardial infarction, new-onset heart failure, ischemic stroke, and all-cause mortality were all study outcomes. As a sensitivity analysis, the study team conducted an instrumental variable assessment.

More specifically, the findings showed that bariatric surgery was linked with the following after a median follow-up of 4.0 years:

• Myocardial infarction (hazard ratio, 0.63; 95% confidence interval, 0.59-0.68)
• Stroke (HR, 0.71; 95% CI, 0.65-0.79)
• New-onset heart failure (HR, 0.46; 95% CI, 0.44-0.49)
• Reduced risk of death (9.2 vs. 14.7 per 1000 person-years; HR, 0.63; 95% CI, 0.60-0.66)

Findings for those over the age of 65 were similar – lower risks of all-cause mortality (HR, 0.64), new-onset heart failure (HR, 0.52), myocardial infarction (HR, 0.70), and stroke (HR, 0.76; all P < .001). Similar findings were shown in subgroup analyses in men and women and in patients with and without diabetes.

The study cohort primarily consisted of Medicare patients, which limits the generalizability of the data. Lack of data on medications taken for cardiovascular and weight loss purposes and potential coding errors because the information was gathered from an administrative database were all limitations of the study, the researchers note.

An additional limitation was that residual unmeasured confounders, particularly patient-focused physical, social, and mental support factors, could play a role in whether a patient opted to have bariatric surgery, the study authors note.

“Additional studies are needed to compare cardiovascular outcomes after bariatric surgery with weight loss medications like glucagon-like peptide-1 (GLP-1) analogues,” the researchers add.

This study was partially funded by philanthropic contributions by the Khouri family, Bailey family, and Haslam family to the Cleveland Clinic for co-author Dr. Milind Y. Desai’s research. Dr. Mentias has disclosed no relevant financial relationships. Dr. Powell-Wiley disclosed relationships with the National Institute on Minority Health and Health Disparities and the Division of Intramural Research of the National, Heart, Lung, and Blood Institute of the National Institutes of Health.

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

Bariatric surgery can reduce the risk of long-term cardiovascular outcomes in older Medicare beneficiaries with obesity, a large new observational study in which a third of the patients were over age 65 years suggests.

Overall, patients who underwent bariatric surgery had 37% lower all-cause mortality and were significantly less likely to have admissions for new-onset heart failure (64% risk reduction), myocardial infarction (37% risk reduction), and ischemic stroke (29% risk reduction), compared with similar patients who received more conservative treatment, after a median of 4 years of follow-up, report Amgad Mentias, MD, MS, a clinical cardiologist at the Cleveland Clinic Foundation, Ohio, and colleagues.

The results were published in the Journal of the American College of Cardiology.

Previous studies on bariatric surgery outcomes have primarily focused on individuals from select health care networks or medical facilities with restricted coverage in the United States or on patients with diabetes, noted Tiffany M. Powell-Wiley, MD, MPH, of the National Institutes of Health’s National Heart, Lung, and Blood Institute, Bethesda, Maryland, and colleagues in an accompanying editorial.

Contemporary cohort of patients

“A lot of the studies showed long-term outcomes outside of the U.S., specifically in Europe,” Dr. Mentias added.

The aim of this study was to evaluate the long-term association between bariatric surgery and risk of adverse cardiovascular outcomes in a contemporary large cohort from the United States.

Older patients (> 65 years) and those without diabetes were looked at as specific subgroups.

The researchers assessed 189,770 patients. There were 94,885 matched patients in each cohort. Mean age was 62.33 years. Female patients comprised 70% of the cohort. The study group had an average BMI of 44.7 kg/m2.

The study cohort was matched 1:1. Participants were either part of a control group with obesity or a group of Medicare beneficiaries who had bariatric surgery between 2013 and 2019. Sex, propensity score matching on 87 clinical variables, age, and BMI were used to match patients.

Myocardial infarction, new-onset heart failure, ischemic stroke, and all-cause mortality were all study outcomes. As a sensitivity analysis, the study team conducted an instrumental variable assessment.

More specifically, the findings showed that bariatric surgery was linked with the following after a median follow-up of 4.0 years:

• Myocardial infarction (hazard ratio, 0.63; 95% confidence interval, 0.59-0.68)
• Stroke (HR, 0.71; 95% CI, 0.65-0.79)
• New-onset heart failure (HR, 0.46; 95% CI, 0.44-0.49)
• Reduced risk of death (9.2 vs. 14.7 per 1000 person-years; HR, 0.63; 95% CI, 0.60-0.66)

Findings for those over the age of 65 were similar – lower risks of all-cause mortality (HR, 0.64), new-onset heart failure (HR, 0.52), myocardial infarction (HR, 0.70), and stroke (HR, 0.76; all P < .001). Similar findings were shown in subgroup analyses in men and women and in patients with and without diabetes.

The study cohort primarily consisted of Medicare patients, which limits the generalizability of the data. Lack of data on medications taken for cardiovascular and weight loss purposes and potential coding errors because the information was gathered from an administrative database were all limitations of the study, the researchers note.

An additional limitation was that residual unmeasured confounders, particularly patient-focused physical, social, and mental support factors, could play a role in whether a patient opted to have bariatric surgery, the study authors note.

“Additional studies are needed to compare cardiovascular outcomes after bariatric surgery with weight loss medications like glucagon-like peptide-1 (GLP-1) analogues,” the researchers add.

This study was partially funded by philanthropic contributions by the Khouri family, Bailey family, and Haslam family to the Cleveland Clinic for co-author Dr. Milind Y. Desai’s research. Dr. Mentias has disclosed no relevant financial relationships. Dr. Powell-Wiley disclosed relationships with the National Institute on Minority Health and Health Disparities and the Division of Intramural Research of the National, Heart, Lung, and Blood Institute of the National Institutes of Health.

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

Bariatric surgery can reduce the risk of long-term cardiovascular outcomes in older Medicare beneficiaries with obesity, a large new observational study in which a third of the patients were over age 65 years suggests.

Overall, patients who underwent bariatric surgery had 37% lower all-cause mortality and were significantly less likely to have admissions for new-onset heart failure (64% risk reduction), myocardial infarction (37% risk reduction), and ischemic stroke (29% risk reduction), compared with similar patients who received more conservative treatment, after a median of 4 years of follow-up, report Amgad Mentias, MD, MS, a clinical cardiologist at the Cleveland Clinic Foundation, Ohio, and colleagues.

The results were published in the Journal of the American College of Cardiology.

Previous studies on bariatric surgery outcomes have primarily focused on individuals from select health care networks or medical facilities with restricted coverage in the United States or on patients with diabetes, noted Tiffany M. Powell-Wiley, MD, MPH, of the National Institutes of Health’s National Heart, Lung, and Blood Institute, Bethesda, Maryland, and colleagues in an accompanying editorial.

Contemporary cohort of patients

“A lot of the studies showed long-term outcomes outside of the U.S., specifically in Europe,” Dr. Mentias added.

The aim of this study was to evaluate the long-term association between bariatric surgery and risk of adverse cardiovascular outcomes in a contemporary large cohort from the United States.

Older patients (> 65 years) and those without diabetes were looked at as specific subgroups.

The researchers assessed 189,770 patients. There were 94,885 matched patients in each cohort. Mean age was 62.33 years. Female patients comprised 70% of the cohort. The study group had an average BMI of 44.7 kg/m2.

The study cohort was matched 1:1. Participants were either part of a control group with obesity or a group of Medicare beneficiaries who had bariatric surgery between 2013 and 2019. Sex, propensity score matching on 87 clinical variables, age, and BMI were used to match patients.

Myocardial infarction, new-onset heart failure, ischemic stroke, and all-cause mortality were all study outcomes. As a sensitivity analysis, the study team conducted an instrumental variable assessment.

More specifically, the findings showed that bariatric surgery was linked with the following after a median follow-up of 4.0 years:

• Myocardial infarction (hazard ratio, 0.63; 95% confidence interval, 0.59-0.68)
• Stroke (HR, 0.71; 95% CI, 0.65-0.79)
• New-onset heart failure (HR, 0.46; 95% CI, 0.44-0.49)
• Reduced risk of death (9.2 vs. 14.7 per 1000 person-years; HR, 0.63; 95% CI, 0.60-0.66)

Findings for those over the age of 65 were similar – lower risks of all-cause mortality (HR, 0.64), new-onset heart failure (HR, 0.52), myocardial infarction (HR, 0.70), and stroke (HR, 0.76; all P < .001). Similar findings were shown in subgroup analyses in men and women and in patients with and without diabetes.

The study cohort primarily consisted of Medicare patients, which limits the generalizability of the data. Lack of data on medications taken for cardiovascular and weight loss purposes and potential coding errors because the information was gathered from an administrative database were all limitations of the study, the researchers note.

An additional limitation was that residual unmeasured confounders, particularly patient-focused physical, social, and mental support factors, could play a role in whether a patient opted to have bariatric surgery, the study authors note.

“Additional studies are needed to compare cardiovascular outcomes after bariatric surgery with weight loss medications like glucagon-like peptide-1 (GLP-1) analogues,” the researchers add.

This study was partially funded by philanthropic contributions by the Khouri family, Bailey family, and Haslam family to the Cleveland Clinic for co-author Dr. Milind Y. Desai’s research. Dr. Mentias has disclosed no relevant financial relationships. Dr. Powell-Wiley disclosed relationships with the National Institute on Minority Health and Health Disparities and the Division of Intramural Research of the National, Heart, Lung, and Blood Institute of the National Institutes of Health.

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

A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.

The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.

“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.

“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.

The findings were published online  in BMJ.

In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.

Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.

Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.

This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.

Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.

High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).

High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).

High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).

Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.

In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).

In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.

High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).

In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.

“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.

“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.

Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.

“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.

As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
 

Non-HDL cholesterol a better marker?

For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.

“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”

Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.

What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.

“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.

The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.

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

A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.

The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.

“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.

“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.

The findings were published online  in BMJ.

In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.

Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.

Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.

This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.

Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.

High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).

High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).

High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).

Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.

In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).

In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.

High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).

In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.

“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.

“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.

Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.

“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.

As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
 

Non-HDL cholesterol a better marker?

For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.

“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”

Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.

What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.

“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.

The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.

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

A network meta-analysis of 42 clinical trials concludes that rosuvastatin, simvastatin, and atorvastatin are the statins most effective at lowering non-high-density-lipoprotein cholesterol (non-HDL-C) in people with diabetes and at risk for cardiovascular disease.

The analysis focused on the efficacy of statin treatment on reducing non-HDL-C, as opposed to reducing low-density-lipoprotein cholesterol (LDL-C), which has traditionally been used as a surrogate to determine cardiovascular disease risk from hypercholesterolemia.

“The National Cholesterol Education Program in the United States recommends that LDL-C values should be used to estimate the risk of cardiovascular disease related to lipoproteins,” lead author Alexander Hodkinson, MD, senior National Institute for Health Research fellow, University of Manchester, England, told this news organization.

“But we believe that non-high-density-lipoprotein cholesterol is more strongly associated with the risk of cardiovascular disease, because non-HDL-C combines all the bad types of cholesterol, which LDL-C misses, so it could be a better tool than LDL-C for assessing CVD risk and effects of treatment. We already knew which of the statins reduce LDL-C, but we wanted to know which ones reduced non-HDL-C; hence the reason for our study,” Dr. Hodkinson said.

The findings were published online  in BMJ.

In April 2021, the National Institute for Health and Care Excellence (NICE) in the United Kingdom updated guidelines for adults with diabetes to recommend that non-HDL-C should replace LDL-C as the primary target for reducing the risk for cardiovascular disease with lipid-lowering treatment.

Currently, NICE is alone in its recommendation. Other international guidelines do not have a non-HDL-C target and use LDL-C reduction instead. These include guidelines from the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association (AHA), and the National Lipid Association.

Non–HDL-C is simple to calculate and can easily be done by clinicians by subtracting HDL-C from the total cholesterol level, he added.

This analysis compared the effectiveness of different statins at different intensities in reducing levels of non-HDL-C in 42 randomized controlled trials that included 20,193 adults with diabetes.

Compared with placebo, rosuvastatin, given at moderate- and high-intensity doses, and simvastatin and atorvastatin at high-intensity doses, were the best at lowering levels of non-HDL-C over an average treatment period of 12 weeks.

High-intensity rosuvastatin led to a 2.31 mmol/L reduction in non-HDL-C (95% credible interval, –3.39 to –1.21). Moderate-intensity rosuvastatin led to a 2.27 mmol/L reduction in non-HDL-C (95% credible interval, –3.00 to –1.49).

High-intensity simvastatin led to a 2.26 mmol/L reduction in non-HDL-C (95% credible interval, –2.99 to –1.51).

High-intensity atorvastatin led to a 2.20 mmol/L reduction in non-HDL-C (95% credible interval, –2.69 to –1.70).

Atorvastatin and simvastatin at any intensity and pravastatin at low intensity were also effective in reducing levels of non-HDL-C, the researchers noted.

In 4,670 patients who were at great risk for a major cardiovascular event, atorvastatin at high intensity showed the largest reduction in levels of non-HDL-C (1.98 mmol/L; 95% credible interval, –4.16 to 0.26).

In addition, high-intensity simvastatin and rosuvastatin were the most effective in reducing LDL-C.

High-intensity simvastatin led to a 1.93 mmol/L reduction in LDL-C (95% credible interval, –2.63 to –1.21), and high-intensity rosuvastatin led to a 1.76 mmol/L reduction in LDL-C (95% credible interval, –2.37 to –1.15).

In four studies, significant reductions in nonfatal myocardial infarction were shown for atorvastatin at moderate intensity, compared with placebo (relative risk, 0.57; 95% confidence interval, 0.43-.76). No significant differences were seen for discontinuations, nonfatal stroke, or cardiovascular death.

“We hope our findings will help guide clinicians on statin selection itself, and what types of doses they should be giving patients. These results support using NICE’s new policy guidelines on cholesterol monitoring, using this non-HDL-C measure, which contains all the bad types of cholesterol for patients with diabetes,” Dr. Hodkinson said.

“This study further emphasizes what we have known about the benefit of statin therapy in patients with type 2 diabetes,” Prakash Deedwania, MD, professor of medicine, University of California, San Francisco, told this news organization.

Dr. Deedwania and others have published data on patients with diabetes that showed that treatment with high-intensity atorvastatin was associated with significant reductions in major adverse cardiovascular events.

“Here they use non-HDL cholesterol as a target. The NICE guidelines are the only guidelines looking at non-HDL cholesterol; however, all guidelines suggest an LDL to be less than 70 in all people with diabetes, and for those with recent acute coronary syndromes, the latest evidence suggests the LDL should actually be less than 50,” said Dr. Deedwania, spokesperson for the AHA and ACC.

As far as which measure to use, he believes both are useful. “It’s six of one and half a dozen of the other, in my opinion. The societies have not recommended non-HDL cholesterol and it’s easier to stay with what is readily available for clinicians, and using LDL cholesterol is still okay. The results of this analysis are confirmatory, in that looking at non-HDL cholesterol gives results very similar to what these statins have shown for their effect on LDL cholesterol,” he said.
 

Non-HDL cholesterol a better marker?

For Robert Rosenson, MD, director of metabolism and lipids at Mount Sinai Health System and professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, New York, non-HDL cholesterol is becoming an important marker of risk for several reasons.

“The focus on LDL cholesterol has been due to the causal relationship of LDL with atherosclerotic cardiovascular disease, but in the last few decades, non-HDL has emerged because more people are overweight, have insulin resistance, and have diabetes,” Dr. Rosenson told this news organization. “In those situations, the LDL cholesterol underrepresents the risk of the LDL particles. With insulin resistance, the particles become more triglycerides and less cholesterol, so on a per-particle basis, you need to get more LDL particles to get to a certain LDL cholesterol concentration.”

Non-HDL cholesterol testing does not require fasting, another advantage of using it to monitor cholesterol, he added.

What is often forgotten is that moderate- to high-intensity statins have very good triglyceride-lowering effects, Dr. Rosenson said.

“This article highlights that, by using higher doses, you get more triglyceride-lowering. Hopefully, this will get practitioners to recognize that non-HDL cholesterol is a better predictor of risk in people with diabetes,” he said.

The study was funded by the National Institute for Health Research. Dr. Hodkinson, Dr. Rosenson, and Dr. Deedwania report no relevant financial relationships.

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

The addition of aspirin to standard guideline management for blood pressure did not reduce the risk of cardiovascular events among adults with hypertension and controlled systolic blood pressure in a study.

The benefits of aspirin use for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) have been questioned in light of data showing neutral outcomes in low-risk patients and concerns about increased bleeding risk and mortality in healthy older adults, wrote Rita Del Pinto, MD, of University of L’Aquila (Italy) and colleagues in JAMA Network Open.

In the study, Dr. Del Pinto and colleagues conducted a post hoc analysis of data from more than 2,500 participants in SPRINT (Systolic Blood Pressure Intervention Trial), a multicenter, randomized trial conducted from 2010 to 2013.

The goal of SPRINT was to compare intensive and standard blood pressure–lowering strategies for hypertension patients. The primary outcome of the current study was risk of a first cardiovascular event, which included adjudicated myocardial infarction, non–myocardial infarction acute coronary syndrome, stroke, acute heart failure, and CVD death.“There has been considerable improvement in the management of cardiovascular risk factors since the first reports on aspirin use for cardiovascular prevention,” Dr. Del Pinto said in an interview.

“As for hypertension, not only have more effective antihypertensive medications become available, but also evidence has recently emerged in support of a downwards redefinition of blood pressure targets during treatment,” she said. “In this context, in an era when great attention is paid to the personalization of treatment, no specific studies had addressed the association of aspirin use as a primary prevention strategy in a cohort of relatively old, high-risk individuals with treated systolic blood pressure steadily below the recommended target,” she added.

The researchers assessed whether aspirin use in addition to standard blood pressure management (a target of less than 140 mm Hg) decreased risk and improved survival.

The study population included 2,664 adult patients; 29.3% were women, and 24.5% were aged 75 years and older. Half of the patients (1,332) received aspirin and 1,332 did not.

In a multivariate analysis, 42 cardiovascular events occurred in the aspirin group, compared with 20 events in those not exposed to aspirin (hazard ratio, 2.30). The findings were consistent in subgroup analyses of younger individuals, current and former smokers, and patients on statins.

An additional subgroup analysis of individuals randomized to standard care or intensive care in the SPRINT study showed no significant difference in primary outcome rates between individuals who received aspirin and those who did not. The rates for aspirin use vs. non–aspirin use were 5.85% vs. 3.60% in the standard treatment group and 4.66% vs. 2.56% in the intensive treatment group.

The study findings were limited by several factors, including the post hoc design, short follow-up period, and lack of data on the initiation of aspirin and bleeding events, the researchers wrote. However, the results suggest that modern management of hypertension may have redefined the potential benefits of aspirin in patients with hypertension, they concluded.

Findings confirm value of preventive care

“The study was conducted as a post-hoc analysis on an experimental cohort, which must be considered when interpreting the results,” Dr. Del Pinto said.

Despite the limitations, the study findings affirm that effective treatment of major cardiovascular risk factors, such as hypertension, with proven drugs is “a mainstay of the primary prevention of ASCVD,” she emphasized.

As for additional research, “Testing our findings in a dedicated setting with sufficiently long follow-up, where aspirin dose and indication, as well as any possible bleeding event, are reported could expand the clinical meaning of our observations,” said Dr. Del Pinto. “Also, the clinical impact of aspirin, even in combination with novel cardiovascular drugs such as direct oral anticoagulants, in populations exposed to combinations of risk factors, deserves further investigation.”

Data support shared decision-making

“While recent evidence has not shown a benefit of aspirin in the primary prevention of ASCVD in several populations, the subpopulation of patients with hypertension as an ASCVD risk factor is also of interest to the clinician,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview. “The lack of benefit of aspirin in this study, despite its limitations, was surprising, and I would be eager to see how the role of aspirin in ASCVD prevention would continue to evolve in conjunction with improvement in other therapies for modification of risk factors.”

“The decision to continue aspirin in this subgroup of patients should warrant a discussion with patients and a reexamination of risks and benefits until further data are available,” Dr. Pal emphasized. 

Larger studies with long-term follow-ups would be required to further clarify the role of aspirin in primary prevention of ASCVD in patients with hypertension without diabetes or chronic kidney disease, he added.

Data were supplied courtesy of BioLINCC. The study received no outside funding. The researchers and Dr. Pal had no financial conflicts to disclose.

The addition of aspirin to standard guideline management for blood pressure did not reduce the risk of cardiovascular events among adults with hypertension and controlled systolic blood pressure in a study.

The benefits of aspirin use for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) have been questioned in light of data showing neutral outcomes in low-risk patients and concerns about increased bleeding risk and mortality in healthy older adults, wrote Rita Del Pinto, MD, of University of L’Aquila (Italy) and colleagues in JAMA Network Open.

In the study, Dr. Del Pinto and colleagues conducted a post hoc analysis of data from more than 2,500 participants in SPRINT (Systolic Blood Pressure Intervention Trial), a multicenter, randomized trial conducted from 2010 to 2013.

The goal of SPRINT was to compare intensive and standard blood pressure–lowering strategies for hypertension patients. The primary outcome of the current study was risk of a first cardiovascular event, which included adjudicated myocardial infarction, non–myocardial infarction acute coronary syndrome, stroke, acute heart failure, and CVD death.“There has been considerable improvement in the management of cardiovascular risk factors since the first reports on aspirin use for cardiovascular prevention,” Dr. Del Pinto said in an interview.

“As for hypertension, not only have more effective antihypertensive medications become available, but also evidence has recently emerged in support of a downwards redefinition of blood pressure targets during treatment,” she said. “In this context, in an era when great attention is paid to the personalization of treatment, no specific studies had addressed the association of aspirin use as a primary prevention strategy in a cohort of relatively old, high-risk individuals with treated systolic blood pressure steadily below the recommended target,” she added.

The researchers assessed whether aspirin use in addition to standard blood pressure management (a target of less than 140 mm Hg) decreased risk and improved survival.

The study population included 2,664 adult patients; 29.3% were women, and 24.5% were aged 75 years and older. Half of the patients (1,332) received aspirin and 1,332 did not.

In a multivariate analysis, 42 cardiovascular events occurred in the aspirin group, compared with 20 events in those not exposed to aspirin (hazard ratio, 2.30). The findings were consistent in subgroup analyses of younger individuals, current and former smokers, and patients on statins.

An additional subgroup analysis of individuals randomized to standard care or intensive care in the SPRINT study showed no significant difference in primary outcome rates between individuals who received aspirin and those who did not. The rates for aspirin use vs. non–aspirin use were 5.85% vs. 3.60% in the standard treatment group and 4.66% vs. 2.56% in the intensive treatment group.

The study findings were limited by several factors, including the post hoc design, short follow-up period, and lack of data on the initiation of aspirin and bleeding events, the researchers wrote. However, the results suggest that modern management of hypertension may have redefined the potential benefits of aspirin in patients with hypertension, they concluded.

Findings confirm value of preventive care

“The study was conducted as a post-hoc analysis on an experimental cohort, which must be considered when interpreting the results,” Dr. Del Pinto said.

Despite the limitations, the study findings affirm that effective treatment of major cardiovascular risk factors, such as hypertension, with proven drugs is “a mainstay of the primary prevention of ASCVD,” she emphasized.

As for additional research, “Testing our findings in a dedicated setting with sufficiently long follow-up, where aspirin dose and indication, as well as any possible bleeding event, are reported could expand the clinical meaning of our observations,” said Dr. Del Pinto. “Also, the clinical impact of aspirin, even in combination with novel cardiovascular drugs such as direct oral anticoagulants, in populations exposed to combinations of risk factors, deserves further investigation.”

Data support shared decision-making

“While recent evidence has not shown a benefit of aspirin in the primary prevention of ASCVD in several populations, the subpopulation of patients with hypertension as an ASCVD risk factor is also of interest to the clinician,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview. “The lack of benefit of aspirin in this study, despite its limitations, was surprising, and I would be eager to see how the role of aspirin in ASCVD prevention would continue to evolve in conjunction with improvement in other therapies for modification of risk factors.”

“The decision to continue aspirin in this subgroup of patients should warrant a discussion with patients and a reexamination of risks and benefits until further data are available,” Dr. Pal emphasized. 

Larger studies with long-term follow-ups would be required to further clarify the role of aspirin in primary prevention of ASCVD in patients with hypertension without diabetes or chronic kidney disease, he added.

Data were supplied courtesy of BioLINCC. The study received no outside funding. The researchers and Dr. Pal had no financial conflicts to disclose.

The addition of aspirin to standard guideline management for blood pressure did not reduce the risk of cardiovascular events among adults with hypertension and controlled systolic blood pressure in a study.

The benefits of aspirin use for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) have been questioned in light of data showing neutral outcomes in low-risk patients and concerns about increased bleeding risk and mortality in healthy older adults, wrote Rita Del Pinto, MD, of University of L’Aquila (Italy) and colleagues in JAMA Network Open.

In the study, Dr. Del Pinto and colleagues conducted a post hoc analysis of data from more than 2,500 participants in SPRINT (Systolic Blood Pressure Intervention Trial), a multicenter, randomized trial conducted from 2010 to 2013.

The goal of SPRINT was to compare intensive and standard blood pressure–lowering strategies for hypertension patients. The primary outcome of the current study was risk of a first cardiovascular event, which included adjudicated myocardial infarction, non–myocardial infarction acute coronary syndrome, stroke, acute heart failure, and CVD death.“There has been considerable improvement in the management of cardiovascular risk factors since the first reports on aspirin use for cardiovascular prevention,” Dr. Del Pinto said in an interview.

“As for hypertension, not only have more effective antihypertensive medications become available, but also evidence has recently emerged in support of a downwards redefinition of blood pressure targets during treatment,” she said. “In this context, in an era when great attention is paid to the personalization of treatment, no specific studies had addressed the association of aspirin use as a primary prevention strategy in a cohort of relatively old, high-risk individuals with treated systolic blood pressure steadily below the recommended target,” she added.

The researchers assessed whether aspirin use in addition to standard blood pressure management (a target of less than 140 mm Hg) decreased risk and improved survival.

The study population included 2,664 adult patients; 29.3% were women, and 24.5% were aged 75 years and older. Half of the patients (1,332) received aspirin and 1,332 did not.

In a multivariate analysis, 42 cardiovascular events occurred in the aspirin group, compared with 20 events in those not exposed to aspirin (hazard ratio, 2.30). The findings were consistent in subgroup analyses of younger individuals, current and former smokers, and patients on statins.

An additional subgroup analysis of individuals randomized to standard care or intensive care in the SPRINT study showed no significant difference in primary outcome rates between individuals who received aspirin and those who did not. The rates for aspirin use vs. non–aspirin use were 5.85% vs. 3.60% in the standard treatment group and 4.66% vs. 2.56% in the intensive treatment group.

The study findings were limited by several factors, including the post hoc design, short follow-up period, and lack of data on the initiation of aspirin and bleeding events, the researchers wrote. However, the results suggest that modern management of hypertension may have redefined the potential benefits of aspirin in patients with hypertension, they concluded.

Findings confirm value of preventive care

“The study was conducted as a post-hoc analysis on an experimental cohort, which must be considered when interpreting the results,” Dr. Del Pinto said.

Despite the limitations, the study findings affirm that effective treatment of major cardiovascular risk factors, such as hypertension, with proven drugs is “a mainstay of the primary prevention of ASCVD,” she emphasized.

As for additional research, “Testing our findings in a dedicated setting with sufficiently long follow-up, where aspirin dose and indication, as well as any possible bleeding event, are reported could expand the clinical meaning of our observations,” said Dr. Del Pinto. “Also, the clinical impact of aspirin, even in combination with novel cardiovascular drugs such as direct oral anticoagulants, in populations exposed to combinations of risk factors, deserves further investigation.”

Data support shared decision-making

“While recent evidence has not shown a benefit of aspirin in the primary prevention of ASCVD in several populations, the subpopulation of patients with hypertension as an ASCVD risk factor is also of interest to the clinician,” Suman Pal, MD, of the University of New Mexico, Albuquerque, said in an interview. “The lack of benefit of aspirin in this study, despite its limitations, was surprising, and I would be eager to see how the role of aspirin in ASCVD prevention would continue to evolve in conjunction with improvement in other therapies for modification of risk factors.”

“The decision to continue aspirin in this subgroup of patients should warrant a discussion with patients and a reexamination of risks and benefits until further data are available,” Dr. Pal emphasized. 

Larger studies with long-term follow-ups would be required to further clarify the role of aspirin in primary prevention of ASCVD in patients with hypertension without diabetes or chronic kidney disease, he added.

Data were supplied courtesy of BioLINCC. The study received no outside funding. The researchers and Dr. Pal had no financial conflicts to disclose.

WASHINGTON – Patients with type 2 diabetes and established atherosclerotic cardiovascular disease treated with both an sodium-glucose transporter 2 inhibitor and a glucagonlike peptide–1 receptor agonist had a significant 80% cut in their rate of all-cause death during 1-year follow-up, compared with matched patients treated with an agent from either class alone in an observational, retrospective study of more than 15,000 people in the U.S. Veterans Affairs health system.

For the study’s primary endpoint, the combined rate of all-cause death, nonfatal MI, or nonfatal stroke, combined treatment with both an agent from the sodium-glucose transporter 2 (SGLT2) inhibitor class and from the glucagonlike peptide–1 receptor agonist (GLP-1 RA) class linked with a significant, roughly 50% cut in events during 1-year follow-up, compared with patients treated with an agent from just one of these two classes, Persio D. Lopez, MD, reported at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

This improvement in the combined endpoint outcome resulted entirely from reduced all-cause mortality. Dual treatment showed no significant association with the incidence of nonfatal MIs or strokes, compared with monotherapy, with rates that were nearly identical regardless of whether patients took one of the agents or both, said Dr. Lopez, a cardiologist at Mount Sinai Morningside and the James J. Peters VA Medical Center, both in New York.
 

Combining classes for hard-to-control diabetes

“We’re not sure what drives combined use” of agents from both drug classes in these types of patients, admitted Dr. Lopez during his talk. “Our hypothesis is that dual treatment is used in patients with harder-to-control diabetes.”

Salim S. Virani, MD, PhD, who practices in the VA system but was not involved with the study, agreed that this is the likely explanation for most instances of high-risk VA patients with diabetes who receive agents from both classes.

Mitchel L. Zoler/MDedge News

“I have a few patients” on both classes, usually “patients with higher starting A1c levels who need greater glycemic control,” said Dr. Virani, professor of medicine at Baylor College of Medicine and a cardiologist at the Michael E. DeBakey VA Medical Center, both in Houston.

U.S. use of either drug class, let alone both, in patients with type 2 diabetes is still struggling to gain traction in U.S. practice and remains limited to a minority of these patients, a prescribing pattern reflected in recent VA data. Analysis of more than half a million patients in the VA system with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) who received treatment at any of 130 VA medical centers throughout 2020 showed that 11% had received an SGLT2 inhibitor, and 8% a GLP-1 RA.

The most frequently used antidiabetes drug classes in these patients were insulin in 36%, biguanides in 47%, and sulfonylureas in 22%.

These data also showed a striking level of variability among the 130 VA centers, with some of the sites prescribing either an SGLT2 inhibitor or a GLP-1 RA to as few as about 3% each of these patients, while other centers had a roughly 10-fold higher prescription rate for each of about 25%-30% of their patients with type 2 diabetes and ASCVD.

Despite the overall modest level of use of both classes in these types of patients as recently as 2020, no barriers exist at the VA to prescribing an agent from one or both classes “if you provide a good reason” for a patient to receive the drugs, Dr. Virani said in an interview. He also predicted that use of both classes in these patients, including combination treatment, will likely soon expand.
 

‘A lot of interest’ in combining an SGLT2 inhibitor and a GLP-1 RA

“There will be a lot of interest in combing the two classes. It makes intuitive sense [to treat with both classes] because most patients with diabetes need more than one drug” for glycemic control, he noted. “Why not use two classes that each reduce a patient’s risk” for adverse outcomes involving ASCVD, heart failure, and renal dysfunction, added Dr. Virani.

The study run by Dr. Lopez and his associates used data collected in the National VA Database and included 121,156 patients with both type 2 diabetes and established ASCVD. Using propensity-score matching the researchers compiled three subgroups that each included 5,277 matched patients. One subgroup had patients prescribed an SGLT2 inhibitor, a second subgroup included patients on a GLP-1 RA, and a third subgroup had patients on agents from both classes. Patient matching relied on age, sex, left ventricular ejection fraction, hemoglobin A1c level, systolic blood pressure, and the presence of coronary artery disease or peripheral artery disease.

Patients included in the analysis averaged about 67 years of age; 97% were men, their average body mass index was about 34 kg/m², their average A1c was about 7.9%, their average estimated glomerular filtration rate was about 55-66 mL/min per 1.73 m², and their average left ventricular ejection fraction was about 55%. The database provided a median follow-up of 902 days (about 2.5 years). The prespecified primary endpoint focused on events that occurred during the first year of follow-up, but the investigators also ran a 3-year follow-up analysis on a post hoc basis.

The most common SGLT2 inhibitor received by these patients was empagliflozin (Jardiance), used on virtually everyone who received an agent from this class. In contrast, the GLP-1 RA drugs that patients received split more widely. The most prescribed agent was liraglutide (Victoza), followed by semaglutide (Ozempic), and dulaglutide (Trulicity), with fewer than 5% receiving exenatide (Bydureon, Byetta).

Regarding other treatments, about 97% of all patients received a statin, about 94% were on a renin-angiotensin system inhibitor, about 90% were on metformin, and roughly 75% were on insulin, aspirin, and a beta-blocker, with smaller numbers on other types of agents.

For the study’s primary endpoint, the 1-year incidence of combined ASCVD events including all-cause death, patients on agents from both classes had a significant 46% reduced rate compared with those on an SGLT2 inhibitor only, and a significant 49% reduced rate, compared with those on a GLP-1 RA only. These between-group separations broadened slightly during 3-year follow-up. Dr. Lopez did not report results of a direct comparison between patients on just an SGLT2 inhibitor and those on just a GLP-1 RA.

For the endpoint of all-cause death, those on combined treatment had a 1-year rate that was 83% below the rate among patients on only an SGLT2 inhibitor, and 81% below the rate among patients who received a GLP-1 RA but not the other class.

Dr. Lopez cautioned that selection bias could have influenced the outcomes of patients who received both classes rather than one or the other, and he also highlighted that the analysis relied on administrative data rather than information gleaned from more detailed medical records or prospectively collected findings and was limited by only including a very small number of women.

“Our results need to be validated in prospective studies,” he declared.

Dr. Lopez and Dr. Virani had no commercial disclosures.

WASHINGTON – Patients with type 2 diabetes and established atherosclerotic cardiovascular disease treated with both an sodium-glucose transporter 2 inhibitor and a glucagonlike peptide–1 receptor agonist had a significant 80% cut in their rate of all-cause death during 1-year follow-up, compared with matched patients treated with an agent from either class alone in an observational, retrospective study of more than 15,000 people in the U.S. Veterans Affairs health system.

For the study’s primary endpoint, the combined rate of all-cause death, nonfatal MI, or nonfatal stroke, combined treatment with both an agent from the sodium-glucose transporter 2 (SGLT2) inhibitor class and from the glucagonlike peptide–1 receptor agonist (GLP-1 RA) class linked with a significant, roughly 50% cut in events during 1-year follow-up, compared with patients treated with an agent from just one of these two classes, Persio D. Lopez, MD, reported at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

This improvement in the combined endpoint outcome resulted entirely from reduced all-cause mortality. Dual treatment showed no significant association with the incidence of nonfatal MIs or strokes, compared with monotherapy, with rates that were nearly identical regardless of whether patients took one of the agents or both, said Dr. Lopez, a cardiologist at Mount Sinai Morningside and the James J. Peters VA Medical Center, both in New York.
 

Combining classes for hard-to-control diabetes

“We’re not sure what drives combined use” of agents from both drug classes in these types of patients, admitted Dr. Lopez during his talk. “Our hypothesis is that dual treatment is used in patients with harder-to-control diabetes.”

Salim S. Virani, MD, PhD, who practices in the VA system but was not involved with the study, agreed that this is the likely explanation for most instances of high-risk VA patients with diabetes who receive agents from both classes.

Mitchel L. Zoler/MDedge News

“I have a few patients” on both classes, usually “patients with higher starting A1c levels who need greater glycemic control,” said Dr. Virani, professor of medicine at Baylor College of Medicine and a cardiologist at the Michael E. DeBakey VA Medical Center, both in Houston.

U.S. use of either drug class, let alone both, in patients with type 2 diabetes is still struggling to gain traction in U.S. practice and remains limited to a minority of these patients, a prescribing pattern reflected in recent VA data. Analysis of more than half a million patients in the VA system with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) who received treatment at any of 130 VA medical centers throughout 2020 showed that 11% had received an SGLT2 inhibitor, and 8% a GLP-1 RA.

The most frequently used antidiabetes drug classes in these patients were insulin in 36%, biguanides in 47%, and sulfonylureas in 22%.

These data also showed a striking level of variability among the 130 VA centers, with some of the sites prescribing either an SGLT2 inhibitor or a GLP-1 RA to as few as about 3% each of these patients, while other centers had a roughly 10-fold higher prescription rate for each of about 25%-30% of their patients with type 2 diabetes and ASCVD.

Despite the overall modest level of use of both classes in these types of patients as recently as 2020, no barriers exist at the VA to prescribing an agent from one or both classes “if you provide a good reason” for a patient to receive the drugs, Dr. Virani said in an interview. He also predicted that use of both classes in these patients, including combination treatment, will likely soon expand.
 

‘A lot of interest’ in combining an SGLT2 inhibitor and a GLP-1 RA

“There will be a lot of interest in combing the two classes. It makes intuitive sense [to treat with both classes] because most patients with diabetes need more than one drug” for glycemic control, he noted. “Why not use two classes that each reduce a patient’s risk” for adverse outcomes involving ASCVD, heart failure, and renal dysfunction, added Dr. Virani.

The study run by Dr. Lopez and his associates used data collected in the National VA Database and included 121,156 patients with both type 2 diabetes and established ASCVD. Using propensity-score matching the researchers compiled three subgroups that each included 5,277 matched patients. One subgroup had patients prescribed an SGLT2 inhibitor, a second subgroup included patients on a GLP-1 RA, and a third subgroup had patients on agents from both classes. Patient matching relied on age, sex, left ventricular ejection fraction, hemoglobin A1c level, systolic blood pressure, and the presence of coronary artery disease or peripheral artery disease.

Patients included in the analysis averaged about 67 years of age; 97% were men, their average body mass index was about 34 kg/m², their average A1c was about 7.9%, their average estimated glomerular filtration rate was about 55-66 mL/min per 1.73 m², and their average left ventricular ejection fraction was about 55%. The database provided a median follow-up of 902 days (about 2.5 years). The prespecified primary endpoint focused on events that occurred during the first year of follow-up, but the investigators also ran a 3-year follow-up analysis on a post hoc basis.

The most common SGLT2 inhibitor received by these patients was empagliflozin (Jardiance), used on virtually everyone who received an agent from this class. In contrast, the GLP-1 RA drugs that patients received split more widely. The most prescribed agent was liraglutide (Victoza), followed by semaglutide (Ozempic), and dulaglutide (Trulicity), with fewer than 5% receiving exenatide (Bydureon, Byetta).

Regarding other treatments, about 97% of all patients received a statin, about 94% were on a renin-angiotensin system inhibitor, about 90% were on metformin, and roughly 75% were on insulin, aspirin, and a beta-blocker, with smaller numbers on other types of agents.

For the study’s primary endpoint, the 1-year incidence of combined ASCVD events including all-cause death, patients on agents from both classes had a significant 46% reduced rate compared with those on an SGLT2 inhibitor only, and a significant 49% reduced rate, compared with those on a GLP-1 RA only. These between-group separations broadened slightly during 3-year follow-up. Dr. Lopez did not report results of a direct comparison between patients on just an SGLT2 inhibitor and those on just a GLP-1 RA.

For the endpoint of all-cause death, those on combined treatment had a 1-year rate that was 83% below the rate among patients on only an SGLT2 inhibitor, and 81% below the rate among patients who received a GLP-1 RA but not the other class.

Dr. Lopez cautioned that selection bias could have influenced the outcomes of patients who received both classes rather than one or the other, and he also highlighted that the analysis relied on administrative data rather than information gleaned from more detailed medical records or prospectively collected findings and was limited by only including a very small number of women.

“Our results need to be validated in prospective studies,” he declared.

Dr. Lopez and Dr. Virani had no commercial disclosures.

WASHINGTON – Patients with type 2 diabetes and established atherosclerotic cardiovascular disease treated with both an sodium-glucose transporter 2 inhibitor and a glucagonlike peptide–1 receptor agonist had a significant 80% cut in their rate of all-cause death during 1-year follow-up, compared with matched patients treated with an agent from either class alone in an observational, retrospective study of more than 15,000 people in the U.S. Veterans Affairs health system.

For the study’s primary endpoint, the combined rate of all-cause death, nonfatal MI, or nonfatal stroke, combined treatment with both an agent from the sodium-glucose transporter 2 (SGLT2) inhibitor class and from the glucagonlike peptide–1 receptor agonist (GLP-1 RA) class linked with a significant, roughly 50% cut in events during 1-year follow-up, compared with patients treated with an agent from just one of these two classes, Persio D. Lopez, MD, reported at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

This improvement in the combined endpoint outcome resulted entirely from reduced all-cause mortality. Dual treatment showed no significant association with the incidence of nonfatal MIs or strokes, compared with monotherapy, with rates that were nearly identical regardless of whether patients took one of the agents or both, said Dr. Lopez, a cardiologist at Mount Sinai Morningside and the James J. Peters VA Medical Center, both in New York.
 

Combining classes for hard-to-control diabetes

“We’re not sure what drives combined use” of agents from both drug classes in these types of patients, admitted Dr. Lopez during his talk. “Our hypothesis is that dual treatment is used in patients with harder-to-control diabetes.”

Salim S. Virani, MD, PhD, who practices in the VA system but was not involved with the study, agreed that this is the likely explanation for most instances of high-risk VA patients with diabetes who receive agents from both classes.

Mitchel L. Zoler/MDedge News

“I have a few patients” on both classes, usually “patients with higher starting A1c levels who need greater glycemic control,” said Dr. Virani, professor of medicine at Baylor College of Medicine and a cardiologist at the Michael E. DeBakey VA Medical Center, both in Houston.

U.S. use of either drug class, let alone both, in patients with type 2 diabetes is still struggling to gain traction in U.S. practice and remains limited to a minority of these patients, a prescribing pattern reflected in recent VA data. Analysis of more than half a million patients in the VA system with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) who received treatment at any of 130 VA medical centers throughout 2020 showed that 11% had received an SGLT2 inhibitor, and 8% a GLP-1 RA.

The most frequently used antidiabetes drug classes in these patients were insulin in 36%, biguanides in 47%, and sulfonylureas in 22%.

These data also showed a striking level of variability among the 130 VA centers, with some of the sites prescribing either an SGLT2 inhibitor or a GLP-1 RA to as few as about 3% each of these patients, while other centers had a roughly 10-fold higher prescription rate for each of about 25%-30% of their patients with type 2 diabetes and ASCVD.

Despite the overall modest level of use of both classes in these types of patients as recently as 2020, no barriers exist at the VA to prescribing an agent from one or both classes “if you provide a good reason” for a patient to receive the drugs, Dr. Virani said in an interview. He also predicted that use of both classes in these patients, including combination treatment, will likely soon expand.
 

‘A lot of interest’ in combining an SGLT2 inhibitor and a GLP-1 RA

“There will be a lot of interest in combing the two classes. It makes intuitive sense [to treat with both classes] because most patients with diabetes need more than one drug” for glycemic control, he noted. “Why not use two classes that each reduce a patient’s risk” for adverse outcomes involving ASCVD, heart failure, and renal dysfunction, added Dr. Virani.

The study run by Dr. Lopez and his associates used data collected in the National VA Database and included 121,156 patients with both type 2 diabetes and established ASCVD. Using propensity-score matching the researchers compiled three subgroups that each included 5,277 matched patients. One subgroup had patients prescribed an SGLT2 inhibitor, a second subgroup included patients on a GLP-1 RA, and a third subgroup had patients on agents from both classes. Patient matching relied on age, sex, left ventricular ejection fraction, hemoglobin A1c level, systolic blood pressure, and the presence of coronary artery disease or peripheral artery disease.

Patients included in the analysis averaged about 67 years of age; 97% were men, their average body mass index was about 34 kg/m², their average A1c was about 7.9%, their average estimated glomerular filtration rate was about 55-66 mL/min per 1.73 m², and their average left ventricular ejection fraction was about 55%. The database provided a median follow-up of 902 days (about 2.5 years). The prespecified primary endpoint focused on events that occurred during the first year of follow-up, but the investigators also ran a 3-year follow-up analysis on a post hoc basis.

The most common SGLT2 inhibitor received by these patients was empagliflozin (Jardiance), used on virtually everyone who received an agent from this class. In contrast, the GLP-1 RA drugs that patients received split more widely. The most prescribed agent was liraglutide (Victoza), followed by semaglutide (Ozempic), and dulaglutide (Trulicity), with fewer than 5% receiving exenatide (Bydureon, Byetta).

Regarding other treatments, about 97% of all patients received a statin, about 94% were on a renin-angiotensin system inhibitor, about 90% were on metformin, and roughly 75% were on insulin, aspirin, and a beta-blocker, with smaller numbers on other types of agents.

For the study’s primary endpoint, the 1-year incidence of combined ASCVD events including all-cause death, patients on agents from both classes had a significant 46% reduced rate compared with those on an SGLT2 inhibitor only, and a significant 49% reduced rate, compared with those on a GLP-1 RA only. These between-group separations broadened slightly during 3-year follow-up. Dr. Lopez did not report results of a direct comparison between patients on just an SGLT2 inhibitor and those on just a GLP-1 RA.

For the endpoint of all-cause death, those on combined treatment had a 1-year rate that was 83% below the rate among patients on only an SGLT2 inhibitor, and 81% below the rate among patients who received a GLP-1 RA but not the other class.

Dr. Lopez cautioned that selection bias could have influenced the outcomes of patients who received both classes rather than one or the other, and he also highlighted that the analysis relied on administrative data rather than information gleaned from more detailed medical records or prospectively collected findings and was limited by only including a very small number of women.

“Our results need to be validated in prospective studies,” he declared.

Dr. Lopez and Dr. Virani had no commercial disclosures.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

In a head-to-head comparison of fractional flow reserve (FFR) and intravenous ultrasound (IVUS) for guiding revascularization during percutaneous intervention (PCI), outcomes were noninferior at 2 years, but the approaches appear to have different strengths, according to results of the FLAVOUR trial.

For the primary composite outcome of death from any cause, myocardial infarction, or revascularization at 24 months, the approaches performed comparatively, but there were substantial differences in the number of revascularization procedures performed, reported Bon-Kwon Koo, MD, at the annual scientific sessions of the American College of Cardiology.

At 24 months, 8.1% of the FFR group and 8.5% of the IVUS group had a primary event. The 0.4% difference was not significantly different and fulfilled the definition of noninferiority (P = .015). When the components of the primary endpoint were compared along with rates of stroke, the rates were also similar and not significantly different.

However, the proportion of patients who received a stent (44.4% vs. 65.3%), the total number of stents per patient (0.6 vs. 0.9), and the total stent length per patient (16.5 vs. 25.2) were significantly lower (all P < .001) in the FFR group.

FLAVOUR (Fractional Flow Reserve And IVUS for Clinical Outcomes in Patients With Intermediate Stenosis) confirmed the investigators’ hypothesis that an FFR-guided strategy for intermediate coronary stenosis is noninferior to IVUS for outcomes. In addition, patient-reported angina outcomes on the Seattle Angina Questionnaire were nearly identical across domains, including angina frequency, physical limitations, and treatment satisfaction.
 

FFR vs. IVUS differences revealed

However, the more important value of this study might its role in showing how the two approaches differ in ways unrelated to the primary outcome, according to Dr. Koo, chair of cardiology at Seoul (South Korea) National University Hospital, as well as several experts that commented on the results.

Most notably, the fact that FFR-guided PCI provides similar outcomes at 2 years even though it was associated with a substantially reduced rate of revascularizations is telling about its role relative to IVUS.

“These data confirm how a lot of us are already approaching this,” said an ACC-invited expert, Frederick G. Welt, MD, director of the cardiac catheterization at the University of Utah, Salt Lake City. “FFR should be used to decide who should get an intervention, and IVUS should be use to optimize the intervention.”

Dr. Koo explained that FFR is an invasive tool that provides a physiological assessment of the degree to which a stenosis is causing ischemia. IVUS is a tool that permits visualization and measurement of plaque severity and characteristics to better optimize PCI. They can both help guide PCI, but they are not necessarily competing strategies. Often, the information they provide is complementary.

In this multicenter trial conducted at 18 centers in Korea and China, 1,682 candidates with de novo stenoses of intermediate severity, defined as 40%-70%, were randomized to FFR- or IVUS-guided PCI. At 24 months, outcomes could be assessed in 832 of the FFR patients and 836 of the IVUS patients, which represented more than 99% of both groups.

In the study, the indications for stent placement were predefined for the FFR-guided and IVUS-guided approaches. The criteria to define optimal outcomes post PCI were also predefined. For FFR, this included a postprocedure value of at least 0.88. For IVUS, the definition of optimal outcome included a plaque burden of 55% or less at the stent edge and a minimal stent area of at least 5.5 mm².

The primary outcome for those with optimal versus suboptimal FFR-guided PCI were similar at all time points. For those with an optimal post-PCI result, the event rate was only slightly higher for those with an optimal relative to a suboptimal result (12.3% vs. 11.8%).
 

Suboptimal IVUS differs from suboptimal FFR

In contrast, the event rates over the course of follow-up were consistently higher among those with a suboptimal relative to an optimal IVUS-guided PCI. At the end of 2 years, the numerically greater rate of events among those with a suboptimal IVUS-guided PCI was not significant (9.8% vs. 8.5%; P = .212), but the gap was larger than that seen with FFR-guided PCI.

FFR-guided and IVUS-guided PCI performed similarly for the primary outcome across numerous stratifications. These included age older or younger than 65 years, male or female sex, presence or absence of multivessel disease, and presence of diabetes. They were also similar for those with acute coronary syndrome (ACS) as an indication for PCI, which accounted for about 30% of patients, relative to those without ACS.

“I would say that at least some interventionalists in the U.S. would be uncomfortable using FFR in ACS patients,” said Dr. Welt, pointing out a potential difference between how these tools are used to guide PCI. Still, because “there are not a lot of data to compare these technologies,” he expressed appreciation for a study looking at these tools side-by-side.

A similar point was made by Ajay Kirtane, MD, director of Cardiac Catheterization Laboratories at New York–Presbyterian/Columbia University Irving Medical Center. With the slightly lower rates of primary events in those treated optimally according to IVUS relative to those treated optimally by FFR (8.5% vs. 12.3%), he suggested IVUS appears better for evaluating the physiology of the stenosis.

Dr. Kirtane pointed out that two-thirds of the lesions were left behind in those guided by FFR versus only about half of the lesions when PCI was guided by IVUS, yet outcomes were similar. He indicated that the data support current practice in which FFR is most commonly used to select PCI patients with intermediate disease for stent placement.

Dr. Koo has financial relationships with Abbott, Boston Scientific, and Philips Volcano. Dr. Welt has financial relationships with Medtronic and Xenter. Dr. Kirtane has financial relationships with Abbott, Amgen, Boston Scientific, Chiesi, Cardiovascular Systems Incorporate, Medtronic, Philips/Spectranetics, Recor Medical, and Regeneron. The study received a research grant from Boston Scientific.

At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.

The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.

“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”

Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.

This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.

Key take-homes

The AHA statement on NAFLD is sweeping. Among its key take-home messages:

• Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
• Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
• Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
• Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.

The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.

The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”

Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.” 

Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.

“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.

“NAFLD has not been at the forefront of  cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.

“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.

Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.


 

At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.

The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.

“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”

Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.

This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.

Key take-homes

The AHA statement on NAFLD is sweeping. Among its key take-home messages:

• Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
• Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
• Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
• Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.

The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.

The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”

Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.” 

Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.

“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.

“NAFLD has not been at the forefront of  cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.

“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.

Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.


 

At least one in four adults worldwide is thought to have nonalcoholic fatty liver disease, a major risk factor for cardiovascular disease (CVD), which is the leading cause of death in NAFLD, but the condition is widely underdiagnosed, according to a new American Heart Association scientific statement on NAFLD and cardiovascular risks.

The statement, published in Arteriosclerosis, Thrombosis, and Vascular Biology, aims to increase awareness of NAFLD among cardiologists and other clinicians treating vulnerable patients. It pulls together the existing evidence for using imaging to diagnose NAFLD as well as the role of current and emerging treatments for managing the disease.

“NAFLD is common, but most patients are undiagnosed,” statement writing committee chair P. Barton Duell, MD, said in an interview. “The identification of normal liver enzyme levels does not exclude the diagnosis of NAFLD. Early diagnosis and treatment are necessary to improve the health of patients with established NAFLD, as well as preventing the development of NAFLD in patients who are at risk for the condition.”

Dr. Duell is a professor at the Knight Cardiovascular Institute and division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University, Portland.

This is the AHA’s first scientific statement on NAFLD. In 2021, the association issued a statement on obesity and CVD). Also in 2021, a multiorganization group headed by the American Gastroenterological Association published a “Call to Action” on nonalcoholic steatohepatitis (NASH) , a form of NAFLD that’s characterized by inflammation and scarring of the liver, and typically requires a liver biopsy for diagnosis.

Key take-homes

The AHA statement on NAFLD is sweeping. Among its key take-home messages:

• Calling into question the effectiveness of AST and ALT testing for diagnosing NAFLD and NASH.
• Providing context to the role of insulin resistance – either with or without diabetes – as well as obesity (particularly visceral adiposity), metabolic syndrome, and dyslipidemia in NAFLD.
• Advocating for lifestyle interventions – diet, exercise, weight loss and alcohol avoidance – as the key therapeutic intervention for NAFLD.
• Asserting that glucagonlike peptide–1 receptor agonists may modestly improve NAFLD.

The statement also tackles the differences in terminology different organizations use to describe NAFLD. “The terminology section is important to ensure everyone is using the right terminology in assessing patients, as well as choosing appropriate treatment interventions,” Dr. Duell said.

The statement also explores genetic factors that can predispose people to NAFLD, Dr. Duell pointed out, and it goes into detail about strategies for screening NAFLD and NASH. “It is not possible to diagnose NAFLD without understanding the pros and cons of various screening modalities, as well as the lack of sensitivity of some tests for detection of NAFLD We hope this information will increase success in screening for and early identification of NAFLD.”

Dr. Duell explained the rationale for issuing the statement. “Rates of NAFLD are increasing worldwide in association with rising rates of elevated body mass index and the metabolic syndrome, but the condition is commonly undiagnosed,” he said. “This allows patients to experience progression of disease, leading to hepatic and cardiovascular complications.” 

Avoiding NAFLD risk factors along with early diagnosis and treatment “may have the potential to mitigate long-term complications from NAFLD,” Dr. Duell said.

“This is one of first times where we really look at cardiovascular risks associated with NAFLD and pinpoint the risk factors, the imaging tools that can be used for diagnosing fatty liver disease, and ultimately what potential treatments we can consider,” Tiffany M. Powell-Wiley, MD, MPH, author of the AHA statement on obesity and CV risk, said in an interview.

“NAFLD has not been at the forefront of  cardiologists’ minds, but this statement highlights the importance of liver fat as a fat depot,” said Dr. Powell-Wiley, chief of the Social Determinants of Obesity and Cardiovascular Risk Laboratory at the National Heart, Lung, and Blood Institute in Bethesda, Md.

“It does provide greater clarity for us as cardiologists, especially when thinking about what is required for diagnosis and ultimately how this relates to cardiovascular disease for people with fatty liver disease,” she said.

Dr. Duell and Dr. Powell-Wiley have no relevant relationships to disclose.


 

People who use phosphodiesterase type 5 inhibitors (PDE5Is), a class of medications most often prescribed for erectile dysfunction, may run an increased risk of vision-threatening ocular conditions, researchers say.

Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.

In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.

“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.

The study was published in JAMA Ophthalmology.

Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.

The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.

Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.

To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.

They identified 1,146 patients who had been diagnosed with at least one of the three conditions.

The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.

For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.

The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).

Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).

A version of this article first appeared on Medscape.com

People who use phosphodiesterase type 5 inhibitors (PDE5Is), a class of medications most often prescribed for erectile dysfunction, may run an increased risk of vision-threatening ocular conditions, researchers say.

Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.

In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.

“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.

The study was published in JAMA Ophthalmology.

Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.

The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.

Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.

To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.

They identified 1,146 patients who had been diagnosed with at least one of the three conditions.

The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.

For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.

The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).

Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).

A version of this article first appeared on Medscape.com

People who use phosphodiesterase type 5 inhibitors (PDE5Is), a class of medications most often prescribed for erectile dysfunction, may run an increased risk of vision-threatening ocular conditions, researchers say.

Patients in an insurance database who were prescribed sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Stendra) were almost twice as likely as were patients not prescribed the drugs to have ischemic optic neuropathy, retinal vascular occlusion, or serous retinal detachment.

In 2020, physicians wrote about 20 million monthly prescriptions for PDE5Is in the United States alone, said Mahyar Etminan, PharmD, associate professor of ophthalmology at the University of British Columbia, Vancouver.

“We don’t want to alarm people taking them, but generally speaking, if they experience visual problems or changes in vision, then these drugs may be the culprits, and they should check it out,” he said in an interview.

The study was published in JAMA Ophthalmology.

Previous reports, including postmarketing studies by the drug makers, have documented ocular events. The monographs for sildenafil, tadalafil, vardenafil, and avanafil warn users about ischemic optic neuropathy, the researchers found.

The monographs for sildenafil, tadalafil, and vardenafil list retinal vascular occlusion as a potential adverse event but do not quantify the risk. None of the drug monographs mention serous retinal detachment.

Previous research has associated PDE5Is with compromised perfusion of the optic nerve. Some researchers have speculated that the choroid blood vessels can undergo smooth muscle relaxation through a cyclic guanosine monophosphate pathway that can lead to choroidal congestion.

To get a better handle on the ocular risks of PDE51s, Dr. Etminan and his colleagues analyzed health insurance claim records from the PharMetrics Plus database of 213,033 men who had not experienced any of the three ocular conditions in the year before they became regular users of the medications.

They identified 1,146 patients who had been diagnosed with at least one of the three conditions.

The overall number of conditions diagnosed was small relative to the size of the population, 15.5 cases per 10,000 person-years. “So that’s still relatively rare, but the problem is that these are very heavily used medications,” Dr. Etminan said.

For each man diagnosed with one of the ocular conditions, the researchers matched four control persons who were the same age and could be followed for the same length of time. There was a total of 4,584 control persons.

The researchers compared regular users of PDE5Is (those who had received at least one prescription for a PDE5I every 3 months in the year before the ocular diagnosis) with nonusers (those who had not received a PDE5I prescription during that time).

Patients with the ocular conditions were more likely than were those in the control group to have hypertension, diabetes, cardiovascular disease, or sleep apnea. After controlling for these covariates, the researchers found that the users were overall 85% more likely to be diagnosed with one or more of them (incidence rate ratio [IRR], 1.85).

A version of this article first appeared on Medscape.com

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.