Richard Mark Kirkner

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

Clinical guidelines recommend use of exacerbation history in choosing therapies to predict the risk for chronic obstructive pulmonary disease exacerbations, but an analysis of data from three different clinical studies has found that exacerbation history alone is not the most accurate risk-prediction tool – and that it may even cause harm in some situations.

“Our results present a cautionary tale for the potential risk of harm to patients when naively applying risk stratification algorithms across different clinical settings,” lead author Joseph Khoa Ho, PharmD, a master’s candidate in pharmaceutical sciences at the University of British Columbia, Vancouver, told this news organization.

“We show that risk-prediction models have better accuracy than exacerbation history alone for predicting the future risk of COPD exacerbations,” he said. “However, the prediction models required re-evaluation and setting-specific recalibration in order to yield higher clinical utility.”

The study, known as IMPACT, analyzed three trials that enrolled 4,107 patients at varying levels of moderate or severe exacerbation risks: the placebo arm of the Study to Understand Mortality and Morbidity in COPD (SUMMIT; N = 2,421); the Long-term Oxygen Treatment Trial (LOTT; N = 595); and the placebo arm of the Towards a Revolution in COPD Health trial (TORCH; N = 1,091). The exacerbation risks were low, medium, and high in the three respective trials.

The study, published online in the journal CHEST, compared the performance of three risk-stratification algorithms: exacerbation history; the model that Loes C.M. Bertens, PhD, and colleagues in the Netherlands developed in 2013; and the latest version of the Acute COPD Exacerbation Prediction Tool, known as ACCEPT.
 

Results of the analysis

The study used area under the curve (AUC), a method of evaluating effectiveness or efficiency, to compare performance of the prediction algorithms. ACCEPT outperformed exacerbation history and the Bertens algorithm in all the LOTT (medium risk) and TORCH (high risk) samples, both of which were statistically significant. In SUMMIT (low risk), Bertens and ACCEPT outperformed exacerbation history, which was statistically significant.

The AUC for exacerbation history alone in predicting future exacerbations in SUMMIT, LOTT, and TORCH was 0.59 (95% confidence interval, 0.57-0.61), 0.63 (95% CI, 0.59-0.67), and 0.65 (95% CI, 0.63-0.68), respectively. Bertens had a higher AUC, compared with exacerbation history alone in SUMMIT (increase of 0.10, P < .001) and TORCH (increase of 0.05, P < .001), but not in LOTT (increase of 0.01, P = .84).

ACCEPT had higher AUC, compared with exacerbation history alone in all study samples, by 0.08 (P < .001), 0.07 (P = .001) and 0.10 (P < .001), respectively. Compared with Bertens, ACCEPT had higher AUC by 0.06 (P = .001) in LOTT and 0.05 (P < .001) in TORCH, whereas the AUCs were not different in SUMMIT (change of –0.02, P = .16).
 

Study rationale

Senior author Mohsen Sadatsafavi, MD, PhD, associate professor of pharmaceutical sciences at the University of British Columbia, told this news organization that this study was inspired by a study in cardiology earlier in 2022 that found that the performance of the multitude of risk-prediction tools used to evaluate cardiovascular disease risk can vary widely if they’re not calibrated for new patient populations.

“The main finding was that exacerbation history alone can be harmful even if it is applied at different risk levels,” Dr. Sadatsafavi said of the IMPACT study. “No algorithm could be universally applicable, but exacerbation history has a very high chance of being worse than not doing any risk stratification at all and simply giving medication to all patients.”

Exacerbation history was considered harmful because it generated a lower net benefit than the either Bertens or ACCEPT, the IMPACT study found.

The benefit of the two risk-prediction tools is that they can be recalibrated, Dr. Sadatsafavi said. “You don’t have that luxury with exacerbation history, because it’s just a fixed positive or negative history,” he said. “We need to be quite cognizant of the difference in lung attacks in different populations and the fact that exacerbation history has very different performance in different groups and might be harmful when applied in certain populations. We suggest the use of the risk-stratification tools as a better proper statistical model.”
 

Expert comment

“As the authors point out, current guidelines for COPD management recommend preventive exacerbation therapy considering the patient’s exacerbation history,” Mary Jo S. Farmer, MD, PhD, assistant professor at the University of Massachusetts Chan Medical School-Baystate, Worcester, said via email. “However, this strategy has demonstrated harm in some situations.”

She noted that the multivariable prediction models were more accurate than exacerbation history alone for predicting 12-month risk of moderate/severe COPD exacerbations but that no algorithm was superior in clinical utility across all samples. 

“The authors conclude that the highest accuracy of a risk prediction model can be achieved when the model is recalibrated based on the baseline exacerbation risk of the study population in question,” Dr. Farmer added. 

The study received funding from the Canadian Institutes of Health Research. Dr. Ho, Dr. Sadatsafavi, and Dr. Farmer report no relevant financial relationships.

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

Clinical guidelines recommend use of exacerbation history in choosing therapies to predict the risk for chronic obstructive pulmonary disease exacerbations, but an analysis of data from three different clinical studies has found that exacerbation history alone is not the most accurate risk-prediction tool – and that it may even cause harm in some situations.

“Our results present a cautionary tale for the potential risk of harm to patients when naively applying risk stratification algorithms across different clinical settings,” lead author Joseph Khoa Ho, PharmD, a master’s candidate in pharmaceutical sciences at the University of British Columbia, Vancouver, told this news organization.

“We show that risk-prediction models have better accuracy than exacerbation history alone for predicting the future risk of COPD exacerbations,” he said. “However, the prediction models required re-evaluation and setting-specific recalibration in order to yield higher clinical utility.”

The study, known as IMPACT, analyzed three trials that enrolled 4,107 patients at varying levels of moderate or severe exacerbation risks: the placebo arm of the Study to Understand Mortality and Morbidity in COPD (SUMMIT; N = 2,421); the Long-term Oxygen Treatment Trial (LOTT; N = 595); and the placebo arm of the Towards a Revolution in COPD Health trial (TORCH; N = 1,091). The exacerbation risks were low, medium, and high in the three respective trials.

The study, published online in the journal CHEST, compared the performance of three risk-stratification algorithms: exacerbation history; the model that Loes C.M. Bertens, PhD, and colleagues in the Netherlands developed in 2013; and the latest version of the Acute COPD Exacerbation Prediction Tool, known as ACCEPT.
 

Results of the analysis

The study used area under the curve (AUC), a method of evaluating effectiveness or efficiency, to compare performance of the prediction algorithms. ACCEPT outperformed exacerbation history and the Bertens algorithm in all the LOTT (medium risk) and TORCH (high risk) samples, both of which were statistically significant. In SUMMIT (low risk), Bertens and ACCEPT outperformed exacerbation history, which was statistically significant.

The AUC for exacerbation history alone in predicting future exacerbations in SUMMIT, LOTT, and TORCH was 0.59 (95% confidence interval, 0.57-0.61), 0.63 (95% CI, 0.59-0.67), and 0.65 (95% CI, 0.63-0.68), respectively. Bertens had a higher AUC, compared with exacerbation history alone in SUMMIT (increase of 0.10, P < .001) and TORCH (increase of 0.05, P < .001), but not in LOTT (increase of 0.01, P = .84).

ACCEPT had higher AUC, compared with exacerbation history alone in all study samples, by 0.08 (P < .001), 0.07 (P = .001) and 0.10 (P < .001), respectively. Compared with Bertens, ACCEPT had higher AUC by 0.06 (P = .001) in LOTT and 0.05 (P < .001) in TORCH, whereas the AUCs were not different in SUMMIT (change of –0.02, P = .16).
 

Study rationale

Senior author Mohsen Sadatsafavi, MD, PhD, associate professor of pharmaceutical sciences at the University of British Columbia, told this news organization that this study was inspired by a study in cardiology earlier in 2022 that found that the performance of the multitude of risk-prediction tools used to evaluate cardiovascular disease risk can vary widely if they’re not calibrated for new patient populations.

“The main finding was that exacerbation history alone can be harmful even if it is applied at different risk levels,” Dr. Sadatsafavi said of the IMPACT study. “No algorithm could be universally applicable, but exacerbation history has a very high chance of being worse than not doing any risk stratification at all and simply giving medication to all patients.”

Exacerbation history was considered harmful because it generated a lower net benefit than the either Bertens or ACCEPT, the IMPACT study found.

The benefit of the two risk-prediction tools is that they can be recalibrated, Dr. Sadatsafavi said. “You don’t have that luxury with exacerbation history, because it’s just a fixed positive or negative history,” he said. “We need to be quite cognizant of the difference in lung attacks in different populations and the fact that exacerbation history has very different performance in different groups and might be harmful when applied in certain populations. We suggest the use of the risk-stratification tools as a better proper statistical model.”
 

Expert comment

“As the authors point out, current guidelines for COPD management recommend preventive exacerbation therapy considering the patient’s exacerbation history,” Mary Jo S. Farmer, MD, PhD, assistant professor at the University of Massachusetts Chan Medical School-Baystate, Worcester, said via email. “However, this strategy has demonstrated harm in some situations.”

She noted that the multivariable prediction models were more accurate than exacerbation history alone for predicting 12-month risk of moderate/severe COPD exacerbations but that no algorithm was superior in clinical utility across all samples. 

“The authors conclude that the highest accuracy of a risk prediction model can be achieved when the model is recalibrated based on the baseline exacerbation risk of the study population in question,” Dr. Farmer added. 

The study received funding from the Canadian Institutes of Health Research. Dr. Ho, Dr. Sadatsafavi, and Dr. Farmer report no relevant financial relationships.

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

Clinical guidelines recommend use of exacerbation history in choosing therapies to predict the risk for chronic obstructive pulmonary disease exacerbations, but an analysis of data from three different clinical studies has found that exacerbation history alone is not the most accurate risk-prediction tool – and that it may even cause harm in some situations.

“Our results present a cautionary tale for the potential risk of harm to patients when naively applying risk stratification algorithms across different clinical settings,” lead author Joseph Khoa Ho, PharmD, a master’s candidate in pharmaceutical sciences at the University of British Columbia, Vancouver, told this news organization.

“We show that risk-prediction models have better accuracy than exacerbation history alone for predicting the future risk of COPD exacerbations,” he said. “However, the prediction models required re-evaluation and setting-specific recalibration in order to yield higher clinical utility.”

The study, known as IMPACT, analyzed three trials that enrolled 4,107 patients at varying levels of moderate or severe exacerbation risks: the placebo arm of the Study to Understand Mortality and Morbidity in COPD (SUMMIT; N = 2,421); the Long-term Oxygen Treatment Trial (LOTT; N = 595); and the placebo arm of the Towards a Revolution in COPD Health trial (TORCH; N = 1,091). The exacerbation risks were low, medium, and high in the three respective trials.

The study, published online in the journal CHEST, compared the performance of three risk-stratification algorithms: exacerbation history; the model that Loes C.M. Bertens, PhD, and colleagues in the Netherlands developed in 2013; and the latest version of the Acute COPD Exacerbation Prediction Tool, known as ACCEPT.
 

Results of the analysis

The study used area under the curve (AUC), a method of evaluating effectiveness or efficiency, to compare performance of the prediction algorithms. ACCEPT outperformed exacerbation history and the Bertens algorithm in all the LOTT (medium risk) and TORCH (high risk) samples, both of which were statistically significant. In SUMMIT (low risk), Bertens and ACCEPT outperformed exacerbation history, which was statistically significant.

The AUC for exacerbation history alone in predicting future exacerbations in SUMMIT, LOTT, and TORCH was 0.59 (95% confidence interval, 0.57-0.61), 0.63 (95% CI, 0.59-0.67), and 0.65 (95% CI, 0.63-0.68), respectively. Bertens had a higher AUC, compared with exacerbation history alone in SUMMIT (increase of 0.10, P < .001) and TORCH (increase of 0.05, P < .001), but not in LOTT (increase of 0.01, P = .84).

ACCEPT had higher AUC, compared with exacerbation history alone in all study samples, by 0.08 (P < .001), 0.07 (P = .001) and 0.10 (P < .001), respectively. Compared with Bertens, ACCEPT had higher AUC by 0.06 (P = .001) in LOTT and 0.05 (P < .001) in TORCH, whereas the AUCs were not different in SUMMIT (change of –0.02, P = .16).
 

Study rationale

Senior author Mohsen Sadatsafavi, MD, PhD, associate professor of pharmaceutical sciences at the University of British Columbia, told this news organization that this study was inspired by a study in cardiology earlier in 2022 that found that the performance of the multitude of risk-prediction tools used to evaluate cardiovascular disease risk can vary widely if they’re not calibrated for new patient populations.

“The main finding was that exacerbation history alone can be harmful even if it is applied at different risk levels,” Dr. Sadatsafavi said of the IMPACT study. “No algorithm could be universally applicable, but exacerbation history has a very high chance of being worse than not doing any risk stratification at all and simply giving medication to all patients.”

Exacerbation history was considered harmful because it generated a lower net benefit than the either Bertens or ACCEPT, the IMPACT study found.

The benefit of the two risk-prediction tools is that they can be recalibrated, Dr. Sadatsafavi said. “You don’t have that luxury with exacerbation history, because it’s just a fixed positive or negative history,” he said. “We need to be quite cognizant of the difference in lung attacks in different populations and the fact that exacerbation history has very different performance in different groups and might be harmful when applied in certain populations. We suggest the use of the risk-stratification tools as a better proper statistical model.”
 

Expert comment

“As the authors point out, current guidelines for COPD management recommend preventive exacerbation therapy considering the patient’s exacerbation history,” Mary Jo S. Farmer, MD, PhD, assistant professor at the University of Massachusetts Chan Medical School-Baystate, Worcester, said via email. “However, this strategy has demonstrated harm in some situations.”

She noted that the multivariable prediction models were more accurate than exacerbation history alone for predicting 12-month risk of moderate/severe COPD exacerbations but that no algorithm was superior in clinical utility across all samples. 

“The authors conclude that the highest accuracy of a risk prediction model can be achieved when the model is recalibrated based on the baseline exacerbation risk of the study population in question,” Dr. Farmer added. 

The study received funding from the Canadian Institutes of Health Research. Dr. Ho, Dr. Sadatsafavi, and Dr. Farmer report no relevant financial relationships.

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

A prespecified analysis of a large global trial of patients with symptomatic heart failure with mildly reduced and preserved ejection fraction “seals the deal” on the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to manage and improve their symptoms.

The prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included 5,795 patients with mildly reduced and preserved ejection fraction who completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) after taking the SGLT2 inhibitor dapagliflozin or placebo. The results were published online in the Journal of the American College of Cardiology.

“We’ve known from studies prior to DELIVER that SGLT2 inhibitors have been shown to improve health status, patient symptoms and quality of life among those that are living with heart failure and mildly reduced [HFmrEF] and preserved [HFpEF] ejection fraction,” lead author Mikhail N. Kosiborod, MD, vice president for research at Saint Luke’s Health System, and codirector of the St. Luke’s Michael and Marly Haverty Cardiometabolic Center of Excellence at St. Luke’s Mid America Heart Institute, Kansas City, Mo., said in an interview. “But the picture was incomplete for a number of different reasons, partly because the previous studies were either relatively modest in size, geographically limited, or suggested potential attenuation of these benefits in patients with completely normal ejection fraction.”

Specifically, the study authors noted the EMPEROR-Preserved trial of the SGLT2 inhibitor empagliflozin showed improvement in health status vs. placebo across the range of EF except in those with normal EF of 65% or greater. The PRESERVED-HF trial of dapagliflozin demonstrated a more robust response than EMPEROR-Preserved or DELIVER, but PRESERVED-HF patients were recruited only in the United States and had more debilitating HF symptoms at baseline.

“Because of the results of the DELIVER trial and because of how large, extensive, and inclusive the trial was, it really seals the deal on the value of SGLT2 inhibitors in patients with heart failure,” said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City.

The DELIVER analysis found that the effects of dapagliflozin on reducing cardiovascular death and worsening HF were greatest in patients who had the most debilitating symptoms at baseline, measured as KCCQ total symptom score (TSS) as 63 or less, the lowest of three tertiles used in the analysis. At baseline, these patients had the highest rates of CV death or worsening HF than those in the other two tertiles: KCCQ-TSS of 63-84, and greater than 84.

Compared with placebo, treated patients in the lowest KCCQ-TSS quartile had a 30% reduction in risk for the primary composite outcome, which consisted of time to first CV death or HF event (hazard ratio, 0.70; 95% confidence interval, 0.58-0.84; P < .001). In the second tertile, the relative risk reduction was 19% (HR, 0.81; 95% CI, 0.65-1.01; P < .006), and the highest quartile showed no significant difference between treatment and placebo (HR, 1.07; 95% CI, 0.83-1.37; P < .62).

“The most important take home message is that the SGLT2 inhibitor dapagliflozin significantly improved patient symptoms as measured by the Kansas City Cardiomyopathy Questionnaire symptom score,” Dr. Kosiborod said. “It improved those symptoms within 1 month and those benefits were sustained out to 8 months.”

DELIVER patients also showed improvement in all other key KCCQ domains across the board, he added. “In addition, dapagliflozin also improved the proportion of patients who had small, moderate, and large improvements in a responder analysis. So really, by every measure that we had, dapagliflozin had a significant beneficial effect.”

The DELIVER results taken collectively with the EMPEROR-Preserved and PRESERVED-HF trials cinch the deal for SGLT2 inhibitors, Dr. Kosiborod said. “They deliver on the triple goal of care in patients with heart failure. They reduce the risk of cardiovascular death and worsening heart failure and they improve patient symptoms, function and quality of life – and they accomplish that across the entire continuum of heart failure regardless of ejection fraction, regardless of whether patients are hospitalized or in an ambulatory setting, regardless of age or background therapies or other comorbidities.”

He added: “It’s a pretty historic development because we haven’t had that before.”

AstraZeneca funded the DELIVER trial. Dr. Kosiborod disclosed financial relationships with Alnylam, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos and Vifor Pharma.
 

A prespecified analysis of a large global trial of patients with symptomatic heart failure with mildly reduced and preserved ejection fraction “seals the deal” on the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to manage and improve their symptoms.

The prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included 5,795 patients with mildly reduced and preserved ejection fraction who completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) after taking the SGLT2 inhibitor dapagliflozin or placebo. The results were published online in the Journal of the American College of Cardiology.

“We’ve known from studies prior to DELIVER that SGLT2 inhibitors have been shown to improve health status, patient symptoms and quality of life among those that are living with heart failure and mildly reduced [HFmrEF] and preserved [HFpEF] ejection fraction,” lead author Mikhail N. Kosiborod, MD, vice president for research at Saint Luke’s Health System, and codirector of the St. Luke’s Michael and Marly Haverty Cardiometabolic Center of Excellence at St. Luke’s Mid America Heart Institute, Kansas City, Mo., said in an interview. “But the picture was incomplete for a number of different reasons, partly because the previous studies were either relatively modest in size, geographically limited, or suggested potential attenuation of these benefits in patients with completely normal ejection fraction.”

Specifically, the study authors noted the EMPEROR-Preserved trial of the SGLT2 inhibitor empagliflozin showed improvement in health status vs. placebo across the range of EF except in those with normal EF of 65% or greater. The PRESERVED-HF trial of dapagliflozin demonstrated a more robust response than EMPEROR-Preserved or DELIVER, but PRESERVED-HF patients were recruited only in the United States and had more debilitating HF symptoms at baseline.

“Because of the results of the DELIVER trial and because of how large, extensive, and inclusive the trial was, it really seals the deal on the value of SGLT2 inhibitors in patients with heart failure,” said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City.

The DELIVER analysis found that the effects of dapagliflozin on reducing cardiovascular death and worsening HF were greatest in patients who had the most debilitating symptoms at baseline, measured as KCCQ total symptom score (TSS) as 63 or less, the lowest of three tertiles used in the analysis. At baseline, these patients had the highest rates of CV death or worsening HF than those in the other two tertiles: KCCQ-TSS of 63-84, and greater than 84.

Compared with placebo, treated patients in the lowest KCCQ-TSS quartile had a 30% reduction in risk for the primary composite outcome, which consisted of time to first CV death or HF event (hazard ratio, 0.70; 95% confidence interval, 0.58-0.84; P < .001). In the second tertile, the relative risk reduction was 19% (HR, 0.81; 95% CI, 0.65-1.01; P < .006), and the highest quartile showed no significant difference between treatment and placebo (HR, 1.07; 95% CI, 0.83-1.37; P < .62).

“The most important take home message is that the SGLT2 inhibitor dapagliflozin significantly improved patient symptoms as measured by the Kansas City Cardiomyopathy Questionnaire symptom score,” Dr. Kosiborod said. “It improved those symptoms within 1 month and those benefits were sustained out to 8 months.”

DELIVER patients also showed improvement in all other key KCCQ domains across the board, he added. “In addition, dapagliflozin also improved the proportion of patients who had small, moderate, and large improvements in a responder analysis. So really, by every measure that we had, dapagliflozin had a significant beneficial effect.”

The DELIVER results taken collectively with the EMPEROR-Preserved and PRESERVED-HF trials cinch the deal for SGLT2 inhibitors, Dr. Kosiborod said. “They deliver on the triple goal of care in patients with heart failure. They reduce the risk of cardiovascular death and worsening heart failure and they improve patient symptoms, function and quality of life – and they accomplish that across the entire continuum of heart failure regardless of ejection fraction, regardless of whether patients are hospitalized or in an ambulatory setting, regardless of age or background therapies or other comorbidities.”

He added: “It’s a pretty historic development because we haven’t had that before.”

AstraZeneca funded the DELIVER trial. Dr. Kosiborod disclosed financial relationships with Alnylam, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos and Vifor Pharma.
 

A prespecified analysis of a large global trial of patients with symptomatic heart failure with mildly reduced and preserved ejection fraction “seals the deal” on the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors to manage and improve their symptoms.

The prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial included 5,795 patients with mildly reduced and preserved ejection fraction who completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) after taking the SGLT2 inhibitor dapagliflozin or placebo. The results were published online in the Journal of the American College of Cardiology.

“We’ve known from studies prior to DELIVER that SGLT2 inhibitors have been shown to improve health status, patient symptoms and quality of life among those that are living with heart failure and mildly reduced [HFmrEF] and preserved [HFpEF] ejection fraction,” lead author Mikhail N. Kosiborod, MD, vice president for research at Saint Luke’s Health System, and codirector of the St. Luke’s Michael and Marly Haverty Cardiometabolic Center of Excellence at St. Luke’s Mid America Heart Institute, Kansas City, Mo., said in an interview. “But the picture was incomplete for a number of different reasons, partly because the previous studies were either relatively modest in size, geographically limited, or suggested potential attenuation of these benefits in patients with completely normal ejection fraction.”

Specifically, the study authors noted the EMPEROR-Preserved trial of the SGLT2 inhibitor empagliflozin showed improvement in health status vs. placebo across the range of EF except in those with normal EF of 65% or greater. The PRESERVED-HF trial of dapagliflozin demonstrated a more robust response than EMPEROR-Preserved or DELIVER, but PRESERVED-HF patients were recruited only in the United States and had more debilitating HF symptoms at baseline.

“Because of the results of the DELIVER trial and because of how large, extensive, and inclusive the trial was, it really seals the deal on the value of SGLT2 inhibitors in patients with heart failure,” said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City.

The DELIVER analysis found that the effects of dapagliflozin on reducing cardiovascular death and worsening HF were greatest in patients who had the most debilitating symptoms at baseline, measured as KCCQ total symptom score (TSS) as 63 or less, the lowest of three tertiles used in the analysis. At baseline, these patients had the highest rates of CV death or worsening HF than those in the other two tertiles: KCCQ-TSS of 63-84, and greater than 84.

Compared with placebo, treated patients in the lowest KCCQ-TSS quartile had a 30% reduction in risk for the primary composite outcome, which consisted of time to first CV death or HF event (hazard ratio, 0.70; 95% confidence interval, 0.58-0.84; P < .001). In the second tertile, the relative risk reduction was 19% (HR, 0.81; 95% CI, 0.65-1.01; P < .006), and the highest quartile showed no significant difference between treatment and placebo (HR, 1.07; 95% CI, 0.83-1.37; P < .62).

“The most important take home message is that the SGLT2 inhibitor dapagliflozin significantly improved patient symptoms as measured by the Kansas City Cardiomyopathy Questionnaire symptom score,” Dr. Kosiborod said. “It improved those symptoms within 1 month and those benefits were sustained out to 8 months.”

DELIVER patients also showed improvement in all other key KCCQ domains across the board, he added. “In addition, dapagliflozin also improved the proportion of patients who had small, moderate, and large improvements in a responder analysis. So really, by every measure that we had, dapagliflozin had a significant beneficial effect.”

The DELIVER results taken collectively with the EMPEROR-Preserved and PRESERVED-HF trials cinch the deal for SGLT2 inhibitors, Dr. Kosiborod said. “They deliver on the triple goal of care in patients with heart failure. They reduce the risk of cardiovascular death and worsening heart failure and they improve patient symptoms, function and quality of life – and they accomplish that across the entire continuum of heart failure regardless of ejection fraction, regardless of whether patients are hospitalized or in an ambulatory setting, regardless of age or background therapies or other comorbidities.”

He added: “It’s a pretty historic development because we haven’t had that before.”

AstraZeneca funded the DELIVER trial. Dr. Kosiborod disclosed financial relationships with Alnylam, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, Pharmacosmos and Vifor Pharma.
 

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

NASHVILLE, TENN. – Patients with dementia and active seizures experience faster cognitive and functional decline and have a greater risk of dying younger than people with dementia who don’t have seizures, according to a multicenter study presented at the 2022 annual meeting of the American Epilepsy Society.

“When we compared patients with seizures with those who did not have seizures, we found that patients with seizures were more likely to have more severe cognitive impairment; they were more likely to have physical dependence and so worse functional outcomes; and they also had higher mortality rates at a younger age,” lead study author Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, Charlottesville, said in an interview.

“The average age of mortality for seizure patients was around 72 years and the average age of mortality for nonseizure patients was around 79 years, so there was a 7- to 8-year difference in mortality,” she said.
 

Seizures make matters worse

The study analyzed data on 26,425 patients with dementia, 374 (1.4%) of whom had seizures, collected from 2005 to 2021 at 39 Alzheimer’s disease centers in the United States. Patients who had seizures were significantly younger when cognitive decline began (ages 62.9 vs. 68.4 years, P < .001) and died younger (72.99 vs. 79.72 years, P < .001).

The study also found a number of factors associated with active seizures, including a history of dominant Alzheimer’s disease mutation (odds ratio, 5.55; P < .001), stroke (OR, 3.17; P < .001), transient ischemic attack (OR, 1.72; P = .003), traumatic brain injury (OR, 1.92; P < .001), Parkinson’s disease (OR, 1.79; P = .025), active depression (OR, 1.61; P < .001) and lower education (OR, 0.97; P =.043).

After the study made adjustments for sex and other associated factors, it found that patients with seizures were still at a 76% higher risk of dying younger (hazard ratio, 1.76; P < .001).

The study also determined that patients with seizures had worse functional assessment scores and were more likely to be physically dependent on others (OR, 2.52; P < .001). Seizure patients also performed worse on Mini-Mental Status Examination (18.50 vs. 22.88; P < .001) and Clinical Dementia Rating-Sum of boxes (7.95 vs. 4.28; P < .001) after adjusting for age and duration of cognitive decline.
 

A tip for caregivers

Dr. Zawar acknowledged that differentiating seizures from transient bouts of confusion in people with dementia can be difficult for family members and caregivers, but she offered advice to help them do so. “If they notice any unusual confusion or any altered mentation which is episodic in nature,” she said, “they should bring it to the neurologist’s attention as early as possible, because there are studies that have shown the diagnosis of seizures is delayed, and if they are treated in time they can be well-controlled.” Electroencephalography can also confirm the presence of seizures, she added.

Double whammy

One limitation of this study is the lack of details on the types of seizures the participants had along with the inconsistency of EEGs performed on the study population. “In future studies, I would like to have more EEG data on the types of seizures and the frequency of seizures to assess these factors further,” Dr. Zawar said.

Having more detailed information on the seizures would make the findings more valuable, Andrew J. Cole, MD, director of the epilepsy service at Massachusetts General Hospital in Boston said in an interview. “We know a lot about clinically apparent seizures, as witnessed by this paper, but we still don’t know a whole lot about clinically silent or cryptic or nighttime-only seizures that maybe no one would really recognize as such unless they were specifically looking for them, and this paper doesn’t address that issue,” he said.

While the finding that patients with other neurologic diseases have more seizures even if they also have Alzheimer’s disease isn’t “a huge surprise,” Dr. Cole added. “On the other hand, the paper is important because it shows us that in the course of having Alzheimer’s disease, having seizures also makes your outcome worse, the speed of progression faster, and it complicates the management and living with this disease, and they make that point quite clear.”

Dr. Zawar and Dr. Cole have no relevant disclosures.
 

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

NASHVILLE, TENN. – A study of more than 4 million births over 20 years in five Scandinavian countries has reported that three antiseizure medications should be used with caution in women of child-bearing age because they were associated with low birth weights.

In results presented at the annual meeting of the American Epilepsy Society, Jakob Christensen, MD, DSc, PhD, a professor at Aarhus University Hospital in Denmark, said that the study found that carbamazepine, oxcarbazepine, and topiramate were associated with low birth weight and increased risk of infants being born small for gestational age.

• Carbamazepine, 1.44 (95% confidence interval [CI], 1.21-1.71).
• Oxcarbazepine, 1.32 (95% CI, 1.03-1.69).
• Topiramate, 1.60 (95% CI, 1.15-2.24).
• Pregabalin, 1.23 (95% CI, 1.02-1.48).
• Clobazam, 4.36 (95% CI, 1.66-11.45).

The odds ratios for being born small for gestational age were:

• Carbamazepine, 1.25 (95% CI, 1.11-1.41).
• Oxcarbazepine, 1.48 (95% CI, 1.27-1.73).
• Topiramate, 1.52 (95% CI, 1.20-1.91).

“Prenatal exposure to carbamazepine, oxcarbazepine, and topiramate were associated with all estimates of adverse birth weight outcomes, thus confirming results from preclinical studies in animals and previous smaller studies in humans,” Dr. Christensen said.

He noted a lack of evidence for newer medications because their use was relatively low over the 20 years of the study. “However, for drugs like lamotrigine where we have a high number of exposed children, the finding of no association with low birth weight is reassuring, indicating the drug is safe,” Dr. Christensen said.
 

Use with caution

This study adds supportive evidence for expanding the list of antiseizure medications associated with small for gestational age infants, Elizabeth Gerard, MD, director of the Women with Epilepsy Program and associate professor of neurology at Northwestern University in Chicago, said in an interview.

“Previous clinical trials demonstrated that topiramate and zonisamide as well as phenobarbital were associated with small for gestational age,” she said. “This study added to the list carbamazepine and oxcarbazepine. Previously it wasn’t clear from clinical data but there were some hints that carbamazepine and oxcarbazepine might be associated with small for gestational age, but this is the first study to present robust data that carbamazepine and oxcarbazepine are associated with small for gestational age infants as well.”

She noted that these drugs can be used cautiously in women of child-bearing age and pregnant women. “I think these lines of evidence suggest that women with epilepsy should be more carefully monitored, at least with these high-quality, standard-of-care drugs, for fetal growth monitoring and perhaps most of them, especially those on at-risk drugs, should have detailed growth gradings,” Dr. Gerard said. Pregnant women on these antiseizure medications should have ultrasound beginning at 24 weeks gestation to monitor fetal growth, she said.

The NordForsk Nordic Program and Health and Welfare and the Independent Research Fund Denmark provided funding for the study. Dr. Christensen disclosed financial relationships with Union Chimique Belge Nordic and Eisai. Dr. Gerard disclosed relationships with Xenon Pharmaceuticals and Eisai.

Use of a tumor necrosis factor inhibitor (TNFi) or triple therapy with conventional, synthetic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis have similar beneficial effects in reducing patients’ vascular inflammation and cardiovascular (CV) risk, according to results from a randomized, active comparator trial.

“The good news is, providers can rest assured that aggressive treatment for RA does reduce vascular inflammation and therefore cardiovascular risk,” lead author Daniel H. Solomon, MD, MPH, of Brigham and Women’s Hospital in Boston, told this news organization. “Part of the reason that treating people with potent disease-modifying agents is important is not only because of reductions in pain and improvements in function on the level of arthritis, but also because of the vascular impact.”

The small study, published in Annals of the Rheumatic Diseases, randomly assigned 115 patients with active RA despite methotrexate use to one of two treatment protocols for 24 weeks: addition of a TNFi or triple therapy with the addition of sulfasalazine and hydroxychloroquine. Participants had 18F-fluorodeoxyglucose (FDG)–PET/CT scans at baseline and 24 weeks to assess change in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. The study achieved its outcomes despite a low 56.5% rate of adherence to 80% or more of randomized treatments.

Dr. Solomon said this is the first randomized trial comparing the effects of DMARDs on vascular inflammation in RA. The researchers hypothesized that TNFi would be superior to triple therapy for reducing vascular inflammation. “We found that they both reduced vascular inflammation on PET scanning to the same degree,” Dr. Solomon said.

Study results

In the TNFi group, the mean of the maximum of the TBR in the most diseased segment (MDS) of the index vessel declined from 2.72 to 2.47 for a delta of –0.24. In the triple-therapy patients, MDS declined from 2.62 to 2.43 for a delta of –0.19 (difference in deltas –0.02; 95% confidence interval, –0.19 to 0.15; P = .79).

Dr. Solomon explained the choice of FDG-PET/CT scanning to evaluate vascular inflammation in the study participants. “We know that FDG-PET/CT scanning correlates with CV risk, and we know that treatments like statins that impact CV risk reduce the inflammation as observed on FDG-PET/CT,” he said.

Although the study found no difference between the TNFi and triple therapy in terms of vascular outcomes, the conclusion is “a bit more nuanced,” Dr. Solomon said. “It tells us first that reducing inflammation with different strategies in rheumatoid arthritis can similarly impact vascular inflammation. That’s great news. These are aggressive treatment strategies, so if you can reduce vascular inflammation in a significant manner, that should result in reduced cardiovascular risk over time.” 

Although the choice of TNFi or triple therapy may not matter for reducing CV risk, Dr. Solomon said, “It matters that you choose something that’s aggressive and that you use it in people who have active disease. That’s another part of the story: People who have active disease have worse vascular inflammation, which translates into a reduction in cardiovascular risk – but it’s not differentially reduced.”

Underlying mechanisms of CVD in RA

Commenting on the research for this news organization, Lihi Eder, MD, PhD, codirector of the cardio-rheumatology program at Women’s College Hospital in Toronto, said the study findings build on what’s known about some of the underlying mechanisms of cardiovascular diseases in RA and how to optimize treatments to reduce the risk.

“Importantly,” she said, “none of these treatment strategies was superior, suggesting that both treatment options are acceptable when considering cardiovascular risk reduction, in addition to controlling RA activity.”

The strengths of the study are its randomized, controlled design “conducted by a strong team of investigators,” and that it addressed questions relevant to routine practice, said Dr. Eder, who was not involved with the study.

The study’s use of FDG-PET/CT as a surrogate outcome is a limitation, she noted. “Although it would have been very challenging to perform a similar study that will include clinical events as a study outcome.” Another limitation, she said, was the low adherence rate to randomized treatments.

“Additional studies that will compare other modes of action [for example, interleukin-6 inhibitors, Janus kinase inhibitors, anti-CD20 monoclonal antibodies] could broaden our understanding regarding the inflammatory pathways driving CV risk in RA,” Dr. Eder added.

The study received funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. AbbVie and Amgen supplied drugs used in the study. Dr. Solomon disclosed receiving research support from AbbVie, Amgen, CorEvitas, and Moderna, and royalties from UpToDate. Dr. Eder reports no relevant financial relationships.

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

Use of a tumor necrosis factor inhibitor (TNFi) or triple therapy with conventional, synthetic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis have similar beneficial effects in reducing patients’ vascular inflammation and cardiovascular (CV) risk, according to results from a randomized, active comparator trial.

“The good news is, providers can rest assured that aggressive treatment for RA does reduce vascular inflammation and therefore cardiovascular risk,” lead author Daniel H. Solomon, MD, MPH, of Brigham and Women’s Hospital in Boston, told this news organization. “Part of the reason that treating people with potent disease-modifying agents is important is not only because of reductions in pain and improvements in function on the level of arthritis, but also because of the vascular impact.”

The small study, published in Annals of the Rheumatic Diseases, randomly assigned 115 patients with active RA despite methotrexate use to one of two treatment protocols for 24 weeks: addition of a TNFi or triple therapy with the addition of sulfasalazine and hydroxychloroquine. Participants had 18F-fluorodeoxyglucose (FDG)–PET/CT scans at baseline and 24 weeks to assess change in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. The study achieved its outcomes despite a low 56.5% rate of adherence to 80% or more of randomized treatments.

Dr. Solomon said this is the first randomized trial comparing the effects of DMARDs on vascular inflammation in RA. The researchers hypothesized that TNFi would be superior to triple therapy for reducing vascular inflammation. “We found that they both reduced vascular inflammation on PET scanning to the same degree,” Dr. Solomon said.

Study results

In the TNFi group, the mean of the maximum of the TBR in the most diseased segment (MDS) of the index vessel declined from 2.72 to 2.47 for a delta of –0.24. In the triple-therapy patients, MDS declined from 2.62 to 2.43 for a delta of –0.19 (difference in deltas –0.02; 95% confidence interval, –0.19 to 0.15; P = .79).

Dr. Solomon explained the choice of FDG-PET/CT scanning to evaluate vascular inflammation in the study participants. “We know that FDG-PET/CT scanning correlates with CV risk, and we know that treatments like statins that impact CV risk reduce the inflammation as observed on FDG-PET/CT,” he said.

Although the study found no difference between the TNFi and triple therapy in terms of vascular outcomes, the conclusion is “a bit more nuanced,” Dr. Solomon said. “It tells us first that reducing inflammation with different strategies in rheumatoid arthritis can similarly impact vascular inflammation. That’s great news. These are aggressive treatment strategies, so if you can reduce vascular inflammation in a significant manner, that should result in reduced cardiovascular risk over time.” 

Although the choice of TNFi or triple therapy may not matter for reducing CV risk, Dr. Solomon said, “It matters that you choose something that’s aggressive and that you use it in people who have active disease. That’s another part of the story: People who have active disease have worse vascular inflammation, which translates into a reduction in cardiovascular risk – but it’s not differentially reduced.”

Underlying mechanisms of CVD in RA

Commenting on the research for this news organization, Lihi Eder, MD, PhD, codirector of the cardio-rheumatology program at Women’s College Hospital in Toronto, said the study findings build on what’s known about some of the underlying mechanisms of cardiovascular diseases in RA and how to optimize treatments to reduce the risk.

“Importantly,” she said, “none of these treatment strategies was superior, suggesting that both treatment options are acceptable when considering cardiovascular risk reduction, in addition to controlling RA activity.”

The strengths of the study are its randomized, controlled design “conducted by a strong team of investigators,” and that it addressed questions relevant to routine practice, said Dr. Eder, who was not involved with the study.

The study’s use of FDG-PET/CT as a surrogate outcome is a limitation, she noted. “Although it would have been very challenging to perform a similar study that will include clinical events as a study outcome.” Another limitation, she said, was the low adherence rate to randomized treatments.

“Additional studies that will compare other modes of action [for example, interleukin-6 inhibitors, Janus kinase inhibitors, anti-CD20 monoclonal antibodies] could broaden our understanding regarding the inflammatory pathways driving CV risk in RA,” Dr. Eder added.

The study received funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. AbbVie and Amgen supplied drugs used in the study. Dr. Solomon disclosed receiving research support from AbbVie, Amgen, CorEvitas, and Moderna, and royalties from UpToDate. Dr. Eder reports no relevant financial relationships.

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

Use of a tumor necrosis factor inhibitor (TNFi) or triple therapy with conventional, synthetic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis have similar beneficial effects in reducing patients’ vascular inflammation and cardiovascular (CV) risk, according to results from a randomized, active comparator trial.

“The good news is, providers can rest assured that aggressive treatment for RA does reduce vascular inflammation and therefore cardiovascular risk,” lead author Daniel H. Solomon, MD, MPH, of Brigham and Women’s Hospital in Boston, told this news organization. “Part of the reason that treating people with potent disease-modifying agents is important is not only because of reductions in pain and improvements in function on the level of arthritis, but also because of the vascular impact.”

The small study, published in Annals of the Rheumatic Diseases, randomly assigned 115 patients with active RA despite methotrexate use to one of two treatment protocols for 24 weeks: addition of a TNFi or triple therapy with the addition of sulfasalazine and hydroxychloroquine. Participants had 18F-fluorodeoxyglucose (FDG)–PET/CT scans at baseline and 24 weeks to assess change in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. The study achieved its outcomes despite a low 56.5% rate of adherence to 80% or more of randomized treatments.

Dr. Solomon said this is the first randomized trial comparing the effects of DMARDs on vascular inflammation in RA. The researchers hypothesized that TNFi would be superior to triple therapy for reducing vascular inflammation. “We found that they both reduced vascular inflammation on PET scanning to the same degree,” Dr. Solomon said.

Study results

In the TNFi group, the mean of the maximum of the TBR in the most diseased segment (MDS) of the index vessel declined from 2.72 to 2.47 for a delta of –0.24. In the triple-therapy patients, MDS declined from 2.62 to 2.43 for a delta of –0.19 (difference in deltas –0.02; 95% confidence interval, –0.19 to 0.15; P = .79).

Dr. Solomon explained the choice of FDG-PET/CT scanning to evaluate vascular inflammation in the study participants. “We know that FDG-PET/CT scanning correlates with CV risk, and we know that treatments like statins that impact CV risk reduce the inflammation as observed on FDG-PET/CT,” he said.

Although the study found no difference between the TNFi and triple therapy in terms of vascular outcomes, the conclusion is “a bit more nuanced,” Dr. Solomon said. “It tells us first that reducing inflammation with different strategies in rheumatoid arthritis can similarly impact vascular inflammation. That’s great news. These are aggressive treatment strategies, so if you can reduce vascular inflammation in a significant manner, that should result in reduced cardiovascular risk over time.” 

Although the choice of TNFi or triple therapy may not matter for reducing CV risk, Dr. Solomon said, “It matters that you choose something that’s aggressive and that you use it in people who have active disease. That’s another part of the story: People who have active disease have worse vascular inflammation, which translates into a reduction in cardiovascular risk – but it’s not differentially reduced.”

Underlying mechanisms of CVD in RA

Commenting on the research for this news organization, Lihi Eder, MD, PhD, codirector of the cardio-rheumatology program at Women’s College Hospital in Toronto, said the study findings build on what’s known about some of the underlying mechanisms of cardiovascular diseases in RA and how to optimize treatments to reduce the risk.

“Importantly,” she said, “none of these treatment strategies was superior, suggesting that both treatment options are acceptable when considering cardiovascular risk reduction, in addition to controlling RA activity.”

The strengths of the study are its randomized, controlled design “conducted by a strong team of investigators,” and that it addressed questions relevant to routine practice, said Dr. Eder, who was not involved with the study.

The study’s use of FDG-PET/CT as a surrogate outcome is a limitation, she noted. “Although it would have been very challenging to perform a similar study that will include clinical events as a study outcome.” Another limitation, she said, was the low adherence rate to randomized treatments.

“Additional studies that will compare other modes of action [for example, interleukin-6 inhibitors, Janus kinase inhibitors, anti-CD20 monoclonal antibodies] could broaden our understanding regarding the inflammatory pathways driving CV risk in RA,” Dr. Eder added.

The study received funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. AbbVie and Amgen supplied drugs used in the study. Dr. Solomon disclosed receiving research support from AbbVie, Amgen, CorEvitas, and Moderna, and royalties from UpToDate. Dr. Eder reports no relevant financial relationships.

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

NASHVILLE, TENN. – Researchers have reported for the first time a process that may explain the progression of absence seizures that seems to provoke dysregulation of the insulating layer surrounding nerve fibers, perpetuating a cycle of increasing nerve damage and more frequent seizures later on.

“This study was the first to demonstrate that, at least in some forms of epilepsy, myelin plasticity is part of the maladaptive plasticity response that underlines epilepsy progression,” Juliet Knowles, MD, PhD, assistant professor at Stanford (Calif.) University, said in an interview. She reported the findings at the 2022 annual meeting of the American Epilepsy Society.

Dr. Knowles and colleagues made their discovery using laboratory mice. They used an imaging technique known as qMTI – quantitative magnetization transfer in conjunction with diffusion MRI – to map changes in myelin sheath thickness, or myelin plasticity, in major white matter tracks of the brain.

“Over the last decade we’ve come to understand that myelin, which is the insulating substance that coats the projections of brain cells or neurons, is more dynamic than we used to think,” she said. “In fact, throughout life,  myelin’s structure in some regions of the brain can be changed in response to neuro activity. It’s a newly appreciated form of brain plasticity.”

However, she said, myelin plasticity has mostly been studied in healthy brains; “We don’t know very much about what role myelin plasticity might play in disease states like epilepsy,” Dr. Knowles said. The study’s goal was to investigate myelin plasticity specifically in absence seizures.

“We hypothesized that maybe absence seizures prompt activity-dependent myelin plasticity, but that maybe seizure-induced myelin plasticity alters the way that brain networks act in a way that contributes to the disease process,” she said.
 

Maladaptive myelin plasticity

The researchers found that absence seizures were infrequent when they first started, but then they rapidly progressed. “Over a couple of weeks, they’ll go from having very few seizures to having many seizures per hour,” Dr. Knowles said.

Using qMTI, the researchers found increased myelin sheath thickness across the longitudinal extent of the anterior corpus callosum, but they found myelin sheath thickness unchanged in brain regions where absence seizures weren’t prominent.

They also found that genetically blocking activity-dependent myelination markedly decreased seizure progression and decreased ictal somatosensory electroencephalography (EEG) coherence. Conversely, blocking myelin plasticity had no effect on ictal EEG coherence between visual cortices connected by the posterior corpus callosum.  

The next step for the researchers is to develop MRI methods to use in human studies, Dr. Knowles said.

“We are working on developing an imaging approach in these same animal models that we hope we can use also to study in a detailed way white matter plasticity in humans with epilepsy and we’re also continuing our studies in animal models to try to identify ways to target maladaptive myelin plasticity, which ultimately we hope will inform treatment of people with epilepsy,” Dr. Knowles said.
 

Of mice and men

Although this study used mice, Chris Dulla, PhD, associate professor and director of the neuroscience graduate program at Tufts University in Boston, said the finding is “probably pretty transferable” to humans.

“This is the first study that really showed it,” he said of the link between myelin changes and seizure frequency. “I think people have suspected it, but that’s why this is kind of a big deal because this is one of the first studies to show it conclusively.”

He offered suggestions for validating the findings in humans. “The first thing would be to do imaging studies in people where you can examine to see if those white matter tracks are altered in a similar way in people with epilepsy,” he said. “I think now this study gives us good reason to undertake the work that it would take to ask that question and answer it in the human brain.”

Dr. Knowles and Dr. Dulla have no relevant relationships to disclose.

NASHVILLE, TENN. – Researchers have reported for the first time a process that may explain the progression of absence seizures that seems to provoke dysregulation of the insulating layer surrounding nerve fibers, perpetuating a cycle of increasing nerve damage and more frequent seizures later on.

“This study was the first to demonstrate that, at least in some forms of epilepsy, myelin plasticity is part of the maladaptive plasticity response that underlines epilepsy progression,” Juliet Knowles, MD, PhD, assistant professor at Stanford (Calif.) University, said in an interview. She reported the findings at the 2022 annual meeting of the American Epilepsy Society.

Dr. Knowles and colleagues made their discovery using laboratory mice. They used an imaging technique known as qMTI – quantitative magnetization transfer in conjunction with diffusion MRI – to map changes in myelin sheath thickness, or myelin plasticity, in major white matter tracks of the brain.

“Over the last decade we’ve come to understand that myelin, which is the insulating substance that coats the projections of brain cells or neurons, is more dynamic than we used to think,” she said. “In fact, throughout life,  myelin’s structure in some regions of the brain can be changed in response to neuro activity. It’s a newly appreciated form of brain plasticity.”

However, she said, myelin plasticity has mostly been studied in healthy brains; “We don’t know very much about what role myelin plasticity might play in disease states like epilepsy,” Dr. Knowles said. The study’s goal was to investigate myelin plasticity specifically in absence seizures.

“We hypothesized that maybe absence seizures prompt activity-dependent myelin plasticity, but that maybe seizure-induced myelin plasticity alters the way that brain networks act in a way that contributes to the disease process,” she said.
 

Maladaptive myelin plasticity

The researchers found that absence seizures were infrequent when they first started, but then they rapidly progressed. “Over a couple of weeks, they’ll go from having very few seizures to having many seizures per hour,” Dr. Knowles said.

Using qMTI, the researchers found increased myelin sheath thickness across the longitudinal extent of the anterior corpus callosum, but they found myelin sheath thickness unchanged in brain regions where absence seizures weren’t prominent.

They also found that genetically blocking activity-dependent myelination markedly decreased seizure progression and decreased ictal somatosensory electroencephalography (EEG) coherence. Conversely, blocking myelin plasticity had no effect on ictal EEG coherence between visual cortices connected by the posterior corpus callosum.  

The next step for the researchers is to develop MRI methods to use in human studies, Dr. Knowles said.

“We are working on developing an imaging approach in these same animal models that we hope we can use also to study in a detailed way white matter plasticity in humans with epilepsy and we’re also continuing our studies in animal models to try to identify ways to target maladaptive myelin plasticity, which ultimately we hope will inform treatment of people with epilepsy,” Dr. Knowles said.
 

Of mice and men

Although this study used mice, Chris Dulla, PhD, associate professor and director of the neuroscience graduate program at Tufts University in Boston, said the finding is “probably pretty transferable” to humans.

“This is the first study that really showed it,” he said of the link between myelin changes and seizure frequency. “I think people have suspected it, but that’s why this is kind of a big deal because this is one of the first studies to show it conclusively.”

He offered suggestions for validating the findings in humans. “The first thing would be to do imaging studies in people where you can examine to see if those white matter tracks are altered in a similar way in people with epilepsy,” he said. “I think now this study gives us good reason to undertake the work that it would take to ask that question and answer it in the human brain.”

Dr. Knowles and Dr. Dulla have no relevant relationships to disclose.

NASHVILLE, TENN. – Researchers have reported for the first time a process that may explain the progression of absence seizures that seems to provoke dysregulation of the insulating layer surrounding nerve fibers, perpetuating a cycle of increasing nerve damage and more frequent seizures later on.

“This study was the first to demonstrate that, at least in some forms of epilepsy, myelin plasticity is part of the maladaptive plasticity response that underlines epilepsy progression,” Juliet Knowles, MD, PhD, assistant professor at Stanford (Calif.) University, said in an interview. She reported the findings at the 2022 annual meeting of the American Epilepsy Society.

Dr. Knowles and colleagues made their discovery using laboratory mice. They used an imaging technique known as qMTI – quantitative magnetization transfer in conjunction with diffusion MRI – to map changes in myelin sheath thickness, or myelin plasticity, in major white matter tracks of the brain.

“Over the last decade we’ve come to understand that myelin, which is the insulating substance that coats the projections of brain cells or neurons, is more dynamic than we used to think,” she said. “In fact, throughout life,  myelin’s structure in some regions of the brain can be changed in response to neuro activity. It’s a newly appreciated form of brain plasticity.”

However, she said, myelin plasticity has mostly been studied in healthy brains; “We don’t know very much about what role myelin plasticity might play in disease states like epilepsy,” Dr. Knowles said. The study’s goal was to investigate myelin plasticity specifically in absence seizures.

“We hypothesized that maybe absence seizures prompt activity-dependent myelin plasticity, but that maybe seizure-induced myelin plasticity alters the way that brain networks act in a way that contributes to the disease process,” she said.
 

Maladaptive myelin plasticity

The researchers found that absence seizures were infrequent when they first started, but then they rapidly progressed. “Over a couple of weeks, they’ll go from having very few seizures to having many seizures per hour,” Dr. Knowles said.

Using qMTI, the researchers found increased myelin sheath thickness across the longitudinal extent of the anterior corpus callosum, but they found myelin sheath thickness unchanged in brain regions where absence seizures weren’t prominent.

They also found that genetically blocking activity-dependent myelination markedly decreased seizure progression and decreased ictal somatosensory electroencephalography (EEG) coherence. Conversely, blocking myelin plasticity had no effect on ictal EEG coherence between visual cortices connected by the posterior corpus callosum.  

The next step for the researchers is to develop MRI methods to use in human studies, Dr. Knowles said.

“We are working on developing an imaging approach in these same animal models that we hope we can use also to study in a detailed way white matter plasticity in humans with epilepsy and we’re also continuing our studies in animal models to try to identify ways to target maladaptive myelin plasticity, which ultimately we hope will inform treatment of people with epilepsy,” Dr. Knowles said.
 

Of mice and men

Although this study used mice, Chris Dulla, PhD, associate professor and director of the neuroscience graduate program at Tufts University in Boston, said the finding is “probably pretty transferable” to humans.

“This is the first study that really showed it,” he said of the link between myelin changes and seizure frequency. “I think people have suspected it, but that’s why this is kind of a big deal because this is one of the first studies to show it conclusively.”

He offered suggestions for validating the findings in humans. “The first thing would be to do imaging studies in people where you can examine to see if those white matter tracks are altered in a similar way in people with epilepsy,” he said. “I think now this study gives us good reason to undertake the work that it would take to ask that question and answer it in the human brain.”

Dr. Knowles and Dr. Dulla have no relevant relationships to disclose.

NASHVILLE, TENN. – Medicare and Medicaid spending on antiseizure medications has more than doubled over the past decade, but the number of overall prescriptions hasn’t increased nearly as much, pointing to a major shift to newer, costlier, brand-name drugs – a trend in spending that may not be sustainable, the lead author of a study of drug costs said.

The study, presented at the 2022 annual meeting of the American Epilepsy Society, evaluated claims data for prescriptions for common antiseizure medications in the Medicare Part D and Medicaid databases from 2012 to 2020. The study excluded gabapentin and pregabalin because they’re frequently prescribed for other indications in addition to epileptic seizures.

“We found that third-generation medications, even though they accounted for the smallest percentage of claims in 2020, took up the most astronomical portion of the money that was spent,” lead author Deepti Zutshi, MD, an associate professor of neurology at Wayne State University in Detroit, said in an interview.

The study found that Medicare Part D spending on antiseizure medications increased from $1.16 billion in 2012 to $2.68 billion in 2020. In Medicaid, spending followed a similar trend, increasing from $973 million in 2012 to $1.05 billion in 2020.
 

Analyzing Medicare/Medicaid claims data

The study categorized drugs two ways: by brand or generic; and by first, second, or third generation, Dr. Zutshi said. First-generation drugs include medications such as phenobarbital, phenytoin, valproate, and carbamazepine. Second-generation medications were released in the early 2000s and include  medications such as lamotrigine and levetiracetam. Examples of third-generation drugs include lacosamide, vigabatrin, clobazam, and perampanel.

Prescribers shifted significantly to third-generation treatments, Dr. Zutshi said. In Medicare Part D, the total spent on third-generation antiseizure medications went from $124 million in 2012 to $1.08 billion in 2020, representing a quadrupling in percentage of costs, from 10.7% to 40.4%. The total number of claims for third-generation antiseizure medications was 240,000 in 2012 (1.3%) and 1.1 million in 2020 (4.4%).

When looking at brand versus generic, the total spent on brand-name antiseizure medications increased nearly threefold from $546 million in 2012 to $1.62 million in 2020, with the share of all funding spent on brand-name antiseizure medications jumping from 46.8% to 60.2%. However, the proportion of total claims for branded antiseizure medications actually dropped, from 9.24% in 2012 to 6.62% in 2020.

Medicaid trends followed a similar pattern. Third-generation antiseizure medications accounted for 1.7% of total claims in 2012 and 6% in 2020. Spending on third-generation antiseizure medications grew nearly eight times: from $147 million, or 15.1% of funding spent on antiseizure medications, in 2012 to $1.15 billion in 2020, a 56.1% share of costs. The total spend of branded antiseizure medications in Medicaid was $605 million in 2012 and $1.46 billion in 2020 – a jump in the share of total spending from 62.2% to 71.3%. As in Medicare Part D, the percentage of total claims for branded antiseizure medications in Medicaid also dropped from 2012 to 2020, from 12.1% to 6.8%.
 

Why the substantial increase in spending?

“The reason we are prescribing these more expensive medications may be that the third-generation medications have better side-effect profiles, improved safety and outcomes in pregnancy, or that they have less drug interactions with other medications,” Dr. Zutshi said.

That’s desirable for older patients on Medicare who are more likely to have comorbidities and be on other medications, or women of child-bearing age on Medicaid, Dr. Zutshi said. “But I don’t think people realize what the cost is to Medicare and Medicaid,” she said, “so this was a bit of a shocking finding in our paper when we looked at this. I wasn’t expecting to see the substantial increase of spending focusing on just a few medications.”

Neurologists and other providers have to be more aware of individual patients’ needs as well as cost when prescribing branded or third-generation antiseizure medications, Dr. Zutshi said. “We have to do what’s best for all of our patients, but it has to be sustainable. If not,  we could start losing the ability to prescribe these medications in these vulnerable population groups, so we have to use them judiciously,” Dr. Zutshi said.
 

Controlling costs versus managing seizures

Timothy E. Welty, PharmD, a professor of pharmacy at Drake University in Des Moines, Iowa, noted some potential issues with the study’s methodology, namely that, while it excluded gabapentin and pregabalin, it did include other antiseizure medications that are used for other indications without accounting for them. Additionally, the pharmacy claims data the study used didn’t cross match with any diagnostic data.

Controlling drug costs is noteworthy, he said, but managing seizures is equally important. “You have to think not only in terms of preventing seizures and what impact that has on health care costs specifically, but what impact that has on overall costs to society,” Dr. Welty said. “Doing the best we  can to get their seizures under control as quickly as possible has great benefits for the patient outside of health care costs.”

He added, “We just really need to educate pharmacists and decision makers within third-party payers, be it Medicare, Medicaid, private insurance, whatever, on the advances that are being made in the use of seizure medications to treat epilepsy and stop seizures, but it’s a far broader issue than just how many dollars are we spending on seizure medication.”

Dr. Zutshi and Dr. Welty have no relevant disclosures to report.

NASHVILLE, TENN. – Medicare and Medicaid spending on antiseizure medications has more than doubled over the past decade, but the number of overall prescriptions hasn’t increased nearly as much, pointing to a major shift to newer, costlier, brand-name drugs – a trend in spending that may not be sustainable, the lead author of a study of drug costs said.

The study, presented at the 2022 annual meeting of the American Epilepsy Society, evaluated claims data for prescriptions for common antiseizure medications in the Medicare Part D and Medicaid databases from 2012 to 2020. The study excluded gabapentin and pregabalin because they’re frequently prescribed for other indications in addition to epileptic seizures.

“We found that third-generation medications, even though they accounted for the smallest percentage of claims in 2020, took up the most astronomical portion of the money that was spent,” lead author Deepti Zutshi, MD, an associate professor of neurology at Wayne State University in Detroit, said in an interview.

The study found that Medicare Part D spending on antiseizure medications increased from $1.16 billion in 2012 to $2.68 billion in 2020. In Medicaid, spending followed a similar trend, increasing from $973 million in 2012 to $1.05 billion in 2020.
 

Analyzing Medicare/Medicaid claims data

The study categorized drugs two ways: by brand or generic; and by first, second, or third generation, Dr. Zutshi said. First-generation drugs include medications such as phenobarbital, phenytoin, valproate, and carbamazepine. Second-generation medications were released in the early 2000s and include  medications such as lamotrigine and levetiracetam. Examples of third-generation drugs include lacosamide, vigabatrin, clobazam, and perampanel.

Prescribers shifted significantly to third-generation treatments, Dr. Zutshi said. In Medicare Part D, the total spent on third-generation antiseizure medications went from $124 million in 2012 to $1.08 billion in 2020, representing a quadrupling in percentage of costs, from 10.7% to 40.4%. The total number of claims for third-generation antiseizure medications was 240,000 in 2012 (1.3%) and 1.1 million in 2020 (4.4%).

When looking at brand versus generic, the total spent on brand-name antiseizure medications increased nearly threefold from $546 million in 2012 to $1.62 million in 2020, with the share of all funding spent on brand-name antiseizure medications jumping from 46.8% to 60.2%. However, the proportion of total claims for branded antiseizure medications actually dropped, from 9.24% in 2012 to 6.62% in 2020.

Medicaid trends followed a similar pattern. Third-generation antiseizure medications accounted for 1.7% of total claims in 2012 and 6% in 2020. Spending on third-generation antiseizure medications grew nearly eight times: from $147 million, or 15.1% of funding spent on antiseizure medications, in 2012 to $1.15 billion in 2020, a 56.1% share of costs. The total spend of branded antiseizure medications in Medicaid was $605 million in 2012 and $1.46 billion in 2020 – a jump in the share of total spending from 62.2% to 71.3%. As in Medicare Part D, the percentage of total claims for branded antiseizure medications in Medicaid also dropped from 2012 to 2020, from 12.1% to 6.8%.
 

Why the substantial increase in spending?

“The reason we are prescribing these more expensive medications may be that the third-generation medications have better side-effect profiles, improved safety and outcomes in pregnancy, or that they have less drug interactions with other medications,” Dr. Zutshi said.

That’s desirable for older patients on Medicare who are more likely to have comorbidities and be on other medications, or women of child-bearing age on Medicaid, Dr. Zutshi said. “But I don’t think people realize what the cost is to Medicare and Medicaid,” she said, “so this was a bit of a shocking finding in our paper when we looked at this. I wasn’t expecting to see the substantial increase of spending focusing on just a few medications.”

Neurologists and other providers have to be more aware of individual patients’ needs as well as cost when prescribing branded or third-generation antiseizure medications, Dr. Zutshi said. “We have to do what’s best for all of our patients, but it has to be sustainable. If not,  we could start losing the ability to prescribe these medications in these vulnerable population groups, so we have to use them judiciously,” Dr. Zutshi said.
 

Controlling costs versus managing seizures

Timothy E. Welty, PharmD, a professor of pharmacy at Drake University in Des Moines, Iowa, noted some potential issues with the study’s methodology, namely that, while it excluded gabapentin and pregabalin, it did include other antiseizure medications that are used for other indications without accounting for them. Additionally, the pharmacy claims data the study used didn’t cross match with any diagnostic data.

Controlling drug costs is noteworthy, he said, but managing seizures is equally important. “You have to think not only in terms of preventing seizures and what impact that has on health care costs specifically, but what impact that has on overall costs to society,” Dr. Welty said. “Doing the best we  can to get their seizures under control as quickly as possible has great benefits for the patient outside of health care costs.”

He added, “We just really need to educate pharmacists and decision makers within third-party payers, be it Medicare, Medicaid, private insurance, whatever, on the advances that are being made in the use of seizure medications to treat epilepsy and stop seizures, but it’s a far broader issue than just how many dollars are we spending on seizure medication.”

Dr. Zutshi and Dr. Welty have no relevant disclosures to report.

NASHVILLE, TENN. – Medicare and Medicaid spending on antiseizure medications has more than doubled over the past decade, but the number of overall prescriptions hasn’t increased nearly as much, pointing to a major shift to newer, costlier, brand-name drugs – a trend in spending that may not be sustainable, the lead author of a study of drug costs said.

The study, presented at the 2022 annual meeting of the American Epilepsy Society, evaluated claims data for prescriptions for common antiseizure medications in the Medicare Part D and Medicaid databases from 2012 to 2020. The study excluded gabapentin and pregabalin because they’re frequently prescribed for other indications in addition to epileptic seizures.

“We found that third-generation medications, even though they accounted for the smallest percentage of claims in 2020, took up the most astronomical portion of the money that was spent,” lead author Deepti Zutshi, MD, an associate professor of neurology at Wayne State University in Detroit, said in an interview.

The study found that Medicare Part D spending on antiseizure medications increased from $1.16 billion in 2012 to $2.68 billion in 2020. In Medicaid, spending followed a similar trend, increasing from $973 million in 2012 to $1.05 billion in 2020.
 

Analyzing Medicare/Medicaid claims data

The study categorized drugs two ways: by brand or generic; and by first, second, or third generation, Dr. Zutshi said. First-generation drugs include medications such as phenobarbital, phenytoin, valproate, and carbamazepine. Second-generation medications were released in the early 2000s and include  medications such as lamotrigine and levetiracetam. Examples of third-generation drugs include lacosamide, vigabatrin, clobazam, and perampanel.

Prescribers shifted significantly to third-generation treatments, Dr. Zutshi said. In Medicare Part D, the total spent on third-generation antiseizure medications went from $124 million in 2012 to $1.08 billion in 2020, representing a quadrupling in percentage of costs, from 10.7% to 40.4%. The total number of claims for third-generation antiseizure medications was 240,000 in 2012 (1.3%) and 1.1 million in 2020 (4.4%).

When looking at brand versus generic, the total spent on brand-name antiseizure medications increased nearly threefold from $546 million in 2012 to $1.62 million in 2020, with the share of all funding spent on brand-name antiseizure medications jumping from 46.8% to 60.2%. However, the proportion of total claims for branded antiseizure medications actually dropped, from 9.24% in 2012 to 6.62% in 2020.

Medicaid trends followed a similar pattern. Third-generation antiseizure medications accounted for 1.7% of total claims in 2012 and 6% in 2020. Spending on third-generation antiseizure medications grew nearly eight times: from $147 million, or 15.1% of funding spent on antiseizure medications, in 2012 to $1.15 billion in 2020, a 56.1% share of costs. The total spend of branded antiseizure medications in Medicaid was $605 million in 2012 and $1.46 billion in 2020 – a jump in the share of total spending from 62.2% to 71.3%. As in Medicare Part D, the percentage of total claims for branded antiseizure medications in Medicaid also dropped from 2012 to 2020, from 12.1% to 6.8%.
 

Why the substantial increase in spending?

“The reason we are prescribing these more expensive medications may be that the third-generation medications have better side-effect profiles, improved safety and outcomes in pregnancy, or that they have less drug interactions with other medications,” Dr. Zutshi said.

That’s desirable for older patients on Medicare who are more likely to have comorbidities and be on other medications, or women of child-bearing age on Medicaid, Dr. Zutshi said. “But I don’t think people realize what the cost is to Medicare and Medicaid,” she said, “so this was a bit of a shocking finding in our paper when we looked at this. I wasn’t expecting to see the substantial increase of spending focusing on just a few medications.”

Neurologists and other providers have to be more aware of individual patients’ needs as well as cost when prescribing branded or third-generation antiseizure medications, Dr. Zutshi said. “We have to do what’s best for all of our patients, but it has to be sustainable. If not,  we could start losing the ability to prescribe these medications in these vulnerable population groups, so we have to use them judiciously,” Dr. Zutshi said.
 

Controlling costs versus managing seizures

Timothy E. Welty, PharmD, a professor of pharmacy at Drake University in Des Moines, Iowa, noted some potential issues with the study’s methodology, namely that, while it excluded gabapentin and pregabalin, it did include other antiseizure medications that are used for other indications without accounting for them. Additionally, the pharmacy claims data the study used didn’t cross match with any diagnostic data.

Controlling drug costs is noteworthy, he said, but managing seizures is equally important. “You have to think not only in terms of preventing seizures and what impact that has on health care costs specifically, but what impact that has on overall costs to society,” Dr. Welty said. “Doing the best we  can to get their seizures under control as quickly as possible has great benefits for the patient outside of health care costs.”

He added, “We just really need to educate pharmacists and decision makers within third-party payers, be it Medicare, Medicaid, private insurance, whatever, on the advances that are being made in the use of seizure medications to treat epilepsy and stop seizures, but it’s a far broader issue than just how many dollars are we spending on seizure medication.”

Dr. Zutshi and Dr. Welty have no relevant disclosures to report.

A novel approach for stratifying patients into one of two phenotypes for coronary artery disease (CAD) helped differentiate those who would benefit from percutaneous coronary intervention (PCI) from those who wouldn’t, researchers in Belgium reported in a subanalysis of a single-center, randomized clinical trial.

“What this study adds is that we are actually creating a refined definition of the appropriateness criteria for PCI,” lead study author Carlos Collet, MD, PhD, of the Cardiovascular Center at OLV Hospital in Aalst, Belgium, said in an interview. “We have been too long implanting stents in diffuse disease that actually have no benefit for the patient.”

The study found that patients with diffuse CAD were almost twice as likely to have residual angina 3 months after PCI than patients with focal CAD, with respective rates of 51.9% vs. 27.5% after PCI (P = .02).

The researchers analyzed 103 patients from the TARGET-FFR (Trial of Angiography vs. pressure-Ratio-Guided Enhancement Techniques–Fractional Flow Reserve) conducted at the Golden Jubilee National Hospital in Glasgow. Study patients completed the 7-item Seattle Angina Questionnaire at baseline and at 3 months after PCI, which provided the researchers information on outcomes.

The study, published in JACC: Cardiovascular Interventions, used median pullback pressure gradient (PPG) to define focal and diffuse CAD. The operators used the PressureWire X Guidewire (Abbott Vascular) to measure fractional flow reserve (FFR).

The procedure involved administering a 200-mcg bolus of intracoronary nitrate and then positioning the pressure wire sensor at the tip of the guide catheter equalized with aortic pressure. The pressure wire was then advanced to the position sensor in the distal third of the vessel. After hyperemia was induced, coronary flow reserve was assessed using bolus thermodilution. Manual FFR pullback maneuvers were done at a constant speed for 20-30 seconds. The PPG index was calculated post hoc from the manual FFR pullback recordings obtained pre-PCI.

In this study, patients with low PPG needed longer (48 mm vs. 37 mm; P = .015) and more (1.5 vs. 1.0; P = .036) stents during PCI, Dr. Collet and colleagues reported. They concluded that patients with low PPG can be treated with medical therapy.

“The beauty of the PPG is that everything happens before you implant the stent,” Dr. Collet said. “We’re starting to understand that we cannot treat diffuse disease with a focal disease therapy.”

The challenge with differentiating diffuse from focal CAD has been that it relies on visual assessment. “It’s subject to operator variability, and that’s the reason why there are no trials with focal or diffuse disease specifically because, until now, we didn’t have any metric that quantified the diffuseness or the focality of the disease,” Dr. Collet said.

The PPG itself isn’t novel, Dr. Collet said. “The novelty is that for first time we can quantify in a reproducible way the information from the pullback,” he added.

Courtesy Cardiovascular Research Foundation

“What this study tells us is that once you have a patient with diffuse coronary artery disease, don’t try PCI because it will not help half of them,” Patrick W. Serruys, MD, PhD, a cardiologist at the National University of Ireland, Galway, and author of the accompanying editorial, said in an interview.

He noted that one limitation of the study was that Dr. Collet and colleagues used mechanical PPG to measure the pressure gradient. “We use now a surrogate, which is angiography,” Dr. Serruys said. “It’s not exactly the same as a measurement of pressure with the pressure wire, but we know from many, many studies that it’s quite a good surrogate.” Future research should focus on use of angiography without the pressure wire to evaluate the pressure gradient.

The ongoing PPG Global registry will aim to further validate findings from the subanalysis, Dr. Collet said, and the PPG Primetime study will evaluate deferring PCI in patients with low PPG.

Dr. Collet disclosed relationships with Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, OpSens, Abbott Vascular and Philips Volcano. Dr. Serruys disclosed relationships with Sinomedical Sciences Technology, Sahajanand Medical Technological, Philips Volcano, Xeltis and HeartFlow.

A novel approach for stratifying patients into one of two phenotypes for coronary artery disease (CAD) helped differentiate those who would benefit from percutaneous coronary intervention (PCI) from those who wouldn’t, researchers in Belgium reported in a subanalysis of a single-center, randomized clinical trial.

“What this study adds is that we are actually creating a refined definition of the appropriateness criteria for PCI,” lead study author Carlos Collet, MD, PhD, of the Cardiovascular Center at OLV Hospital in Aalst, Belgium, said in an interview. “We have been too long implanting stents in diffuse disease that actually have no benefit for the patient.”

The study found that patients with diffuse CAD were almost twice as likely to have residual angina 3 months after PCI than patients with focal CAD, with respective rates of 51.9% vs. 27.5% after PCI (P = .02).

The researchers analyzed 103 patients from the TARGET-FFR (Trial of Angiography vs. pressure-Ratio-Guided Enhancement Techniques–Fractional Flow Reserve) conducted at the Golden Jubilee National Hospital in Glasgow. Study patients completed the 7-item Seattle Angina Questionnaire at baseline and at 3 months after PCI, which provided the researchers information on outcomes.

The study, published in JACC: Cardiovascular Interventions, used median pullback pressure gradient (PPG) to define focal and diffuse CAD. The operators used the PressureWire X Guidewire (Abbott Vascular) to measure fractional flow reserve (FFR).

The procedure involved administering a 200-mcg bolus of intracoronary nitrate and then positioning the pressure wire sensor at the tip of the guide catheter equalized with aortic pressure. The pressure wire was then advanced to the position sensor in the distal third of the vessel. After hyperemia was induced, coronary flow reserve was assessed using bolus thermodilution. Manual FFR pullback maneuvers were done at a constant speed for 20-30 seconds. The PPG index was calculated post hoc from the manual FFR pullback recordings obtained pre-PCI.

In this study, patients with low PPG needed longer (48 mm vs. 37 mm; P = .015) and more (1.5 vs. 1.0; P = .036) stents during PCI, Dr. Collet and colleagues reported. They concluded that patients with low PPG can be treated with medical therapy.

“The beauty of the PPG is that everything happens before you implant the stent,” Dr. Collet said. “We’re starting to understand that we cannot treat diffuse disease with a focal disease therapy.”

The challenge with differentiating diffuse from focal CAD has been that it relies on visual assessment. “It’s subject to operator variability, and that’s the reason why there are no trials with focal or diffuse disease specifically because, until now, we didn’t have any metric that quantified the diffuseness or the focality of the disease,” Dr. Collet said.

The PPG itself isn’t novel, Dr. Collet said. “The novelty is that for first time we can quantify in a reproducible way the information from the pullback,” he added.

Courtesy Cardiovascular Research Foundation

“What this study tells us is that once you have a patient with diffuse coronary artery disease, don’t try PCI because it will not help half of them,” Patrick W. Serruys, MD, PhD, a cardiologist at the National University of Ireland, Galway, and author of the accompanying editorial, said in an interview.

He noted that one limitation of the study was that Dr. Collet and colleagues used mechanical PPG to measure the pressure gradient. “We use now a surrogate, which is angiography,” Dr. Serruys said. “It’s not exactly the same as a measurement of pressure with the pressure wire, but we know from many, many studies that it’s quite a good surrogate.” Future research should focus on use of angiography without the pressure wire to evaluate the pressure gradient.

The ongoing PPG Global registry will aim to further validate findings from the subanalysis, Dr. Collet said, and the PPG Primetime study will evaluate deferring PCI in patients with low PPG.

Dr. Collet disclosed relationships with Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, OpSens, Abbott Vascular and Philips Volcano. Dr. Serruys disclosed relationships with Sinomedical Sciences Technology, Sahajanand Medical Technological, Philips Volcano, Xeltis and HeartFlow.

A novel approach for stratifying patients into one of two phenotypes for coronary artery disease (CAD) helped differentiate those who would benefit from percutaneous coronary intervention (PCI) from those who wouldn’t, researchers in Belgium reported in a subanalysis of a single-center, randomized clinical trial.

“What this study adds is that we are actually creating a refined definition of the appropriateness criteria for PCI,” lead study author Carlos Collet, MD, PhD, of the Cardiovascular Center at OLV Hospital in Aalst, Belgium, said in an interview. “We have been too long implanting stents in diffuse disease that actually have no benefit for the patient.”

The study found that patients with diffuse CAD were almost twice as likely to have residual angina 3 months after PCI than patients with focal CAD, with respective rates of 51.9% vs. 27.5% after PCI (P = .02).

The researchers analyzed 103 patients from the TARGET-FFR (Trial of Angiography vs. pressure-Ratio-Guided Enhancement Techniques–Fractional Flow Reserve) conducted at the Golden Jubilee National Hospital in Glasgow. Study patients completed the 7-item Seattle Angina Questionnaire at baseline and at 3 months after PCI, which provided the researchers information on outcomes.

The study, published in JACC: Cardiovascular Interventions, used median pullback pressure gradient (PPG) to define focal and diffuse CAD. The operators used the PressureWire X Guidewire (Abbott Vascular) to measure fractional flow reserve (FFR).

The procedure involved administering a 200-mcg bolus of intracoronary nitrate and then positioning the pressure wire sensor at the tip of the guide catheter equalized with aortic pressure. The pressure wire was then advanced to the position sensor in the distal third of the vessel. After hyperemia was induced, coronary flow reserve was assessed using bolus thermodilution. Manual FFR pullback maneuvers were done at a constant speed for 20-30 seconds. The PPG index was calculated post hoc from the manual FFR pullback recordings obtained pre-PCI.

In this study, patients with low PPG needed longer (48 mm vs. 37 mm; P = .015) and more (1.5 vs. 1.0; P = .036) stents during PCI, Dr. Collet and colleagues reported. They concluded that patients with low PPG can be treated with medical therapy.

“The beauty of the PPG is that everything happens before you implant the stent,” Dr. Collet said. “We’re starting to understand that we cannot treat diffuse disease with a focal disease therapy.”

The challenge with differentiating diffuse from focal CAD has been that it relies on visual assessment. “It’s subject to operator variability, and that’s the reason why there are no trials with focal or diffuse disease specifically because, until now, we didn’t have any metric that quantified the diffuseness or the focality of the disease,” Dr. Collet said.

The PPG itself isn’t novel, Dr. Collet said. “The novelty is that for first time we can quantify in a reproducible way the information from the pullback,” he added.

Courtesy Cardiovascular Research Foundation

“What this study tells us is that once you have a patient with diffuse coronary artery disease, don’t try PCI because it will not help half of them,” Patrick W. Serruys, MD, PhD, a cardiologist at the National University of Ireland, Galway, and author of the accompanying editorial, said in an interview.

He noted that one limitation of the study was that Dr. Collet and colleagues used mechanical PPG to measure the pressure gradient. “We use now a surrogate, which is angiography,” Dr. Serruys said. “It’s not exactly the same as a measurement of pressure with the pressure wire, but we know from many, many studies that it’s quite a good surrogate.” Future research should focus on use of angiography without the pressure wire to evaluate the pressure gradient.

The ongoing PPG Global registry will aim to further validate findings from the subanalysis, Dr. Collet said, and the PPG Primetime study will evaluate deferring PCI in patients with low PPG.

Dr. Collet disclosed relationships with Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, OpSens, Abbott Vascular and Philips Volcano. Dr. Serruys disclosed relationships with Sinomedical Sciences Technology, Sahajanand Medical Technological, Philips Volcano, Xeltis and HeartFlow.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.